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Fakih Y, Al Sakan M, El Ghazawi A, Khoury M, Refaat MM. Exploring Resting Sinus Tachycardia in Cancer Care: A Comprehensive Review. J Clin Med 2025; 14:985. [PMID: 39941655 PMCID: PMC11818562 DOI: 10.3390/jcm14030985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/24/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Resting sinus tachycardia is frequently encountered in cancer patients. It affects a wide variety of cancer patients and is associated with distressing symptoms. Cancer-associated resting sinus tachycardia varies in its underlying mechanism. It can stem from the tumor burden or the side effects of chemotherapy/radiotherapy, or it can be secondary to paraneoplastic syndrome or the sequalae of cancer itself (infection, anemia, thrombosis, etc.). The clinical significance of resting sinus tachycardia extends beyond mere symptomatology, as it can potentially indicate severe complications which may facilitate or exacerbate a new or underlying cardiovascular dysfunction. Therefore, this necessitates thorough diagnostic tools to discern the underlying cause and tailor appropriate management strategies, whether pharmacological, non-pharmacological, or conservative. While resting sinus tachycardia has been extensively investigated in the context of cardiovascular disease, its underlying etiology, clinical implication, prognostic value, and treatment options remain vague in the context of cancer. This review aims to explore the topic of resting sinus tachycardia in cancer patients through delving deeper into its underlying mechanism, presenting the current evidence on its effect on cancer-independent cardiovascular and all-cause mortality, as well as providing some insight into the currently available treatment options. It will also propose therapeutic interventions and strategies aimed at optimizing cancer patient care. Lastly, it will highlight research gaps which need to be addressed further, as future research is needed to refine the diagnostic criteria, develop targeted therapies, find alternative cardioprotective/cardio-neutral chemotherapy options, and establish evidence-based guidelines to improve outcomes in this vulnerable patient population.
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Affiliation(s)
- Yeva Fakih
- Faculty of Medicine, American University of Beirut Medical Center, Beirut 1107, Lebanon; (Y.F.); (M.K.)
| | - Moied Al Sakan
- Internal Medicine Department, American University of Beirut Medical Center, Beirut 1107, Lebanon; (M.A.S.); (A.E.G.)
| | - Alaaeddine El Ghazawi
- Internal Medicine Department, American University of Beirut Medical Center, Beirut 1107, Lebanon; (M.A.S.); (A.E.G.)
| | - Maurice Khoury
- Faculty of Medicine, American University of Beirut Medical Center, Beirut 1107, Lebanon; (Y.F.); (M.K.)
- Internal Medicine Department, American University of Beirut Medical Center, Beirut 1107, Lebanon; (M.A.S.); (A.E.G.)
- Cardiology Department, Division of Cardiac Electrophysiology, American University of Beirut Medical Center, Beirut 1107, Lebanon
| | - Marwan M. Refaat
- Faculty of Medicine, American University of Beirut Medical Center, Beirut 1107, Lebanon; (Y.F.); (M.K.)
- Internal Medicine Department, American University of Beirut Medical Center, Beirut 1107, Lebanon; (M.A.S.); (A.E.G.)
- Cardiology Department, Division of Cardiac Electrophysiology, American University of Beirut Medical Center, Beirut 1107, Lebanon
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Shang Y, Zhao H, Li D. Effect and Safety of Orelabrutinib and Lenalidomide Plus R-mini CDOP in Relapsed/Refractory Aggressive B-cell Non-Hodgkin Lymphoma. Turk J Haematol 2023; 40:284-285. [PMID: 37656047 PMCID: PMC10701323 DOI: 10.4274/tjh.galenos.2023.2023.0263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 08/26/2023] [Indexed: 09/02/2023] Open
Affiliation(s)
- Ying Shang
- Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong, China
| | - Hongyu Zhao
- Central Hospital Affiliated to Shandong First Medical University, Shandong, China
| | - Daqi Li
- Central Hospital Affiliated to Shandong First Medical University, Shandong, China
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Misiak P, Niemirowicz-Laskowska K, Markiewicz KH, Wielgat P, Kurowska I, Czarnomysy R, Misztalewska-Turkowicz I, Car H, Bielawski K, Wilczewska AZ. Doxorubicin-loaded polymeric nanoparticles containing ketoester-based block and cholesterol moiety as specific vehicles to fight estrogen-dependent breast cancer. Cancer Nanotechnol 2023. [DOI: 10.1186/s12645-023-00176-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/28/2023] Open
Abstract
AbstractThe presented research concerns the preparation of polymer nanoparticles (PNPs) for the delivery of doxorubicin. Several block and statistical copolymers, composed of ketoester derivative, N-isopropylacrylamide, and cholesterol, were synthesized. In the nanoprecipitation process, doxorubicin (DOX) molecules were kept in spatial polymeric systems. DOX-loaded PNPs show high efficacy against estrogen-dependent MCF-7 breast cancer cell lines despite low doses of DOX applied and good compatibility with normal cells. Research confirms the effect of PNPs on the degradation of the biological membrane, and the accumulation of reactive oxygen species (ROS), and the ability to cell cycle arrest are strictly linked to cell death.
Graphical Abstract
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Coltelli L, Finale C, Musettini G, Fontana A, Barletta MT, Lucarini AR, Fabiani I, Scalese M, Bocci G, Masini LC, Soria G, Cupini S, Arrighi G, Barbara C, De Maio E, Salvadori B, Marini A, Pellino A, Stasi I, Emdin M, Giaconi S, Marcucci L, Allegrini G. Non-pegylated liposomal doxorubicin in older adjuvant early breast cancer patients: cardiac safety analysis and final results of the COLTONE study. Clin Exp Med 2023; 23:5113-5120. [PMID: 37634231 PMCID: PMC10725369 DOI: 10.1007/s10238-023-01144-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 07/12/2023] [Indexed: 08/29/2023]
Abstract
AIMS To explore the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) plus Cyclophosphamide (CTX) followed by weekly Paclitaxel, in elderly women (≥ 65 years) with high-risk breast cancer. Previously, we described no symptomatic cardiac events within the first 12 months from starting treatment. We now reported the updated results after a median follow-up 76 months. METHODS The cardiac activity was evaluated with left ventricular ejection fraction (LVEF) echocardiograms assessments, before starting chemotherapy and every 6 months, until 30 months from baseline, then yearly for at least 5 years. RESULTS Forty-seven women were recruited by two Units of Medical Oncology (Ethics Committee authorization CESM-AOUP, 3203/2011; EudraCT identification number: 2010-024067-41, for Pisa and Pontedera Hospitals). An episode of grade 3 CHF (NCI-CTCAE, version 3.0) occurred after 18 months the beginning of chemotherapy. The echocardiograms assessments were performed comparing the LVEF values of each patient evaluated at fixed period of time, compared to baseline. We observed a slight changed in terms of mean values at 48, 60, 72 and 84 months. At these time points, a statistically significant reduction of - 3.2%, - 4.6%, - 6.4% and - 7.1%, respectively, was observed. However, LVEF remained above 50% without translation in any relevant clinical signs. No other cardiac significant episodes were reported. To this analysis, in 13 patients (28%) occurred disease relapse and, of them, 11 (23%) died due to metastatic disease. Eight patients died of cancer-unrelated causes. CONCLUSIONS The combination including NPL-DOX in elderly patients revealed low rate of cardiac toxic effects. Comparative trials are encouraged.
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Affiliation(s)
- Luigi Coltelli
- Division of Medical Oncology, Leghorn Hospital, Viale Alfieri 36, Leghorn, Italy.
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy.
| | - Chiara Finale
- Division of Medical Oncology, Leghorn Hospital, Viale Alfieri 36, Leghorn, Italy
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Gianna Musettini
- Division of Medical Oncology, Leghorn Hospital, Viale Alfieri 36, Leghorn, Italy
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Andrea Fontana
- Division of Medical Oncology II, Azienda Ospedaliero-Universitaria Pisana, S. Chiara Hospital Via Roma, 67, Pisa, Italy
| | - Maria Teresa Barletta
- Division of Medical Oncology, Pontedera Hospital, Via Roma, 151, Pontedera, Italy
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Alessandra Renata Lucarini
- Department of Cardiology, Azienda Usl Toscana Nord Ovest, Pisa, Italy
- Department of Internal Medicine, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Iacopo Fabiani
- Cardiology and Cardiovascular Medicine Division, Cardio-Thoracic Department, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Marco Scalese
- Institute of Clinical Physiology, Italian National Research Council - CNR, Pisa, Italy
| | - Guido Bocci
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luna Chiara Masini
- Division of Medical Oncology, Leghorn Hospital, Viale Alfieri 36, Leghorn, Italy
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Giulia Soria
- Division of Medical Oncology, Leghorn Hospital, Viale Alfieri 36, Leghorn, Italy
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Samanta Cupini
- Division of Medical Oncology, Leghorn Hospital, Viale Alfieri 36, Leghorn, Italy
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Giada Arrighi
- Division of Medical Oncology, Pontedera Hospital, Via Roma, 151, Pontedera, Italy
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Cecilia Barbara
- Division of Medical Oncology, Leghorn Hospital, Viale Alfieri 36, Leghorn, Italy
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Ermelinda De Maio
- Division of Medical Oncology, Leghorn Hospital, Viale Alfieri 36, Leghorn, Italy
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Barbara Salvadori
- Division of Medical Oncology II, Azienda Ospedaliero-Universitaria Pisana, S. Chiara Hospital Via Roma, 67, Pisa, Italy
| | - Andrea Marini
- Division of Medical Oncology, Leghorn Hospital, Viale Alfieri 36, Leghorn, Italy
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Antonio Pellino
- Division of Medical Oncology, Leghorn Hospital, Viale Alfieri 36, Leghorn, Italy
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Irene Stasi
- Division of Medical Oncology, Leghorn Hospital, Viale Alfieri 36, Leghorn, Italy
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Michele Emdin
- Cardiology and Cardiovascular Medicine Division, Cardio-Thoracic Department, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
- Health Science Interdisciplinary Research Center, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Stefano Giaconi
- Department of Cardiology, Azienda Usl Toscana Nord Ovest, Pisa, Italy
- Department of Internal Medicine, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Lorenzo Marcucci
- Division of Medical Oncology, Pontedera Hospital, Via Roma, 151, Pontedera, Italy
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy
| | - Giacomo Allegrini
- Division of Medical Oncology, Leghorn Hospital, Viale Alfieri 36, Leghorn, Italy
- Division of Medical Oncology, Pontedera Hospital, Via Roma, 151, Pontedera, Italy
- Department of Oncology, Azienda USL Toscana Nord Ovest, Pisa, Italy
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Choi AS, Moon TJ, Abuhashim W, Bhalotia A, Qian H, Paulsen KE, Lorkowski M, Ndamira C, Gopalakrishnan R, Krishnamurthy A, Schiemann WP, Karathanasis E. Can targeted nanoparticles distinguish cancer metastasis from inflammation? J Control Release 2023; 362:812-819. [PMID: 37011838 PMCID: PMC10548349 DOI: 10.1016/j.jconrel.2023.03.054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 03/11/2023] [Accepted: 03/30/2023] [Indexed: 04/05/2023]
Abstract
Targeting ligands have been widely used to increase the intratumoral accumulation of nanoparticles and their uptake by cancer cells. However, these ligands aim at targets that are often also upregulated in inflamed tissues. Here, we assessed the ability of targeted nanoparticles to distinguish metastatic cancer from sites of inflammation. Using common targeting ligands and a 60-nm liposome as a representative nanoparticle, we generated three targeted nanoparticle (NP) variants that targeted either fibronectin, folate, or αvβ3 integrin, whose deposition was compared against that of standard untargeted NP. Using fluorescently labeled NPs and ex vivo fluorescence imaging of organs, we assessed the deposition of the NPs into the lungs of mice modeling 4 different biological landscapes, including healthy lungs, aggressive metastasis in lungs, dormant/latent metastasis in lungs, and lungs with general pulmonary inflammation. Among the four NP variants, fibronectin-targeting NP and untargeted NP exhibited the highest deposition in lungs harboring aggressive metastases. However, the deposition of all targeted NP variants in lungs with metastasis was similar to the deposition in lungs with inflammation. Only the untargeted NP was able to exhibit higher deposition in metastasis than inflammation. Moreover, flow-cytometry analysis showed all NP variants accumulated predominantly in immune cells rather than cancer cells. For example, the number of NP+ macrophages and dendritic cells was 16-fold greater than NP+ cancer cells in the case of fibronectin-targeting NP. Overall, targeted NPs were unable to distinguish cancer metastasis from general inflammation, which may have clinical implications to the nanoparticle-mediated delivery of cancer drugs.
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Affiliation(s)
- Andrew S Choi
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Taylor J Moon
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Walid Abuhashim
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Anubhuti Bhalotia
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Huikang Qian
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Kai E Paulsen
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Morgan Lorkowski
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Crystal Ndamira
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Ramamurthy Gopalakrishnan
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Animesha Krishnamurthy
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - William P Schiemann
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America; Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Efstathios Karathanasis
- Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America; Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America.
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Li L, Chen R, Zhou D, Sun J, Wang L, Zhu L, Shen H, Xie W, Ye X. The efficacy and cardiac toxicity of different-dose pegylated liposomal doxorubicin in elderly patients with diffuse large B lymphoma. Cancer Med 2023; 12:4184-4194. [PMID: 36200320 PMCID: PMC9972167 DOI: 10.1002/cam4.5280] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 04/25/2022] [Accepted: 08/12/2022] [Indexed: 11/08/2022] Open
Abstract
OBJECTIVES In order to explore the impact of pegylated liposomal doxorubicin (PLD) dose intensity on survival outcomes of newly diagnosed elderly patients with diffuse large B-cell lymphoma (DLBCL), we performed a retrospective study to compare the efficacy and adverse effects of RCEOP (70 mg/m2 ), RCdOP (20-30 mg/m2 ) and RCDOP (30-45 mg/m2 ). The optimal PLD dose of patients with different clinical characteristics of subgroups was explored to provide a clue for the selection of clinical PLD dose. METHODS A total of 335 DLBCL patients (60-85 years old) who were newly diagnosed and completed at least four cycles of RCE(D)OP were selected. The patients were mainly divided into RCEOP (126 cases) (epirubicin 70 mg/m2 ), RCdOP (151 cases) (PLD 20-30 mg/m2 ) and RCdOP (58 cases) (PLD 30-45 mg/m2 ). The effects of different doses of PLD on clinical efficacy, cardiotoxicity and prognosis of patients were retrospectively analyzed. Subgroup analysis was performed to compare the clinical characteristics of different subgroups. RESULTS Our study showed that PLD and epirubicin had similar efficacy (overall survival (OS) p = 0.776; progression-free survival (PFS) p = 0.959). RCDOP (30-45 mg/m2 PLD) group had a higher complete remission (CR) rate of 75.9% compared with RCdOP (20-30 mg/m2 PLD) group (P D vs. d = 0.018). In the overall population, there was no significant difference in survival between RCDOP and RCdOP groups (OS P D vs. d = 0.661; PFS P D vs. d = 0.212). In patients with underlying cardiovascular diseases, the PFS of the RCDOP group was significantly better than the RCdOP group (p = 0.043). Meanwhile, patients in the RCDOP group tended to have a better prognosis than those in the RCEOP group (OS: RCDOP vs. RCEOP p = 0.054, PFS: RCDOP vs. RCEOP p = 0.053). There was no significant difference in the incidence of cardiotoxicity and other adverse events among the three groups. For the low-risk (age-adjusted-International Prognostic Index = 0/1) old patients without cardiovascular disease, RCdOP was considered a better strategy in OS (p = 0.020). CONCLUSION In the general population, the CR rate in the RCDOP group was significantly higher than that in the RCdOP group (p = 0.018). For elderly DLBCL patients with cardiovascular disease, the effect benefit brought by the PLD dose was more obvious, and the PFS of the RCDOP group was significantly better than that of the RCdOP group (p = 0.043). Full dose of PLD is an efficient alternative in the treatment of patients with preexisting cardiovascular diseases.
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Affiliation(s)
- Li Li
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Rongrong Chen
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Program in Clinical Medicine, School of Medicine of Zhejiang University, Hangzhou, Zhejiang, China
| | - De Zhou
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianai Sun
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lulu Wang
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Program in Clinical Medicine, School of Medicine of Zhejiang University, Hangzhou, Zhejiang, China
| | - Lixia Zhu
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Huafei Shen
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Wanzhuo Xie
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiujin Ye
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Lopez-Mendez TB, Strippoli R, Trionfetti F, Calvo P, Cordani M, Gonzalez-Valdivieso J. Clinical Trials Involving Chemotherapy-Based Nanocarriers in Cancer Therapy: State of the Art and Future Directions. Cancer Nanotechnol 2023. [DOI: 10.1007/978-3-031-17831-3_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Komedchikova EN, Kolesnikova OA, Tereshina ED, Kotelnikova PA, Sogomonyan AS, Stepanov AV, Deyev SM, Nikitin MP, Shipunova VO. Two-Step Targeted Drug Delivery via Proteinaceous Barnase-Barstar Interface and Doxorubicin-Loaded Nano-PLGA Outperforms One-Step Strategy for Targeted Delivery to HER2-Overexpressing Cells. Pharmaceutics 2022; 15:52. [PMID: 36678681 PMCID: PMC9861000 DOI: 10.3390/pharmaceutics15010052] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/18/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
Nanoparticle-based chemotherapy is considered to be an effective approach to cancer diagnostics and therapy in modern biomedicine. However, efficient tumor targeting remains a great challenge due to the lack of specificity, selectivity, and high dosage of chemotherapeutic drugs required. A two-step targeted drug delivery strategy (DDS), involving cancer cell pre-targeting, first with a first nontoxic module and subsequent targeting with a second complementary toxic module, is a solution for decreasing doses for administration and lowering systemic toxicity. To prove two-step DDS efficiency, we performed a direct comparison of one-step and two-step DDS based on chemotherapy loaded PLGA nanoparticles and barnase*barstar interface. Namely, we developed and thoroughly characterized the two-step targeting strategy of HER2-overexpressing cancer cells. The first targeting block consists of anti-HER2 scaffold polypeptide DARPin9_29 fused with barstar. Barstar exhibits an extremely effective binding to ribonuclease barnase with Kaff = 1014 M-1, thus making the barnase*barstar protein pair one of the strongest known protein*protein complexes. A therapeutic PLGA-based nanocarrier coupled to barnase was used as a second targeting block. The PLGA nanoparticles were loaded with diagnostic dye, Nile Blue, and a chemotherapeutic drug, doxorubicin. We showed that the two-step DDS increases the performance of chemotherapy-loaded nanocarriers: IC50 of doxorubicin delivered via two-step DDS was more than 100 times lower than that for one-step DDS: IC50 = 43 ± 3 nM for two-step DDS vs. IC50 = 4972 ± 1965 nM for one-step DDS. The obtained results demonstrate the significant efficiency of two-step DDS over the classical one-step one. We believe that the obtained data will significantly change the direction of research in developing targeted anti-cancer drugs and promote the creation of new generation cancer treatment strategies.
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Affiliation(s)
| | | | | | - Polina A. Kotelnikova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
| | - Anna S. Sogomonyan
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
| | - Alexey V. Stepanov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
| | - Sergey M. Deyev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
| | - Maxim P. Nikitin
- Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
- Nanobiomedicine Division, Sirius University of Science and Technology, 354340 Sochi, Russia
| | - Victoria O. Shipunova
- Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
- Nanobiomedicine Division, Sirius University of Science and Technology, 354340 Sochi, Russia
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Fox CA, Romenskaia I, Dagda RK, Ryan RO. Cardiolipin nanodisks confer protection against doxorubicin-induced mitochondrial dysfunction. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2022; 1864:183984. [PMID: 35724738 DOI: 10.1016/j.bbamem.2022.183984] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/25/2022] [Accepted: 05/31/2022] [Indexed: 06/15/2023]
Abstract
Doxorubicin (DOX) is an aqueous soluble anthracycline therapeutic widely used in cancer treatment. Although DOX anti-cancer activity is dose-dependent, increased dosage enhances the risk of cardiotoxicity. Despite intensive investigation, the molecular basis of this undesirable side effect has yet to be established. In addition to serving as a DNA intercalation agent, DOX is known to bind to the signature mitochondrial phospholipid, cardiolipin (CL). Consistent with this, DOX associates with aqueous soluble nanoparticles, termed nanodisks (ND), comprised solely of CL and an apolipoprotein scaffold. Fluorescence microscopy analysis revealed that DOX uptake, and targeting to the nucleus of cultured hepatocarcinoma (HepG2) or breast cancer (MCF7) cells, was unaffected by its association with CL-ND. Subsequent studies revealed that free DOX and DOX-CL-ND were equivalent in terms of growth inhibition activity in both cell lines. By contrast, in studies with H9C2 cardiomyocytes, DOX-CL-ND induced a lesser concentration-dependent decline in cell viability than free DOX. Whereas incubation of H9C2 cardiomyocytes with free DOX caused a steep decline in maximal oxygen consumption rate, DOX-CL-ND treated cells were largely unaffected. The data indicate that association of DOX with CL-ND does not diminish its cancer cell growth inhibition activity yet confers protection to cardiomyocytes from DOX-induced effects on aerobic respiration. This study illustrates that interaction with CL plays a role in DOX-induced mitochondrial dysfunction and suggests CL-ND provide a tool for investigating the mechanistic basis of DOX-induced cardiotoxicity.
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Affiliation(s)
- Colin A Fox
- Department of Biochemistry and Molecular Biology, University of Nevada, Reno, Reno, NV 89557, United States of America
| | - Irina Romenskaia
- Department of Biochemistry and Molecular Biology, University of Nevada, Reno, Reno, NV 89557, United States of America
| | - Ruben K Dagda
- Department of Cellular and Molecular Pharmacology and Physiology, University of Nevada, Reno, Reno, NV 89557, United States of America
| | - Robert O Ryan
- Department of Biochemistry and Molecular Biology, University of Nevada, Reno, Reno, NV 89557, United States of America.
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Doxorubicin delivery systems with an acetylacetone-based block in cholesterol-terminated copolymers: diverse activity against estrogen-dependent and estrogen-independent breast cancer cells. Chem Phys Lipids 2022; 245:105194. [DOI: 10.1016/j.chemphyslip.2022.105194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 11/20/2022]
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Afrin H, Salazar CJ, Kazi M, Ahamad SR, Alharbi M, Nurunnabi M. Methods of screening, monitoring and management of cardiac toxicity induced by chemotherapeutics. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.01.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Kaposi's Sarcoma in Virally Suppressed People Living with HIV: An Emerging Condition. Cancers (Basel) 2021; 13:cancers13225702. [PMID: 34830857 PMCID: PMC8616070 DOI: 10.3390/cancers13225702] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/06/2021] [Accepted: 11/09/2021] [Indexed: 11/27/2022] Open
Abstract
Simple Summary Kaposi’s sarcoma (KS) in people living with HIV (PLHIV) occurs in the vast majority of cases when viral replication is not controlled and when CD4 immunosuppression is important. However, clinicians are observing more and more cases of KS in PLHIV with suppressed viremia on antiretroviral treatment. These clinical forms seem less aggressive, but cause therapeutic dead ends. Indeed, despite repeated chemotherapy, recurrences are frequent. Immunotherapy and specific treatment regimens should be evaluated in this population. Abstract Since the advent of highly effective combined antiretroviral treatment (cART), and with the implementation of large HIV testing programs and universal access to cART, the burden of AIDS-related comorbidities has dramatically decreased over time. The incidence of Kaposi’s sarcoma (SK), strongly associated with HIV replication and CD4 immunosuppression, was greatly reduced. However, KS remains the most common cancer in patients living with HIV (PLHIV). HIV physicians are increasingly faced with KS in virally suppressed HIV-patients, as reflected by increasing description of case series. Though SK seem less aggressive than those in PLHIV with uncontrolled HIV-disease, some may require systemic chemotherapy. Persistent lack of specific anti-HHV-8 cellular immunity could be involved in the physiopathology of these KS. These clinical forms are a real therapeutic challenge without possible short-term improvement of anti-HHV-8 immunity, and no active replication of HIV to control. The cumulative toxicity of chemotherapies repeatedly leads to a therapeutic dead end. The introduction or maintenance of protease inhibitors in cART does not seem to have an impact on the evolution of these KS. Research programs in this emerging condition are important to consider new strategies.
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Sohail M, Sun Z, Li Y, Gu X, Xu H. Research progress in strategies to improve the efficacy and safety of doxorubicin for cancer chemotherapy. Expert Rev Anticancer Ther 2021; 21:1385-1398. [PMID: 34636282 DOI: 10.1080/14737140.2021.1991316] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION DOX exerts strong anticancer activity and is commonly used to treat different cancers, including bone sarcomas, soft tissues, bladder, ovary, stomach, thyroid, breast, acute lymphoblastic leukemia, Hodgkin lymphoma, lung cancer, and myeloblastic leukemia. However, the cumulative doses of DOX above 550mg/m2 cause irreversible cardiotoxicity and other severe adverse effects. In this context, concerning DOX, several patents have been published in the last two decades. This activity highlights various aspects of DOX, such as registered patent analysis, pharmacological action, toxicityminimization, formulation development such as those approved by FDA, under clinical trials, and newly developed nano-delivery systems. AREAS COVERED This review analyzes the different aspects of DOX-based chemotherapeutics and the development of drug delivery systems in theliterature published from 2000 to early 2020. EXPERT OPINION DOX-based chemotherapy is still few steps away from being "perfect and safe" therapy. Certain severe systemic side effects are associated with DOX therapy. It is expected that, in the near future, DOX therapy can be much effective by selecting an ideal nanocarrier system, DOX conjugates, proper structural modifications, DOX-immunotherapy, and combination therapy. The advanced formulationsof DOX from the registered patents and recent research articles need clinical trials to bring safe treatment for cancer patients.
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Affiliation(s)
- Muhammad Sohail
- School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University) Ministry of Education, Yantai University, Yantai, People's Republic of China
| | - Zheng Sun
- School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University) Ministry of Education, Yantai University, Yantai, People's Republic of China
| | - Yanli Li
- School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University) Ministry of Education, Yantai University, Yantai, People's Republic of China
| | - Xuejing Gu
- School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University) Ministry of Education, Yantai University, Yantai, People's Republic of China
| | - Hui Xu
- School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University) Ministry of Education, Yantai University, Yantai, People's Republic of China
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Rehman TU, Bratlie KM. Improving selective targeting to cancer-associated fibroblasts by modifying liposomes with arginine based materials. J Drug Target 2021; 30:94-107. [PMID: 34116612 DOI: 10.1080/1061186x.2021.1941059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
A library of arginine-like surface modifiers was tested to improve the targetability of DOPE:DOPC liposomes towards myofibroblasts in a tumour microenvironment. Liposomes were characterised using zeta potential and dynamic light scattering. Cell viability remained unchanged for all liposomes. Liposomes were encapsulated using doxorubicin (DOX) with an encapsulation efficiency >94%. The toxicity of DOX-loaded liposomes was calculated via half-maximal inhibitory concentration (IC50) for fibroblasts and myofibroblasts. These liposomes resulted in significantly lower IC50-values for myofibroblasts compared to fibroblasts, making them more toxic towards the myofibroblasts. Furthermore, a significant increase in cell internalisation was observed for myofibroblasts compared to fibroblasts, using fluorescein-loaded liposomes. Most importantly, a novel regression model was constructed to predict the IC50-values for different modifications using their physicochemical properties. Fourteen modifications (A-N) were used to train and validate this model; subsequently, this regression model predicted IC50-values for three new modifications (O, P and Q) for both fibroblasts and myofibroblasts. Predicted and measured IC50-values showed no significant difference for fibroblasts. For myofibroblasts, modification O showed no significant difference. This study demonstrates that the tested surface modifications can improve targeting to myofibroblasts in the presence of fibroblasts and hence are suitable drug delivery vehicles for myofibroblasts in a tumour microenvironment.
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Affiliation(s)
- Tanzeel Ur Rehman
- Department of Materials Science & Engineering, Iowa State University, Ames, IA, USA
| | - Kaitlin M Bratlie
- Department of Materials Science & Engineering, Iowa State University, Ames, IA, USA.,Department of Chemical & Biological Engineering, Iowa State University, Ames, IA, USA
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15
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Predictors of new-onset heart failure and overall survival in metastatic breast cancer patients treated with liposomal doxorubicin. Sci Rep 2020; 10:18481. [PMID: 33116159 PMCID: PMC7595106 DOI: 10.1038/s41598-020-75614-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 10/16/2020] [Indexed: 01/06/2023] Open
Abstract
Cardiovascular diseases (CVDs) are the major cause of morbidity/mortality among breast cancer (BC) patients. Observation of the daily practice in eight experienced Polish oncology centers was conducted to find all possible predictors of new cases of heart failure (HF) and overall survival (OS) of metastatic BC patients treated with liposomal doxorubicin, taking into account the impact of pre-existing CVDs. HF was the cause of premature discontinuation of liposomal doxorubicin therapy in 13 (3.2%) of 402 patients. The probability of developing HF was higher in women with pre-existing CVDs (HR 4.61; 95%CI 1.38–15.38). Independent of CVDs history, a lower risk of HF was observed in those treated with a cumulative dose of liposomal doxorubicin > 300 mg/m2 (HR 0.14; 95% CI 0.04–0.54) and taxane-naive (HR 0.26; 95% CI 0.07–0.96). Multivariate analysis including the presence of pre-existing CVDs and occurrence of new HF, revealed a liposomal doxorubicin in cumulative doses of > 300 mg/m2 as a beneficial predictor for OS (HR 0.61; 95% CI 0.47–0.78) independently of subsequent chemotherapy (HR 0.72; 95% CI 0.57–0.92) or endocrine therapy (HR 0.65; 95% CI 0.49–0.87). Higher doses of liposomal doxorubicin can decrease mortality in metastatic BC without increasing the risk of HF. The clinical benefit is achieved regardless of pre-existing CVDs and subsequent anticancer therapy.
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16
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Bhatia R, Sharma A, Narang RK, Rawal RK. Recent Nanocarrier Approaches for Targeted Drug Delivery in Cancer Therapy. Curr Mol Pharmacol 2020; 14:350-366. [PMID: 32744982 DOI: 10.2174/1874467213666200730114943] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 06/02/2020] [Accepted: 06/05/2020] [Indexed: 01/16/2023]
Abstract
Cancer is one of the most serious health concerns in the 21st century whose prevalence is beyond boundaries and can affect any organ of the human body. The conventional chemotherapeutic treatment strategies lack specificity to tumors and are associated with toxic effects on the immune system and other organ systems. In the past decades, there has been continuous progress in the development of smart nanocarrier systems for target-specific delivery of drugs against a variety of tumors, including intracellular gene-specific targeting. These nanocarriers are able to recognize the tumor cells and deliver the therapeutic agent in fixed proportions, causing no or very less harm to healthy cells. Nanosystems have modified physicochemical properties, improved bioavailability, and long retention in blood, which enhances their potency. A huge number of nanocarrier based formulations have been developed and are in clinical trials. Nanocarrier systems include polymeric micelles, liposomes, dendrimers, carbon nanotubes, gold nanoparticles, etc. Recent advancements in nanocarrier systems include mesoporous silica nanoparticles (MSNs), metal organic frameworks, and quantum dots. In the present review, various nanocarrier based drug delivery systems, along with their applications in the management of cancer, have been described with special emphasis on MSNs.
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Affiliation(s)
- Rohit Bhatia
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Ferozepur G.T. Road, Moga-142 001, Punjab, India
| | - Amit Sharma
- Department of Pharmaceutics, ISF College of Pharmacy, Ferozepur G.T. Road, Moga-142 001, Punjab, India
| | - Raj K Narang
- Department of Pharmaceutics, ISF College of Pharmacy, Ferozepur G.T. Road, Moga-142 001, Punjab, India
| | - Ravindra K Rawal
- Department of Chemistry, Maharishi Markandeshwar (Deemed to be University), Mullana-133207, Haryana, India
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Wang Q, Tardi P, Sadowski N, Xie S, Heller D, Mayer L. Pharmacokinetics, drug metabolism, and tissue distribution of CPX-351 in animals. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2020; 30:102275. [PMID: 32750494 DOI: 10.1016/j.nano.2020.102275] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 07/10/2020] [Accepted: 07/20/2020] [Indexed: 10/23/2022]
Abstract
CPX-351, a liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar ratio, is indicated for adults with newly diagnosed, therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In preclinical species, this article demonstrated (1) similar release of cytarabine and daunorubicin by CPX-351 in plasma; (2) similar patterns of metabolism of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal cytarabine/daunorubicin combination; (3) prolonged tissue exposure to CPX-351; (4) dramatically different tissue distribution of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal combination (tissue:plasma ratios generally <1 versus >1, respectively); and (5) dramatically lower unbound plasma and tissue concentrations of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal combination. Together, these results provide insight into the safety profile of CPX-351, as well as mechanisms that drive the improved efficacy observed for CPX-351 versus the conventional 7 + 3 cytarabine/daunorubicin regimen in clinical studies.
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Affiliation(s)
- Qi Wang
- Jazz Pharmaceuticals, Palo Alto, CA, USA..
| | - Paul Tardi
- Jazz Pharmaceuticals, Palo Alto, CA, USA..
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Dendrimer-like AB2-type star polymers as nanocarriers for doxorubicin delivery to breast cancer cells: synthesis, characterization, in-vitro release and cytotoxicity studies. JOURNAL OF POLYMER RESEARCH 2020. [DOI: 10.1007/s10965-020-02089-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Ickenstein LM, Garidel P. Lipid-based nanoparticle formulations for small molecules and RNA drugs. Expert Opin Drug Deliv 2020; 16:1205-1226. [PMID: 31530041 DOI: 10.1080/17425247.2019.1669558] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction: Liposomes and lipid-based nanoparticles (LNPs) effectively deliver cargo molecules to specific tissues, cells, and cellular compartments. Patients benefit from these nanoparticle formulations by altered pharmacokinetic properties, higher efficacy, or reduced side effects. While liposomes are an established delivery option for small molecules, Onpattro® (Sanofi Genzyme, Cambridge, MA) is the first commercially available LNP formulation of a small interfering ribonucleic acid (siRNA). Areas covered: This review article summarizes key features of liposomal formulations for small molecule drugs and LNP formulations for RNA therapeutics. We describe liposomal formulations that are commercially available or in late-stage clinical development and the most promising LNP formulations for ASOs, siRNAs, saRNA, and mRNA therapeutics. Expert opinion: Similar to liposomes, LNPs for RNA therapeutics have matured but still possess a niche application status. RNA therapeutics, however, bear an immense hope for difficult to treat diseases and fuel the imagination for further applications of RNA drugs. LNPs face similar challenges as liposomes including limitations in biodistribution, the risk to provoke immune responses, and other toxicities. However, since properties of RNA molecules within the same group are very similar, the entire class of therapeutic molecules would benefit from improvements in a few key parameters of the delivery technology.
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Affiliation(s)
- Ludger M Ickenstein
- Boehringer Ingelheim Pharma GmbH & Co. KG, Innovation Unit, Pharmaceutical Development Biologicals , Biberach an der Riss , Germany
| | - Patrick Garidel
- Boehringer Ingelheim Pharma GmbH & Co. KG, Innovation Unit, Pharmaceutical Development Biologicals , Biberach an der Riss , Germany
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20
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Madariaga A, Rustin GJS, Buckanovich RJ, Trent JC, Oza AM. Wanna Get Away? Maintenance Treatments and Chemotherapy Holidays in Gynecologic Cancers. Am Soc Clin Oncol Educ Book 2019; 39:e152-e166. [PMID: 31099646 DOI: 10.1200/edbk_238755] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Epithelial ovarian cancer has a very high rate of relapse after primary therapy; historically approximately 70% of patients with a complete clinical response to surgery and adjuvant chemotherapy will relapse and die of the disease. Although this number has slowly improved, cure rates remain less than 50%. As such, maintenance therapy with the aim of preventing or delaying disease relapse and the goal of improving overall survival has been the subject of intense study. Numerous earlier studies with agents ranging from radioactive phosphorus to extended frontline therapy or to monthly taxol administration demonstrated encouraging improvements in progression-free survival (PFS) only to find, disappointingly, no benefit in overall survival. In addition, the PFS advantage of maintenance therapy was associated with disconcerting side effects such that maintenance therapy was not adapted as standard of care. Studies with bevacizumab and PARP inhibitors have demonstrated a PFS advantage with a manageable side-effect profile. However, an overall survival advantage remains unclear, and the use of these approaches thus remains controversial. Furthermore, in recurrent disease, the length of chemotherapy and benefits of extended chemotherapy is unclear. Thus, additional trials assessing maintenance strategies in ovarian and other gynecologic malignancies are needed.
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Affiliation(s)
- Ainhoa Madariaga
- 1 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | | | | | | | - Amit M Oza
- 1 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
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21
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Sayed N, Ameen M, Wu JC. Personalized medicine in cardio-oncology: the role of induced pluripotent stem cell. Cardiovasc Res 2019; 115:949-959. [PMID: 30768178 PMCID: PMC6933506 DOI: 10.1093/cvr/cvz024] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 01/14/2019] [Accepted: 02/06/2019] [Indexed: 12/19/2022] Open
Abstract
Treatment of cancer has evolved in the last decade with the introduction of new therapies. Despite these successes, the lingering cardiotoxic side-effects from chemotherapy remain a major cause of morbidity and mortality in cancer survivors. These effects can develop acutely during treatment, or even years later. Although many risk factors can be identified prior to beginning therapy, unexpected toxicity still occurs, often with lasting consequences. Specifically, cardiotoxicity results in cardiac cell death, eventually leading to cardiomyopathy and heart failure. Certain risk factors may predispose an individual to experiencing adverse cardiovascular effects, and when unexpected cardiotoxicity occurs, it is generally managed with supportive care. Animal models of chemotherapy-induced cardiotoxicity have provided some mechanistic insights, but the precise mechanisms by which these drugs affect the heart remains unknown. Moreover, the genetic rationale as to why some patients are more susceptible to developing cardiotoxicity has yet to be determined. Many genome-wide association studies have identified genomic variants that could be associated with chemotherapy-induced cardiotoxicity, but the lack of validation has made these studies more speculative rather than definitive. With the advent of human induced pluripotent stem cell (iPSC) technology, researchers not only have the opportunity to model human diseases, but also to screen drugs for their efficacy and toxicity using human cell models. Furthermore, it allows us to conduct validation studies to confirm the role of genomic variants in human diseases. In this review, we discuss the role of iPSCs in modelling chemotherapy-induced cardiotoxicity.
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Affiliation(s)
- Nazish Sayed
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Mohamed Ameen
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
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22
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Neuberger K, Boddupalli A, Bratlie KM. Effects of arginine-based surface modifications of liposomes for drug delivery in Caco-2 colon carcinoma cells. Biochem Eng J 2018. [DOI: 10.1016/j.bej.2018.08.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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23
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Khuphe M, Thornton PD. Poly(hydroxy acid) Nanoparticles for the Encapsulation and Controlled Release of Doxorubicin. MACROMOL CHEM PHYS 2018. [DOI: 10.1002/macp.201800352] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Carvalho PM, Felício MR, Santos NC, Gonçalves S, Domingues MM. Application of Light Scattering Techniques to Nanoparticle Characterization and Development. Front Chem 2018; 6:237. [PMID: 29988578 PMCID: PMC6026678 DOI: 10.3389/fchem.2018.00237] [Citation(s) in RCA: 174] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 06/04/2018] [Indexed: 01/07/2023] Open
Abstract
Over the years, the scientific importance of nanoparticles for biomedical applications has increased. The high stability and biocompatibility, together with the low toxicity of the nanoparticles developed lead to their use as targeted drug delivery systems, bioimaging systems, and biosensors. The wide range of nanoparticles size, from 10 nm to 1 μm, as well as their optical properties, allow them to be studied using microscopy and spectroscopy techniques. In order to be effectively used, the physicochemical properties of nanoparticle formulations need to be taken into account, namely, particle size, surface charge distribution, surface derivatization and/or loading capacity, and related interactions. These properties need to be optimized considering the final nanoparticle intended biodistribution and target. In this review, we cover light scattering based techniques, namely dynamic light scattering and zeta-potential, used for the physicochemical characterization of nanoparticles. Dynamic light scattering is used to measure nanoparticles size, but also to evaluate their stability over time in suspension, at different pH and temperature conditions. Zeta-potential is used to characterize nanoparticles surface charge, obtaining information about their stability and surface interaction with other molecules. In this review, we focus on nanoparticle characterization and application in infection, cancer and cardiovascular diseases.
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Affiliation(s)
- Patrícia M Carvalho
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Mário R Felício
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Nuno C Santos
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Sónia Gonçalves
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Marco M Domingues
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
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Olusanya TOB, Haj Ahmad RR, Ibegbu DM, Smith JR, Elkordy AA. Liposomal Drug Delivery Systems and Anticancer Drugs. Molecules 2018; 23:E907. [PMID: 29662019 PMCID: PMC6017847 DOI: 10.3390/molecules23040907] [Citation(s) in RCA: 344] [Impact Index Per Article: 49.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 03/29/2018] [Accepted: 04/09/2018] [Indexed: 12/27/2022] Open
Abstract
Cancer is a life-threatening disease contributing to ~3.4 million deaths worldwide. There are various causes of cancer, such as smoking, being overweight or obese, intake of processed meat, radiation, family history, stress, environmental factors, and chance. The first-line treatment of cancer is the surgical removal of solid tumours, radiation therapy, and chemotherapy. The systemic administration of the free drug is considered to be the main clinical failure of chemotherapy in cancer treatment, as limited drug concentration reaches the tumour site. Most of the active pharmaceutical ingredients (APIs) used in chemotherapy are highly cytotoxic to both cancer and normal cells. Accordingly, targeting the tumour vasculatures is essential for tumour treatment. In this context, encapsulation of anti-cancer drugs within the liposomal system offers secure platforms for the targeted delivery of anti-cancer drugs for the treatment of cancer. This, in turn, can be helpful for reducing the cytotoxic side effects of anti-cancer drugs on normal cells. This short-review focuses on the use of liposomes in anti-cancer drug delivery.
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Affiliation(s)
- Temidayo O B Olusanya
- School of Pharmacy and Pharmaceutical Sciences, University of Sunderland, Sunderland SR1 3SD, UK.
| | - Rita Rushdi Haj Ahmad
- School of Pharmacy and Pharmaceutical Sciences, University of Sunderland, Sunderland SR1 3SD, UK.
| | - Daniel M Ibegbu
- Department of Medical Biochemistry, College of Medicine, University of Nigeria Enugu Campus, Nigeria.
| | - James R Smith
- School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK.
| | - Amal Ali Elkordy
- School of Pharmacy and Pharmaceutical Sciences, University of Sunderland, Sunderland SR1 3SD, UK.
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26
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Bansal N, Amdani S, Lipshultz ER, Lipshultz SE. Chemotherapy-induced cardiotoxicity in children. Expert Opin Drug Metab Toxicol 2017; 13:817-832. [DOI: 10.1080/17425255.2017.1351547] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Neha Bansal
- Department of Pediatrics, Wayne State University School of Medicine and Children’s Hospital of Michigan, Detroit, MI, USA
| | - Shahnawaz Amdani
- Department of Pediatrics, Wayne State University School of Medicine and Children’s Hospital of Michigan, Detroit, MI, USA
| | - Emma R. Lipshultz
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Steven E. Lipshultz
- Department of Pediatrics, Wayne State University School of Medicine and Children’s Hospital of Michigan, Detroit, MI, USA
- Karmanos Cancer Institute, Detroit, MI, USA
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27
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Zaimy MA, Saffarzadeh N, Mohammadi A, Pourghadamyari H, Izadi P, Sarli A, Moghaddam LK, Paschepari SR, Azizi H, Torkamandi S, Tavakkoly-Bazzaz J. New methods in the diagnosis of cancer and gene therapy of cancer based on nanoparticles. Cancer Gene Ther 2017; 24:233-243. [PMID: 28574057 DOI: 10.1038/cgt.2017.16] [Citation(s) in RCA: 151] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Revised: 03/17/2017] [Accepted: 04/12/2017] [Indexed: 12/31/2022]
Abstract
Cancer is one of the leading cause of death in the world with the prevalence of >10 million mortalities annually. Current cancer treatments include surgical intervention, radiation, and taking chemotherapeutic drugs, which often kill the healthy cells and result in toxicity in patients. Therefore, researchers are looking for ways to be able to eliminate just cancerous cells. Intra-tumor heterogeneity of cancerous cells is the main obstacle on the way of an effective cancer treatment. However, better comprehension of molecular basis of tumor and the advent of new diagnostic technologies can help to improve the treatment of various cancers. Therefore, study of epigenetic changes, gene expression of cancerous cells and employing methods that enable us to correct or minimize these changes is critically important. In this paper, we will review the recent advanced strategies being used in the field of cancer research.
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Affiliation(s)
- M A Zaimy
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - N Saffarzadeh
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - A Mohammadi
- Center of Excellence for Biodiversity, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
| | - H Pourghadamyari
- Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - P Izadi
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - A Sarli
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - L K Moghaddam
- Department of Developmental Cell Biology, School of Biological Sciences, Azad University, Tehran North Branch, Tehran, Iran
| | - S R Paschepari
- Department of Developmental Cell Biology, School of Biological Sciences, Azad University, Tehran North Branch, Tehran, Iran
| | - H Azizi
- Department of Medical Parasitology, Zabol University of Medical Sciences, Zabol, Iran
| | - S Torkamandi
- Department of Medical Genetics and immunology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - J Tavakkoly-Bazzaz
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Bardania H, Tarvirdipour S, Dorkoosh F. Liposome-targeted delivery for highly potent drugs. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2017; 45:1478-1489. [DOI: 10.1080/21691401.2017.1290647] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Hassan Bardania
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Shabnam Tarvirdipour
- Biomedical Division, Faculty of Chemical Engineering, Tarbiat Modares University, Tehran, Iran
| | - Farid Dorkoosh
- Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Medical Biomaterial Research Center (MBRC), Tehran University of Medical Sciences, Tehran, Iran
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Cardiac safety of adjuvant non-pegylated liposomal doxorubicin combined with cyclophosphamide and followed by paclitaxel in older breast cancer patients. Breast 2016; 31:186-191. [PMID: 27886643 DOI: 10.1016/j.breast.2016.11.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 11/08/2016] [Accepted: 11/09/2016] [Indexed: 12/21/2022] Open
Abstract
PURPOSE To investigate the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) combined to Cyclophosphamide (CTX) and followed by weekly Paclitaxel, in older patients (≥65 years) with diagnosis of high risk breast cancer. The main end point of this prospective study was the detection of early episodes of symptomatic congestive heart failure (CHF). METHODS The cardiac function was evaluated by left ventricular ejection fraction (LVEF) measurements with repeated echocardiograms, performed 2 weeks before the beginning of chemotherapy and every 6 months, until 30 months after the study entry; then yearly for at least 5 years. RESULTS Forty-seven patients were enrolled from two Italian Divisions of Medical Oncology. Final results revealed no early episodes of symptomatic CHF within the first 12 months from the enrolment. Only two cardiac events were observed: an episode of atrial flutter after the first cycle of NPL-DOX and CTX, with a quick return to normal rhythm, and a grade 3 (scored to NCI-CTCAE, version 3.0) CHF episode, 18 months later chemotherapy start. No other relevant toxicities were reported. CONCLUSIONS This adjuvant combination including NPL-DOX in elderly patients, resulted in a low rate of cardiac toxic effects. Comparative trials should be encouraged to confirm these findings.
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Hörner S, Knauer S, Uth C, Jöst M, Schmidts V, Frauendorf H, Thiele CM, Avrutina O, Kolmar H. Nanoskalige, biologisch abbaubare organisch-anorganische Hybride für effiziente Zellaufnahme und Wirkstofftransport. Angew Chem Int Ed Engl 2016. [DOI: 10.1002/ange.201606065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Sebastian Hörner
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie; Technische Universität Darmstadt; Alarich-Weiss-Straße 4 64287 Darmstadt Deutschland
| | - Sascha Knauer
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie; Technische Universität Darmstadt; Alarich-Weiss-Straße 4 64287 Darmstadt Deutschland
| | - Christina Uth
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie; Technische Universität Darmstadt; Alarich-Weiss-Straße 4 64287 Darmstadt Deutschland
| | - Marina Jöst
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie; Technische Universität Darmstadt; Alarich-Weiss-Straße 4 64287 Darmstadt Deutschland
| | - Volker Schmidts
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie; Technische Universität Darmstadt; Alarich-Weiss-Straße 16 64287 Darmstadt Deutschland
| | - Holm Frauendorf
- Institut für Organische und Biomolekulare Chemie; Georg-August Universität Göttingen; Tammannstraße 2 37077 Göttingen Deutschland
| | - Christina Marie Thiele
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie; Technische Universität Darmstadt; Alarich-Weiss-Straße 16 64287 Darmstadt Deutschland
| | - Olga Avrutina
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie; Technische Universität Darmstadt; Alarich-Weiss-Straße 4 64287 Darmstadt Deutschland
| | - Harald Kolmar
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie; Technische Universität Darmstadt; Alarich-Weiss-Straße 4 64287 Darmstadt Deutschland
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Hörner S, Knauer S, Uth C, Jöst M, Schmidts V, Frauendorf H, Thiele CM, Avrutina O, Kolmar H. Nanoscale Biodegradable Organic–Inorganic Hybrids for Efficient Cell Penetration and Drug Delivery. Angew Chem Int Ed Engl 2016; 55:14842-14846. [DOI: 10.1002/anie.201606065] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 09/27/2016] [Indexed: 02/02/2023]
Affiliation(s)
- Sebastian Hörner
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie Technische Universität Darmstadt Alarich-Weiss-Strasse 4 64287 Darmstadt Germany
| | - Sascha Knauer
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie Technische Universität Darmstadt Alarich-Weiss-Strasse 4 64287 Darmstadt Germany
| | - Christina Uth
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie Technische Universität Darmstadt Alarich-Weiss-Strasse 4 64287 Darmstadt Germany
| | - Marina Jöst
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie Technische Universität Darmstadt Alarich-Weiss-Strasse 4 64287 Darmstadt Germany
| | - Volker Schmidts
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie Technische Universität Darmstadt Alarich-Weiss-Strasse 16 64287 Darmstadt Germany
| | - Holm Frauendorf
- Institut für Organische und Biomolekulare Chemie Georg-August Universität Göttingen Tammannstrasse 2 37077 Göttingen Germany
| | - Christina Marie Thiele
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie Technische Universität Darmstadt Alarich-Weiss-Strasse 16 64287 Darmstadt Germany
| | - Olga Avrutina
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie Technische Universität Darmstadt Alarich-Weiss-Strasse 4 64287 Darmstadt Germany
| | - Harald Kolmar
- Clemens-Schöpf-Institut für Organische Chemie und Biochemie Technische Universität Darmstadt Alarich-Weiss-Strasse 4 64287 Darmstadt Germany
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Manca ML, Cencetti C, Matricardi P, Castangia I, Zaru M, Sales OD, Nacher A, Valenti D, Maccioni AM, Fadda AM, Manconi M. Glycerosomes: Use of hydrogenated soy phosphatidylcholine mixture and its effect on vesicle features and diclofenac skin penetration. Int J Pharm 2016; 511:198-204. [PMID: 27418567 DOI: 10.1016/j.ijpharm.2016.07.009] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Revised: 07/05/2016] [Accepted: 07/08/2016] [Indexed: 10/21/2022]
Abstract
In this work, diclofenac was encapsulated, as sodium salt, in glycerosomes containing 10, 20 or 30% of glycerol in the water phase with the aim to ameliorate its topical efficacy. Taking into account previous findings, glycerosome formulation was modified, in terms of economic suitability, using a cheap and commercially available mixture of hydrogenated soy phosphatidylcholine (P90H). P90H glycerosomes were spherical and multilamellar; photon correlation spectroscopy showed that obtained vesicles were ∼131nm, slightly larger and more polydispersed than those made with dipalmitoylphosphatidylcholine (DPPC) but, surprisingly, they were able to ameliorate the local delivery of diclofenac, which was improved with respect to previous findings, in particular using glycerosomes containing high amount of glycerol (20 and 30%). Finally, this drug delivery system showed a high in vitro biocompatibility toward human keratinocytes.
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Affiliation(s)
- Maria Letizia Manca
- Dept. Scienze della Vita e dell'Ambiente, Drug Science Division, University of Cagliari, 09124 Cagliari, Italy
| | - Claudia Cencetti
- Dept. Chemistry and Drug Technologies, Sapienza, University of Roma, Roma, Italy
| | - Pietro Matricardi
- Dept. Chemistry and Drug Technologies, Sapienza, University of Roma, Roma, Italy.
| | - Ines Castangia
- Dept. Scienze della Vita e dell'Ambiente, Drug Science Division, University of Cagliari, 09124 Cagliari, Italy
| | - Marco Zaru
- Icnoderm srl, Sardegna Ricerche Ed.5, 09010 Pula, Cagliari, Italy
| | - Octavio Diez Sales
- Dept. Farmacia y Tecnologia Farmaceutica, University of Valencia, 46100-Burjassot, Valencia, Spain
| | - Amparo Nacher
- Dept. Farmacia y Tecnologia Farmaceutica, University of Valencia, 46100-Burjassot, Valencia, Spain
| | - Donatella Valenti
- Dept. Scienze della Vita e dell'Ambiente, Drug Science Division, University of Cagliari, 09124 Cagliari, Italy
| | - Anna Maria Maccioni
- Dept. Scienze della Vita e dell'Ambiente, Drug Science Division, University of Cagliari, 09124 Cagliari, Italy
| | - Anna Maria Fadda
- Dept. Scienze della Vita e dell'Ambiente, Drug Science Division, University of Cagliari, 09124 Cagliari, Italy
| | - Maria Manconi
- Dept. Scienze della Vita e dell'Ambiente, Drug Science Division, University of Cagliari, 09124 Cagliari, Italy
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Aminkeng F, Ross CJD, Rassekh SR, Hwang S, Rieder MJ, Bhavsar AP, Smith A, Sanatani S, Gelmon KA, Bernstein D, Hayden MR, Amstutz U, Carleton BC, CPNDS Clinical Practice Recommendations Group. Recommendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicity. Br J Clin Pharmacol 2016; 82:683-95. [PMID: 27197003 PMCID: PMC5338111 DOI: 10.1111/bcp.13008] [Citation(s) in RCA: 172] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Revised: 04/28/2016] [Accepted: 04/29/2016] [Indexed: 12/15/2022] Open
Abstract
AIMS Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline-based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence-based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. METHODS We followed a standard guideline development process, including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. RESULTS RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B - moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow-up, as well as therapeutic options within the current standard of clinical practice. CONCLUSIONS Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT.
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Affiliation(s)
- Folefac Aminkeng
- Centre for Molecular Medicine and Therapeutics, Department of Medical GeneticsUniversity of British ColumbiaVancouverBCCanada
- Child & Family Research InstituteUniversity of British ColumbiaVancouverBCCanada
| | - Colin J. D. Ross
- Child & Family Research InstituteUniversity of British ColumbiaVancouverBCCanada
- Division of Translational Therapeutics, Department of PediatricsUniversity of British ColumbiaVancouverBCCanada
| | - Shahrad R. Rassekh
- Child & Family Research InstituteUniversity of British ColumbiaVancouverBCCanada
- Division of Pediatric Hematology/Oncology/BMT, Department of PediatricsUniversity of British ColumbiaVancouverBCCanada
| | - Soomi Hwang
- Faculty of Pharmaceutical SciencesUniversity of British ColumbiaVancouverBCCanada
| | | | - Amit P. Bhavsar
- Child & Family Research InstituteUniversity of British ColumbiaVancouverBCCanada
- Division of Translational Therapeutics, Department of PediatricsUniversity of British ColumbiaVancouverBCCanada
| | - Anne Smith
- Child & Family Research InstituteUniversity of British ColumbiaVancouverBCCanada
- Pharmaceutical Outcomes & Policy Innovations ProgrammeBC Children's HospitalVancouverBCCanada
| | - Shubhayan Sanatani
- Child & Family Research InstituteUniversity of British ColumbiaVancouverBCCanada
| | | | - Daniel Bernstein
- Department of Pediatrics, Division of CardiologyStanford UniversityStanfordCAUSA
| | - Michael R. Hayden
- Centre for Molecular Medicine and Therapeutics, Department of Medical GeneticsUniversity of British ColumbiaVancouverBCCanada
- Child & Family Research InstituteUniversity of British ColumbiaVancouverBCCanada
- Translational Laboratory in Genetic Medicine, National University of Singapore and Association for ScienceTechnology and Research (A*STAR)Singapore
| | - Ursula Amstutz
- Child & Family Research InstituteUniversity of British ColumbiaVancouverBCCanada
- Division of Translational Therapeutics, Department of PediatricsUniversity of British ColumbiaVancouverBCCanada
- University Institute of Clinical Chemistry, Inselspital Bern University Hospital and University of BernSwitzerland
| | - Bruce C. Carleton
- Child & Family Research InstituteUniversity of British ColumbiaVancouverBCCanada
- Pharmaceutical Outcomes & Policy Innovations ProgrammeBC Children's HospitalVancouverBCCanada
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Bassareo PP, Monte I, Romano C, Deidda M, Piras A, Cugusi L, Coppola C, Galletta F, Mercuro G. Cardiotoxicity from anthracycline and cardioprotection in paediatric cancer patients. J Cardiovasc Med (Hagerstown) 2016; 17 Suppl 1:e55-e63. [PMID: 27183526 DOI: 10.2459/jcm.0000000000000375] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Notwithstanding the steady progress in survival rates of children and adolescents suffering from cancer, the benefits associated with chemotherapy do not come without risks involving multiple organs and systems, including the cardiovascular apparatus. Anthracyclines-often administered in combination with radiation therapy and/or surgery-are the most used chemotherapeutic compounds in order to treat tumours and blood malignancies even in paediatric age. Being an important side-effect of anthracyclines, carduitoxicity may limit their efficacy during the treatment and induce long-term sequelae, observed even many years after therapy completion. The purpose of this review was to perform an overview about all the possible strategies to prevent and/or limit the anthracyclines adverse side-effects for the cardiovascular system in childhood cancer survivors.
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Affiliation(s)
- Pier P Bassareo
- aDepartment of Medical Sciences 'Mario Aresu', University of Cagliari bGeneral Surgery and Medical-Surgery Specialities Department, University of Catania cDivision of Cardiology, Istituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione Giovanni Pascale'-IRCCS, Naples, Italy
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35
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Walls ZF, Gong H, Wilson RJ. Liposomal Coencapsulation of Doxorubicin with Listeriolysin O Increases Potency via Subcellular Targeting. Mol Pharm 2016; 13:1185-90. [PMID: 26751497 DOI: 10.1021/acs.molpharmaceut.5b00674] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Liposomal doxorubicin is a clinically important drug formulation indicated for the treatment of several different forms of cancer. For doxorubicin to exert a therapeutic effect, it must gain access to the nucleus. However, a large proportion of the liposomal doxorubicin dose fails to work because it is sequestered within endolysosomal organelles following endocytosis of the liposomes due to the phenomenon of ion trapping. Listeriolysin O (LLO) is a pore-forming protein that can provide a mechanism for endosomal escape. The present study demonstrates that liposomal coencapsulation of doxorubicin with LLO enables a significantly larger percentage of the dose to colocalize with the nucleus compared to liposomes containing doxorubicin alone. The change in intracellular distribution resulted in a significantly more potent formulation of liposomal doxorubicin as demonstrated in both the ovarian carcinoma cell line A2780 and its doxorubicin-resistant derivative A2780ADR.
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Affiliation(s)
- Zachary F Walls
- Department of Pharmaceutical Sciences, ‡Center for Inflammation, Infectious Disease and Immunity, §Department of Biomedical Sciences, and ∥Department of Biological Sciences, East Tennessee State University , Johnson City, Tennessee 37604, United States
| | - Henry Gong
- Department of Pharmaceutical Sciences, ‡Center for Inflammation, Infectious Disease and Immunity, §Department of Biomedical Sciences, and ∥Department of Biological Sciences, East Tennessee State University , Johnson City, Tennessee 37604, United States
| | - Rebecca J Wilson
- Department of Pharmaceutical Sciences, ‡Center for Inflammation, Infectious Disease and Immunity, §Department of Biomedical Sciences, and ∥Department of Biological Sciences, East Tennessee State University , Johnson City, Tennessee 37604, United States
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Hansen AE, Petersen AL, Henriksen JR, Boerresen B, Rasmussen P, Elema DR, af Rosenschöld PM, Kristensen AT, Kjær A, Andresen TL. Positron Emission Tomography Based Elucidation of the Enhanced Permeability and Retention Effect in Dogs with Cancer Using Copper-64 Liposomes. ACS NANO 2015; 9:6985-6995. [PMID: 26022907 DOI: 10.1021/acsnano.5b01324] [Citation(s) in RCA: 208] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Since the first report of the enhanced permeability and retention (EPR) effect, the research in nanocarrier based antitumor drugs has been intense. The field has been devoted to treatment of cancer by exploiting EPR-based accumulation of nanocarriers in solid tumors, which for many years was considered to be a ubiquitous phenomenon. However, the understanding of differences in the EPR-effect between tumor types, heterogeneities within each patient group, and dependency on tumor development stage in humans is sparse. It is therefore important to enhance our understanding of the EPR-effect in large animals and humans with spontaneously developed cancer. In the present paper, we describe a novel loading method of copper-64 into PEGylated liposomes and use these liposomes to evaluate the EPR-effect in 11 canine cancer patients with spontaneous solid tumors by PET/CT imaging. We thereby provide the first high-resolution analysis of EPR-based tumor accumulation in large animals. We find that the EPR-effect is strong in some tumor types but cannot be considered a general feature of solid malignant tumors since we observed a high degree of accumulation heterogeneity between tumors. Six of seven included carcinomas displayed high uptake levels of liposomes, whereas one of four sarcomas displayed signs of liposome retention. We conclude that nanocarrier-radiotracers could be important in identifying cancer patients that will benefit from nanocarrier-based therapeutics in clinical practice.
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Affiliation(s)
- Anders E Hansen
- †Center for Nanomedicine and Theranostics, DTU Nanotech, Technical University of Denmark, Building 423, DK-2800 Lyngby, Denmark
| | - Anncatrine L Petersen
- †Center for Nanomedicine and Theranostics, DTU Nanotech, Technical University of Denmark, Building 423, DK-2800 Lyngby, Denmark
| | - Jonas R Henriksen
- †Center for Nanomedicine and Theranostics, DTU Nanotech, Technical University of Denmark, Building 423, DK-2800 Lyngby, Denmark
- §DTU Chemistry, Technical University of Denmark, Building 206, DK-2800 Lyngby, Denmark
| | - Betina Boerresen
- ∥Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Dyrlaegevej 16, DK-1870 Frederiksberg, Denmark
| | - Palle Rasmussen
- †Center for Nanomedicine and Theranostics, DTU Nanotech, Technical University of Denmark, Building 423, DK-2800 Lyngby, Denmark
- ⊥DTU Nutech, Hevesy Laboratory, Technical University of Denmark, Frederiksborgvej 399, DK-4000 Roskilde, Denmark
| | - Dennis R Elema
- †Center for Nanomedicine and Theranostics, DTU Nanotech, Technical University of Denmark, Building 423, DK-2800 Lyngby, Denmark
- ⊥DTU Nutech, Hevesy Laboratory, Technical University of Denmark, Frederiksborgvej 399, DK-4000 Roskilde, Denmark
| | - Per Munck af Rosenschöld
- #Radiation Medicine Research Center, Department of Radiation Oncology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
| | - Annemarie T Kristensen
- ∥Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Dyrlaegevej 16, DK-1870 Frederiksberg, Denmark
| | | | - Thomas L Andresen
- †Center for Nanomedicine and Theranostics, DTU Nanotech, Technical University of Denmark, Building 423, DK-2800 Lyngby, Denmark
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Piper SE, McDonagh TA. Chemotherapy-related Cardiomyopathy. Eur Cardiol 2015; 10:19-24. [PMID: 30310418 PMCID: PMC6159418 DOI: 10.15420/ecr.2015.10.01.19] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 07/23/2015] [Indexed: 11/04/2022] Open
Abstract
Advances in chemotherapeutic agents have resulted in significantly improved cancer survival rates. Cardiac toxicity, however, has emerged as a leading cause of morbidity, both during and years after treatment. One of the most common manifestations of cardiotoxicity is that of heart failure and left ventricular systolic dysfunction. In this review, current opinions and guidelines in this field are discussed, with particular focus on the most common culprits, the anthracyclines, and the monoclonal antibody, trastuzumab.
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Affiliation(s)
- Susan E Piper
- King's College London, The James Black Centre, London, UK; Kings College Hospital NHS Foundation Trust, London, UK
| | - Theresa A McDonagh
- King's College London, The James Black Centre, London, UK; Kings College Hospital NHS Foundation Trust, London, UK
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Abstract
Advances in chemotherapeutic agents over the past two decades have resulted in significantly improved cancer survival rates. Cardiac toxicity, however, has emerged as a leading cause of morbidity, both during and years after treatment. One of the most common manifestations of cardiotoxicity is that of heart failure and left ventricular systolic dysfunction. Consequently, the field of cardio-oncology is a rapidly emerging field of sub-specialty, with growing research interests in all aspects of management. In this review, current opinions and guidelines in this field are discussed, with particular focus on the most common culprits, the anthracyclines and the monoclonal antibody, trastuzumab.
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Affiliation(s)
- Susan Piper
- Department of Cardiovascular Research, King's College London, The James Black Center, 125 Coldharbour Lane, London SE5 9NU, UK
- Department of Cardiology, King's College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK
| | - Theresa McDonagh
- Department of Cardiovascular Research, King's College London, The James Black Center, 125 Coldharbour Lane, London SE5 9NU, UK
- Department of Cardiology, King's College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK
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39
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Sankhala KK, Chawla NS, Chawla SP. Aldoxorubicin for the treatment of advanced soft tissue sarcoma. Expert Opin Orphan Drugs 2015. [DOI: 10.1517/21678707.2015.1018179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Toy R, Bauer L, Hoimes C, Ghaghada KB, Karathanasis E. Targeted nanotechnology for cancer imaging. Adv Drug Deliv Rev 2014; 76:79-97. [PMID: 25116445 PMCID: PMC4169743 DOI: 10.1016/j.addr.2014.08.002] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 07/26/2014] [Accepted: 08/04/2014] [Indexed: 02/02/2023]
Abstract
Targeted nanoparticle imaging agents provide many benefits and new opportunities to facilitate accurate diagnosis of cancer and significantly impact patient outcome. Due to the highly engineerable nature of nanotechnology, targeted nanoparticles exhibit significant advantages including increased contrast sensitivity, binding avidity and targeting specificity. Considering the various nanoparticle designs and their adjustable ability to target a specific site and generate detectable signals, nanoparticles can be optimally designed in terms of biophysical interactions (i.e., intravascular and interstitial transport) and biochemical interactions (i.e., targeting avidity towards cancer-related biomarkers) for site-specific detection of very distinct microenvironments. This review seeks to illustrate that the design of a nanoparticle dictates its in vivo journey and targeting of hard-to-reach cancer sites, facilitating early and accurate diagnosis and interrogation of the most aggressive forms of cancer. We will report various targeted nanoparticles for cancer imaging using X-ray computed tomography, ultrasound, magnetic resonance imaging, nuclear imaging and optical imaging. Finally, to realize the full potential of targeted nanotechnology for cancer imaging, we will describe the challenges and opportunities for the clinical translation and widespread adaptation of targeted nanoparticles imaging agents.
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Affiliation(s)
- Randall Toy
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Lisa Bauer
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Physics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Christopher Hoimes
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA; University Hospitals Case Medical Center, Cleveland, OH 44106, USA
| | - Ketan B Ghaghada
- Edward B. Singleton Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA; Department of Radiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Efstathios Karathanasis
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Radiology, Case Western Reserve University, Cleveland, OH 44106, USA.
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Huang Y, Yang T, Zhang W, Lu Y, Ye P, Yang G, Li B, Qi S, Liu Y, He X, Lee RJ, Xu C, Xiang G. A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo. Int J Nanomedicine 2014; 9:4581-95. [PMID: 25302024 PMCID: PMC4189705 DOI: 10.2147/ijn.s69115] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Instability of targeting ligand is a roadblock towards successful development of folate targeted liposomes. Folate ligands have been linked to polyethylene glycol (PEG) and cholesterol by an amide bond to form folate-CONH-PEG-CONH-Cholesterol (F-CONH-PEG-CONH-Chol), which is subject to hydrolysis. To increase the stability of folate ligands and promote the long circulation and targeting effects, we synthesized a chemically stable lipophilic folate derivative, folate-CONH-PEG-NH-Cholesterol (F-CONH-PEG-NH-Chol), where the amide bond was replaced by a C-N bond, to deliver liposomal doxorubicin (Dox). Its physical stability, cellular uptake, cellular toxicity, pharmacokinetics, distribution, anti-tumor efficacy, and cardiac toxicity were investigated. Our results indicate that F-CONH-PEG-NH-Chol conjugated liposomes are taken up selectively by folate receptor-positive HeLa and KB cells. Compared with F-CONH-PEG-CONH-Chol with two carbonate linkages, F-CONH-PEG-NH-Chol better retained its drug entrapment efficiency and folate receptor-targeting activity during prolonged circulation. F-CONH-PEG-NH-Chol thus represents a physically stable and effective ligand for delivering folate receptor-targeted liposomes, with prolonged circulation time and efficient tissue distribution, as well as higher efficacy and less cardiac toxicity. Collectively, these results suggest that this novel conjugate can serve as a promising derivative for the delivery of anti-tumor therapeutic agents.
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Affiliation(s)
- Yifei Huang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Tan Yang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Wendian Zhang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Yao Lu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Peng Ye
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Guang Yang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Bin Li
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Shibo Qi
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Yong Liu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Xingxing He
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Robert J Lee
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Chuanrui Xu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Guangya Xiang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
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Yang T, Li B, Qi S, Liu Y, Gai Y, Ye P, Yang G, Zhang W, Zhang P, He X, Li W, Zhang Z, Xiang G, Xu C. Co-delivery of doxorubicin and Bmi1 siRNA by folate receptor targeted liposomes exhibits enhanced anti-tumor effects in vitro and in vivo. Am J Cancer Res 2014; 4:1096-111. [PMID: 25285163 PMCID: PMC4173760 DOI: 10.7150/thno.9423] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Accepted: 07/29/2014] [Indexed: 12/12/2022] Open
Abstract
Bmi1 gene overexpression is found in various human tumors and has been shown as a potential target for gene treatment. However, siRNA-based treatments targeting Bmi1 gene have been restricted to limited delivery, low bioavailability and hence relatively reduced efficacy. To overcome these barriers, we developed a folate receptor targeted co-delivery system folate-doxorubicin/Bmi1 siRNA liposome (FA-DOX/siRNA-L). The FA-DOX/siRNA-L was prepared through electrostatic interaction between folate doxorubicin liposome (FA-DOX-L) and Bmi1 siRNA. In vitro and in vivo studies showed that FA-DOX/siRNA-L inhibited tumor growth by combinatory role of Bmi1 siRNA and doxorubicin (DOX). Co-delivery of Bmi1 siRNA and DOX by FA-DOX/siRNA-L showed significantly higher efficacy than sole delivery of either DOX or Bmi1 siRNA. Real-time PCR and western blot analysis showed that FA-DOX/siRNA-L silenced the expression of Bmi1 gene. In addition, higher accumulation of the siRNA and DOX in tumor cells indicated that folate ligand displayed tumor targeting effect. These results suggest that Bmi1 is an effective therapeutic target for siRNA based cancer treatment that can be further improved by co-delivery of DOX through targeted liposomes.
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Toy R, Peiris PM, Ghaghada KB, Karathanasis E. Shaping cancer nanomedicine: the effect of particle shape on the in vivo journey of nanoparticles. Nanomedicine (Lond) 2014; 9:121-34. [PMID: 24354814 DOI: 10.2217/nnm.13.191] [Citation(s) in RCA: 393] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Recent advances in nanoparticle technology have enabled the fabrication of nanoparticle classes with unique sizes, shapes and materials, which in turn has facilitated major advancements in the field of nanomedicine. More specifically, in the last decade, nanoscientists have recognized that nanomedicine exhibits a highly engineerable nature that makes it a mainstream scientific discipline that is governed by its own distinctive principles in terms of interactions with cells and intravascular, transvascular and interstitial transport. This review focuses on the recent developments and understanding of the relationship between the shape of a nanoparticle and its navigation through different biological processes. It also seeks to illustrate that the shape of a nanoparticle can govern its in vivo journey and destination, dictating its biodistribution, intravascular and transvascular transport, and, ultimately, targeting of difficult to reach cancer sites.
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Affiliation(s)
- Randall Toy
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
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CSAPO MELINDA, LAZAR LIVIU. Chemotherapy-Induced Cardiotoxicity: Pathophysiology and Prevention. CLUJUL MEDICAL (1957) 2014; 87:135-42. [PMID: 26528012 PMCID: PMC4508592 DOI: 10.15386/cjmed-339] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Revised: 08/25/2014] [Accepted: 08/29/2014] [Indexed: 01/09/2023]
Abstract
Along with the remarkable progress registered in oncological treatment that led to increased survival of cancer patients, treatment-related comorbidities have also become an issue for these long-term survivors. Of particular interest is the development of cardiotoxic events, which, even when asymptomatic, not only have a negative impact on the patient`s cardiac prognosis, but also considerably restrict therapeutic opportunities. The pathophysiology of cytostatic-induced cardiotoxicity implies a series of complex and intricate mechanisms, whose understanding enables the development of preventive and therapeutic strategies. Securing cardiac function is an ongoing challenge for the pharmaceutical industry and the physicians who have to deal currently with these adverse reactions. This review focuses on the main mechanism of cardiac toxicity induced by anticancer drugs and especially on the current strategies applied for preventing and minimizing the cardiac side effects.
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Affiliation(s)
| | - LIVIU LAZAR
- Faculty of Medicine and Pharmacy, University of Oradea, Romania
- Oradea Municipal Hospital, Romania
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45
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Peiris PM, Toy R, Abramowski A, Vicente P, Tucci S, Bauer L, Mayer A, Tam M, Doolittle E, Pansky J, Tran E, Lin D, Schiemann WP, Ghaghada KB, Griswold MA, Karathanasis E. Treatment of cancer micrometastasis using a multicomponent chain-like nanoparticle. J Control Release 2013; 173:51-8. [PMID: 24188960 DOI: 10.1016/j.jconrel.2013.10.031] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 10/17/2013] [Accepted: 10/25/2013] [Indexed: 12/30/2022]
Abstract
While potent cytotoxic agents are available to oncologists, the clinical utility of these agents is limited due to their non-specific distribution in the body and toxicity to normal tissues leading to use of suboptimal doses for eradication of metastatic disease. Furthermore, treatment of micrometastases is impeded by several biobarriers, including their small size and high dispersion to organs, making them nearly inaccessible to drugs. To circumvent these limitations in treating metastatic disease, we developed a multicomponent, flexible chain-like nanoparticle (termed nanochain) that possesses a unique ability to gain access to and be deposited at micrometastatic sites. Moreover, coupling nanochain particles to radiofrequency (RF)-triggered cargo delivery facilitated widespread delivery of drug into hard-to-reach cancer cells. Collectively, these features synergistically facilitate effective treatment and ultimately eradication of micrometastatic disease using a low dose of a cytotoxic drug.
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Affiliation(s)
- Pubudu M Peiris
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Radiology, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Randall Toy
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Aaron Abramowski
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Pete Vicente
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Samantha Tucci
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Lisa Bauer
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Physics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Aaron Mayer
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Morgan Tam
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Elizabeth Doolittle
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Jenna Pansky
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Emily Tran
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Dishen Lin
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA
| | - William P Schiemann
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Ketan B Ghaghada
- Edward B. Singleton Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA; Department of Radiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mark A Griswold
- Department of Radiology, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Efstathios Karathanasis
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Radiology, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
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Lipshultz SE, Adams MJ, Colan SD, Constine LS, Herman EH, Hsu DT, Hudson MM, Kremer LC, Landy DC, Miller TL, Oeffinger KC, Rosenthal DN, Sable CA, Sallan SE, Singh GK, Steinberger J, Cochran TR, Wilkinson JD. Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation 2013; 128:1927-95. [PMID: 24081971 DOI: 10.1161/cir.0b013e3182a88099] [Citation(s) in RCA: 400] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Peiris PM, Toy R, Doolittle E, Pansky J, Abramowski A, Tam M, Vicente P, Tran E, Hayden E, Camann A, Mayer A, Erokwu BO, Berman Z, Wilson D, Baskaran H, Flask CA, Keri RA, Karathanasis E. Imaging metastasis using an integrin-targeting chain-shaped nanoparticle. ACS NANO 2012; 6:8783-95. [PMID: 23005348 PMCID: PMC3487383 DOI: 10.1021/nn303833p] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
While the enhanced permeability and retention effect may promote the preferential accumulation of nanoparticles into well-vascularized primary tumors, it is ineffective in the case of metastases hidden within a large population of normal cells. Due to their small size, high dispersion to organs, and low vascularization, metastatic tumors are less accessible to targeted nanoparticles. To tackle these challenges, we designed a nanoparticle for vascular targeting based on an α(v)β(3) integrin-targeted nanochain particle composed of four iron oxide nanospheres chemically linked in a linear assembly. The chain-shaped nanoparticles enabled enhanced "sensing" of the tumor-associated remodeling of the vascular bed, offering increased likelihood of specific recognition of metastatic tumors. Compared to spherical nanoparticles, the chain-shaped nanoparticles resulted in superior targeting of α(v)β(3) integrin due to geometrically enhanced multivalent docking. We performed multimodal in vivo imaging (fluorescence molecular tomography and magnetic resonance imaging) in a non-invasive and quantitative manner, which showed that the nanoparticles targeted metastases in the liver and lungs with high specificity in a highly aggressive breast tumor model in mice.
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Affiliation(s)
- Pubudu M. Peiris
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Randall Toy
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Elizabeth Doolittle
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Jenna Pansky
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Aaron Abramowski
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Morgan Tam
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Peter Vicente
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Emily Tran
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Elliott Hayden
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Andrew Camann
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Aaron Mayer
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Bernadette O. Erokwu
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - Zachary Berman
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
| | - David Wilson
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | - Harihara Baskaran
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
- Department of Chemical Engineering, Case Western Reserve University, Cleveland, Ohio
| | - Chris A. Flask
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | - Ruth A. Keri
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
- Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio
| | - Efstathios Karathanasis
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
- Department of Radiology, Case Western Reserve University, Cleveland, Ohio
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
- Author to whom correspondence should be addressed: Efstathios Karathanasis, Wickenden Bldg. MS 7207, 10900 Euclid Ave, Cleveland, Ohio 44106, United States of America, Phone: 216.844.5281; Fax: 216.844.4987;
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Dai W, Yang T, Wang Y, Wang X, Wang J, Zhang X, Zhang Q. Peptide PHSCNK as an integrin α5β1 antagonist targets stealth liposomes to integrin-overexpressing melanoma. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2012; 8:1152-61. [DOI: 10.1016/j.nano.2012.01.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2011] [Revised: 09/17/2011] [Accepted: 01/16/2012] [Indexed: 01/11/2023]
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Pearce TR, Shroff K, Kokkoli E. Peptide targeted lipid nanoparticles for anticancer drug delivery. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2012; 24:3803-22, 3710. [PMID: 22674563 DOI: 10.1002/adma.201200832] [Citation(s) in RCA: 147] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Indexed: 05/21/2023]
Abstract
Encapsulating anticancer drugs in nanoparticles has proven to be an effective mechanism to alter the pharmacokinetic and pharmacodynamic profiles of the drugs, leading to clinically useful cancer therapeutics like Doxil and DaunoXome. Underdeveloped tumor vasculature and lymphatics allow these first-generation nanoparticles to passively accumulate within the tumor, but work to create the next-generation nanoparticles that actively participate in the tumor targeting process is underway. Lipid nanoparticles functionalized with targeting peptides are among the most often studied. The goal of this article is to review the recently published literature of targeted nanoparticles to highlight successful designs that improved in vivo tumor therapy, and to discuss the current challenges of designing these nanoparticles for effective in vivo performance.
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Affiliation(s)
- Timothy R Pearce
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA
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50
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Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE. Cardiotoxicity in childhood cancer survivors: strategies for prevention and management. Future Cardiol 2012; 8:647-70. [PMID: 22871201 PMCID: PMC3870660 DOI: 10.2217/fca.12.44] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Advances in cancer treatment have greatly improved survival rates of children with cancer. However, these same chemotherapeutic or radiologic treatments may result in long-term health consequences. Anthracyclines, chemotherapeutic drugs commonly used to treat children with cancer, are known to be cardiotoxic, but the mechanism by which they induce cardiac damage is still not fully understood. A higher cumulative anthracycline dose and a younger age of diagnosis are only a few of the many risk factors that identify the children at increased risk of developing cardiotoxicity. While cardiotoxicity can develop at anytime, starting from treatment initiation and well into adulthood, identifying the best cardioprotective measures to minimize the long-term damage caused by anthracyclines in children is imperative. Dexrazoxane is the only known agent to date, that is associated with less cardiac dysfunction, without reducing the oncologic efficacy of the anthracycline doxorubicin in children. Given the serious long-term health consequences of cancer treatments on survivors of childhood cancers, it is essential to investigate new approaches to improving the safety of cancer treatments.
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Affiliation(s)
- Danielle Harake
- Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Vivian I Franco
- Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jacqueline M Henkel
- Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Tracie L Miller
- Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA
- Holtz Children's Hospital of the University of Miami/Jackson Memorial Medical Center; Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Steven E Lipshultz
- Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA
- Holtz Children's Hospital of the University of Miami/Jackson Memorial Medical Center; Sylvester Comprehensive Cancer Center, Miami, FL, USA
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