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Wang T, Wu C, Hu Y, Zhang Y, Ma J. Stimuli-responsive nanocarrier delivery systems for Pt-based antitumor complexes: a review. RSC Adv 2023; 13:16488-16511. [PMID: 37274408 PMCID: PMC10233443 DOI: 10.1039/d3ra00866e] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/30/2023] [Indexed: 06/06/2023] Open
Abstract
Platinum-based anticancer drugs play a crucial role in the clinical treatment of various cancers. However, the application of platinum-based drugs is heavily restricted by their severe toxicity and drug resistance/cross resistance. Various drug delivery systems have been developed to overcome these limitations of platinum-based chemotherapy. Stimuli-responsive nanocarrier drug delivery systems as one of the most promising strategies attract more attention. And huge progress in stimuli-responsive nanocarrier delivery systems of platinum-based drugs has been made. In these systems, a variety of triggers including endogenous and extracorporeal stimuli have been employed. Endogenous stimuli mainly include pH-, thermo-, enzyme- and redox-responsive nanocarriers. Extracorporeal stimuli include light-, magnetic field- and ultrasound responsive nanocarriers. In this review, we present the recent advances in stimuli-responsive drug delivery systems with different nanocarriers for improving the efficacy and reducing the side effects of platinum-based anticancer drugs.
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Affiliation(s)
- Tianshuai Wang
- Hubei Key Lab of Wudang Local Chinese Medicine Research, Hubei University of Medicine Shiyan 442000 Hubei China
- College of Pharmaceutical Sciences, Hubei University of Medicine Shiyan 442000 Hubei China
| | - Chen Wu
- College of Pharmaceutical Sciences, Hubei University of Medicine Shiyan 442000 Hubei China
| | - Yanggen Hu
- Hubei Key Lab of Wudang Local Chinese Medicine Research, Hubei University of Medicine Shiyan 442000 Hubei China
- College of Pharmaceutical Sciences, Hubei University of Medicine Shiyan 442000 Hubei China
| | - Yan Zhang
- College of Pharmaceutical Sciences, Hubei University of Medicine Shiyan 442000 Hubei China
| | - Junkai Ma
- Hubei Key Lab of Wudang Local Chinese Medicine Research, Hubei University of Medicine Shiyan 442000 Hubei China
- College of Pharmaceutical Sciences, Hubei University of Medicine Shiyan 442000 Hubei China
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2
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Wu Q, Chen X, Wang P, Wu Q, Qi X, Han X, Chen L, Meng X, Xu K. Delivery of Arsenic Trioxide by Multifunction Nanoparticles To Improve the Treatment of Hepatocellular Carcinoma. ACS APPLIED MATERIALS & INTERFACES 2020; 12:8016-8029. [PMID: 31997633 DOI: 10.1021/acsami.9b22802] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2023]
Abstract
Arsenic trioxide (ATO) is effective in the treatment of hematological malignancies and solid tumors. However, its toxicity and side effects are severe, posing an obstacle in its clinical application. A controlled-release ATO carrier with mitochondrial targeting was constructed in this study. The safety and efficacy in vitro were investigated using a hemolysis test, cytotoxicity, proliferation, migration, apoptosis, and other changes in cell behavior. The safety and efficacy were further evaluated in vivo by hematoxylin-eosin staining, terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling staining, and blood testing in tumor-bearing mice. Immunohistochemically and western blotting experiments were conducted to explore the mechanism of combination therapy of material-based chemotherapy and microwave hyperthermia in vitro. We demonstrated that the nano-zirconia (ZrO2) loading platform may be used to administer the ATO, with local precision-controlled release and mitochondrial targeting. Furthermore, we showed the safety of this approach for delivering high doses of ATO. In addition, we explored this new method in combination with in vitro microwave heat therapy, providing a potentially novel intravenous approach to chemotherapy. We described a new non-invasive treatment that improved the efficacy of ATO chemotherapy against hepatocellular carcinoma through nano-ZrO2 carriers.
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MESH Headings
- Animals
- Antineoplastic Agents/administration & dosage
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Apoptosis/drug effects
- Arsenic Trioxide/administration & dosage
- Arsenic Trioxide/pharmacology
- Arsenic Trioxide/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Delayed-Action Preparations
- Drug Carriers/chemistry
- Drug Liberation
- Hep G2 Cells
- Humans
- Hyperthermia, Induced/instrumentation
- Hyperthermia, Induced/methods
- Liver Neoplasms/drug therapy
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Male
- Membrane Potential, Mitochondrial/drug effects
- Mice
- Microscopy, Electron, Scanning
- Microscopy, Electron, Transmission
- Mitochondria/drug effects
- Nanoparticles/chemistry
- Nanoparticles/ultrastructure
- Particle Size
- Xenograft Model Antitumor Assays
- Zirconium/chemistry
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Affiliation(s)
- Qirun Wu
- Department of Radiology , The First Affiliated Hospital of China Medical University , Shenyang 110001 , China
| | - Xiaowei Chen
- Department of Radiology , The First Affiliated Hospital of China Medical University , Shenyang 110001 , China
| | - Peng Wang
- Department of Radiology , The First Affiliated Hospital of China Medical University , Shenyang 110001 , China
| | - Qiong Wu
- Laboratory of Controllable Preparation and Application of Nanomaterials, Laboratory of Cryogenics, Technical Institute of Physics and Chemistry , Chinese Academy of Sciences , Beijing 100190 , China
| | - Xun Qi
- Department of Radiology , The First Affiliated Hospital of China Medical University , Shenyang 110001 , China
| | - Xiangjun Han
- Department of Radiology , The First Affiliated Hospital of China Medical University , Shenyang 110001 , China
| | - Lufeng Chen
- Department of Radiology , The First Affiliated Hospital of China Medical University , Shenyang 110001 , China
| | - Xianwei Meng
- Laboratory of Controllable Preparation and Application of Nanomaterials, Laboratory of Cryogenics, Technical Institute of Physics and Chemistry , Chinese Academy of Sciences , Beijing 100190 , China
| | - Ke Xu
- Department of Radiology , The First Affiliated Hospital of China Medical University , Shenyang 110001 , China
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Lapin NA, Krzykawska-Serda M, Dilliard S, Mackeyev Y, Serda M, Wilson LJ, Curley SA, Corr SJ. The effects of non-invasive radiofrequency electric field hyperthermia on biotransport and biodistribution of fluorescent [60]fullerene derivative in a murine orthotopic model of breast adenocarcinoma. J Control Release 2017; 260:92-99. [PMID: 28527736 PMCID: PMC5549922 DOI: 10.1016/j.jconrel.2017.05.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 05/07/2017] [Accepted: 05/16/2017] [Indexed: 01/09/2023]
Abstract
The aim of this study is to understand the combined and differential biokinetic effects of radiofrequency (RF) electric-field hyperthermia as an adjunctive therapy to [60]fullerene nanoparticle-based drug delivery systems in targeting the micro-vasculature and micro-environments of breast cancer tumors. Intravital microscopy (IVM) is an ideal tool to provide the spatial and temporal resolution needed for quantification in this investigation. The water-soluble and fluorescent [60]fullerene derivative (C60-serPF) was designed to be an amphiphilic nanostructure, which is able to cross several biological membranes and accumulate in tumor tissues by passing through abnormally leaky tumor blood vessels. To elucidate the coupled effects of the highly permeable, but heterogeneous tumor vasculature, with the permeabilizing effects of mild (40-42°C) hyperthermia produced by a local RF field, we controlled variables across tumor and non-tumor mammary gland microvasculature with and without application of RF hyperthermia in each condition. We notice that tumor tissue is characterized by more intense drug extravasation than in contralateral mammary fat pad tissue, which is consistent with enhanced permeability and retention (EPR) effects. The analysis of a permeability parameter (Papp), C60-serPF velocity, and the time of compound influx into the intra- and extra-vascular space suggest that mild RF hyperthermia can improve nanoparticle delivery into tumor tissue.
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Affiliation(s)
- Norman A Lapin
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
| | - Martyna Krzykawska-Serda
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków 30-387, Poland
| | - Sean Dilliard
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX 77005, USA
| | - Yuri Mackeyev
- Department of Chemistry, Rice University, Houston, TX 77005, USA
| | - Maciej Serda
- Department of Chemistry, Rice University, Houston, TX 77005, USA; Institute of Chemistry, University of Silesia in Katowice, 40-006 Katowice, Poland
| | - Lon J Wilson
- Department of Chemistry, Rice University, Houston, TX 77005, USA
| | - Steven A Curley
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Mechanical Engineering and Materials Science, Rice University, Houston, TX 77005, USA
| | - Stuart J Corr
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Department of Chemistry, Rice University, Houston, TX 77005, USA; Department of Biomedical Engineering, University of Houston, Houston, TX 77204, USA.
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Lam MK, Oerlemans C, Froeling M, Deckers R, Barten-Van Rijbroek AD, Viergever MA, Moonen CTW, Bos C, Bartels LW. DCE-MRI and IVIM-MRI of rabbit Vx2 tumors treated with MR-HIFU-induced mild hyperthermia. J Ther Ultrasound 2016; 4:9. [PMID: 26981241 PMCID: PMC4791929 DOI: 10.1186/s40349-016-0052-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 02/29/2016] [Indexed: 02/03/2023] Open
Abstract
Background The purpose of this study is to investigate whether changes could be detected in dynamic contrast-enhanced (DCE) and intra-voxel incoherent motion (IVIM) MR parameters upon MR-guided high-intensity focused ultrasound (MR-HIFU)-induced hyperthermia in a rabbit Vx2 tumor model. Methods Five Vx2 tumor-bearing New Zealand white rabbits were treated with hyperthermia using a clinical MR-HIFU system. Data were acquired before and after hyperthermia. For the DCE analysis, the extended Tofts model was used. For the IVIM analysis, a Bayesian approach was used. Maps were reconstructed of the DCE parameters (Ktrans, kep, and vp) and IVIM parameters (Dt, fp, and Dp). Individual parameter histograms and two-dimensional cross-correlation histograms were constructed to analyze changes in the parameters after hyperthermia. Changes in median values were tested for statistical significance with the Mann-Whitney U test. Results The MR temperature measurements confirmed that mild hyperthermia (40 to 42 °C) was successfully achieved in all rabbits. One rabbit died during treatment and was excluded from the analysis. In the remaining four rabbits, an increase in Dt was observed. In three rabbits, an increase in Ktrans was observed, while in the other rabbits, all three DCE parameter values decreased. Mixed changes were seen for vp and fp. Conclusions Changes in DCE and IVIM parameters were detected after hyperthermia and were variable between the rabbits. DCE- and IVIM-MRI may be promising tools to assess tumor responses to hyperthermia. Further research in a larger number of subjects is necessary in order to assess their value for treatment response monitoring.
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Affiliation(s)
- Mie K Lam
- Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Chris Oerlemans
- Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Martijn Froeling
- Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Roel Deckers
- Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Max A Viergever
- Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Chrit T W Moonen
- Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Clemens Bos
- Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Lambertus W Bartels
- Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands
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5
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Yamamoto M, Zager JS. Isolated hepatic perfusion for metastatic melanoma. J Surg Oncol 2013; 109:383-8. [PMID: 24166748 DOI: 10.1002/jso.23474] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Accepted: 09/26/2013] [Indexed: 11/08/2022]
Abstract
Unresectable hepatic metastases from melanoma present a challenge to the physician. Although there have been advances in systemic therapies for patients with metastatic cutaneous melanoma to the liver, the overall prognosis is poor and is worse in patients with metastatic ocular melanoma. Isolated hepatic perfusion, open or percutaneous, allows high doses of cytotoxic chemotherapy to be delivered directly to the liver while minimizing systemic exposure, and has emerged as a viable treatment options for these complex patients.
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Affiliation(s)
- Maki Yamamoto
- Department of Cutaneous Oncology, H. Lee Moffitt Comprehensive Cancer Center, Tampa, Florida
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Wang Q, Huang J, Ma K, Li T, Chen M, Wang S, Bie P, He Z. Evaluation of ghost cell survival in the area of radiofrequency ablation. PLoS One 2012; 7:e53158. [PMID: 23300883 PMCID: PMC3534026 DOI: 10.1371/journal.pone.0053158] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Accepted: 11/26/2012] [Indexed: 12/28/2022] Open
Abstract
Background and Aim Researchers have demonstrated dead cells in radiofrequency ablation (RFA) lesions that have morphological similarities to viable tumor cells and are thus referred to as ghost cells. However, studies on how long ghost cells persist have not been systematically performed. Methods A tumor model was established by implanting VX2 tumor tissue into the livers of 48 New Zealand rabbits. Two weeks later, these tumors were eliminated with RFA. The lesions were resected at 0 weeks, 1 week, 2 weeks, 4 weeks, 8 weeks, or 12 weeks after treatment, and samples were stained either with hematoxylin and eosin (HE) or nicotinamide adenine dinucleotide (NADH). The presence of the cells and the morphological changes that they underwent were examined by light microscopy. Results Four weeks after RFA, there were no obvious morphological changes observed in HE-stained ghost cells, and NADH staining revealed no viable cells. Eight weeks after RFA, the cell structure became indistinct. Twelve weeks after RFA, ghost cells were no longer present. Conclusions The morphological characteristics of ghost cells are maintained for at least 4 weeks, during which time HE staining cannot be used to differentiate ghost cells from residual tumor cells. NADH staining for cell viability is necessary to differentiate residual tumor cells from ghost cells. This evidence adds to our understanding of the mechanisms of RFA when used on solid tumors.
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Affiliation(s)
- Qi Wang
- The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, P. R. China
| | - Jiansheng Huang
- The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, P. R. China
| | - Kuansheng Ma
- The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, P. R. China
- * E-mail:
| | - Tingjun Li
- The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, P. R. China
| | - Ming Chen
- The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, P. R. China
| | - Shugang Wang
- The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, P. R. China
| | - Ping Bie
- The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, P. R. China
| | - Zhenping He
- The Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, P. R. China
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7
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Gormley AJ, Larson N, Sadekar S, Robinson R, Ray A, Ghandehari H. Guided Delivery of Polymer Therapeutics Using Plasmonic Photothermal Therapy. NANO TODAY 2012; 7:158-167. [PMID: 22737178 PMCID: PMC3380374 DOI: 10.1016/j.nantod.2012.04.002] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
In most drug delivery systems the clinician does not have control over the location of drug delivery after the therapeutic has been administered. As the location of the tumor mass is often known in many patients, a therapy system which enables the clinician to play an active role in nanomedicine localization would provide an advantage. Here, we show a new approach wherein a laser can be used to tag tumor tissue and enhance the delivery of targeted polymer therapeutics. Plasmonic gold nanorods are delivered to the cancerous tissue and heated by a laser to promote a targetable, hyperthermic response. Concurrent administration of a heat shock targeted polymer therapeutic thereby enhances site specific delivery.
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Affiliation(s)
- Adam J. Gormley
- Department of Bioengineering, University of Utah, Salt Lake City, UT, 84108, USA
- Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, 84108, USA
| | - Nate Larson
- Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, 84108, USA
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, 84108, USA
| | - Shraddha Sadekar
- Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, 84108, USA
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, 84108, USA
| | - Ryan Robinson
- Department of Bioengineering, University of Utah, Salt Lake City, UT, 84108, USA
- Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, 84108, USA
| | - Abhijit Ray
- Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, 84108, USA
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, 84108, USA
| | - Hamidreza Ghandehari
- Department of Bioengineering, University of Utah, Salt Lake City, UT, 84108, USA
- Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, 84108, USA
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, 84108, USA
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Boone BA, Bartlett DL, Zureikat AH. Isolated Hepatic Perfusion for the Treatment of Liver Metastases. Curr Probl Cancer 2012; 36:27-76. [DOI: 10.1016/j.currproblcancer.2011.12.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Macrì A, Fortugno A, Saladino E. Rationale and techniques of cytoreductive surgery and peritoneal chemohyperthermia. World J Gastrointest Oncol 2011; 3:169-74. [PMID: 22224171 PMCID: PMC3251740 DOI: 10.4251/wjgo.v3.i12.169] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2011] [Revised: 10/29/2011] [Accepted: 11/08/2011] [Indexed: 02/05/2023] Open
Abstract
The evolution of loco-regional treatments has occurred in the last two decades and has deeply changed the natural history of primitive and secondary peritoneal surface malignancies. Several phase II-III studies have proved the effectiveness of the combination of cytoreductive surgery with peritoneal chemohyperthermia. Cytoreductive surgery allows the reduction of the neoplastic mass and increases tumoral chemosensitivity. The development of chemohyperthermia finds its origins in the necessity to exceed the limits of intraperitoneal chemotherapy performed in normothermia. It permits a continuous high concentration gradient of chemotherapeutic drugs between the peritoneal cavity and the plasma compartment to and a more uniform distribution throughout the abdominal cavity compared to systemic administration.
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Affiliation(s)
- Antonio Macrì
- Antonio Macrì, Anna Fortugno, Edoardo Saladino, Department of Human Pathology, General Surgery Unit, University of Messina, 98125 Messina, Italy
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Gormley AJ, Greish K, Ray A, Robinson R, Gustafson JA, Ghandehari H. Gold nanorod mediated plasmonic photothermal therapy: a tool to enhance macromolecular delivery. Int J Pharm 2011; 415:315-8. [PMID: 21669265 DOI: 10.1016/j.ijpharm.2011.05.068] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Revised: 05/17/2011] [Accepted: 05/26/2011] [Indexed: 11/19/2022]
Abstract
Plasmonic photothermal therapy (PPTT) with gold nanostructures has been used to generate significant heat within tumors to ablate vasculature. Here we report the use of gold nanorod (GNR) mediated PPTT to induce moderate hyperthermia as a tool to enhance the delivery of macromolecules. GNRs were injected intravenously in a mouse sarcoma (S-180) tumor model. After 24h Evans blue dye (EBD) was injected and the right tumor was radiated with a laser diode for 10 min. EBD content in the right and left tumors were extracted in formamide, measured spectrophotometrically and expressed as a thermal enhancement ratio (TER). Enhanced delivery of EBD was observed (up to 1.8-fold) when tumor temperatures reached 43°C or 46°C. No statistical difference was observed between tumors at these two temperatures, though significant hemorrhage was observed in tumors and surrounding areas receiving the higher thermal dose (46°C). These results indicate that tumor directed PPTT may be used to induce moderate hyperthermia and therefore selectively increase the delivery of macromolecules with therapeutic anticancer drugs.
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Affiliation(s)
- Adam J Gormley
- Department of Bioengineering, University of Utah, Salt Lake City, UT 84108, USA
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Yang W, Ahmed M, Elian M, Hady ESA, Levchenko TS, Sawant RR, Signoretti S, Collins M, Torchilin VP, Goldberg SN. Do liposomal apoptotic enhancers increase tumor coagulation and end-point survival in percutaneous radiofrequency ablation of tumors in a rat tumor model? Radiology 2010; 257:685-96. [PMID: 20858851 DOI: 10.1148/radiol.10100500] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
PURPOSE To characterize effects of combining radiofrequency (RF) ablation with proapoptotic intravenous liposome-encapsulated paclitaxel and doxorubicin on tumor destruction, apoptosis and heat-shock protein (HSP) production, intratumoral drug accumulation, and end-point survival. MATERIALS AND METHODS R3230 mammary adenocarcinomas (n = 177) were implanted in 174 rats in this animal care committee-approved study. Tumors received (a) no treatment, (b) RF ablation, (c) paclitaxel, (d) RF ablation followed by paclitaxel (RF ablation-paclitaxel), (e) paclitaxel before RF ablation (paclitaxel-RF ablation), (f) RF ablation followed by doxorubicin (RF ablation-doxorubicin), (g) paclitaxel followed by doxorubicin without RF ablation (paclitaxel-doxorubicin), or (h) paclitaxel before RF ablation, followed by doxorubicin (paclitaxel-RF ablation-doxorubicin). Tumor coagulation area and diameter were compared at 24-96 hours after treatment. Intratumoral paclitaxel uptake with and without RF ablation were compared. Immunohistochemical staining revealed cleaved caspase-3 and 70-kDa HSP (HSP70) expression. Tumors were randomized into eight treatment arms for Kaplan-Meier analysis of defined survival end-point (3.0-cm diameter). RESULTS Paclitaxel-RF ablation increased tumor coagulation over RF ablation or paclitaxel (mean, 14.0 mm ± 0.9 [standard deviation], 6.7 mm ± 0.6, 2.5 mm ± 0.6, respectively; P < .001). Paclitaxel-RF ablation-doxorubicin had similar tumor coagulation (P < .05), compared with paclitaxel-RF ablation, at 24 and 96 hours. Mean intratumoral paclitaxel accumulation for paclitaxel-RF ablation (6.76 μg/g ± 0.35) and RF ablation-paclitaxel (9.28 μg/g ± 0.87) increased over that for paclitaxel (0.63 μg/g ± 0.25, P < .001). Paclitaxel substantially increased apoptosis and decreased HSP70 expression at coagulation margin. Mean end-point survival for paclitaxel-RF ablation-doxorubicin (56.8 days ± 25.3) was greater, compared with that for paclitaxel-RF ablation or RF ablation-paclitaxel (17.6 days ± 2.5), RF ablation-doxorubicin (30.3 days ± 4.9, P < .002), or paclitaxel-doxorubicin (27.9 days ± 4.1, P < .001). CONCLUSION Selecting adjuvant liposomal chemotherapies (paclitaxel, doxorubicin) to target cellular apoptosis and HSP production effectively increases RF ablation-induced tumor coagulation and end-point survival, and combined multidrug approach results in even better outcomes. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100500/-/DC1.
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Affiliation(s)
- Wei Yang
- Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA
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12
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Zhai Y, Xie H, Gu H. Effects of hyperthermia with dextran magnetic fluid on the growth of grafted H22 tumor in mice. Int J Hyperthermia 2009; 25:65-71. [DOI: 10.1080/02656730802363643] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Nikfarjam M, Muralidharan V, Christophi C. Mechanisms of Focal Heat Destruction of Liver Tumors. J Surg Res 2005; 127:208-23. [PMID: 16083756 DOI: 10.1016/j.jss.2005.02.009] [Citation(s) in RCA: 255] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2004] [Revised: 01/11/2005] [Accepted: 02/06/2005] [Indexed: 12/12/2022]
Abstract
BACKGROUND Focal heat destruction has emerged as an effective treatment strategy in selected patients with malignant liver tumors. Radiofrequency ablation, interstitial laser thermotherapy, and microwave treatment are currently the most widely applied thermal ablative techniques. A major limitation of these therapies is incomplete tumor destruction and overall high recurrences. An understanding of the mechanisms of tissue injury induced by focal hyperthermia is essential to ensure more complete tumor destruction. Here, the currently available scientific literature concerning the underlying mechanisms involved in the destruction of liver tumors by focal hyperthermia is reviewed. METHODS Medline was searched from 1960 to 2004 for literature regarding the use of focal hyperthermia for the treatment of liver tumors. All relevant literature was searched for further references. RESULTS Experimental evidence suggests that focal hyperthermic injury occurs in two distinct phases. The first phase results in direct heat injury that is determined by the total thermal energy applied, tumor biology, and the tumor microenvironment. Tumors are more susceptible to heat injury than normal cells as the result of specific biological features, reduced heat dissipating ability, and lower interstitial pH. The second phase of hyperthermic injury is indirect tissue damage that produces a progression of tissue injury after the cessation of the initial heat stimulus. This progressive injury may involve a balance of several factors, including apoptosis, microvascular damage, ischemia-reperfusion injury, Kupffer cell activation, altered cytokine expression, and alterations in the immune response. Blood flow modulation and administration of thermosensitizing agents are two methods currently used to increase the extent of direct thermal injury. The processes involved in the progression of thermal injury and therapies that may potentially modulate them remain poorly understood. CONCLUSION Focal hyperthermia for the treatment of liver tumors involves complex mechanisms. Evidence suggests that focal hyperthermia produces both direct and indirect tissue injury by differing underlying processes. Methods to enhance the effects of treatment to achieve complete tumor destruction should focus on manipulating these processes.
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Affiliation(s)
- Mehrdad Nikfarjam
- Department of Surgery, University of Melbourne, Austin Hospital, Melbourne, Victoria, Australia
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Ahmed M, Liu Z, Lukyanov AN, Signoretti S, Horkan C, Monsky WL, Torchilin VP, Goldberg SN. Combination radiofrequency ablation with intratumoral liposomal doxorubicin: effect on drug accumulation and coagulation in multiple tissues and tumor types in animals. Radiology 2005; 235:469-77. [PMID: 15858089 DOI: 10.1148/radiol.2352031856] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
PURPOSE To determine whether use of radiofrequency (RF) ablation combined with intravenously (IV) administered liposomal doxorubicin, as compared with use of RF ablation or doxorubicin alone, facilitates increased tissue coagulation and interstitial drug accumulation in animal models. MATERIALS AND METHODS The institutional animal care and use committee approved this study. In experiment 1, multiple canine sarcomas were implanted in seven mildly immunosuppressed dogs and grown to a mean diameter of 4.8 cm. Tumors were assigned to three treatment groups: internally cooled RF ablation (12 minutes, 2000-mA pulsed technique) followed by IV liposomal doxorubicin (10 mg per animal) (n = 6), RF ablation alone (n = 6), and liposomal doxorubicin alone (n = 4). In experiment 2, the livers and kidneys of 10 rabbits and the thigh muscles of 10 rats were randomly assigned to one of two treatment groups: conventional RF ablation (90 degrees C +/- 2, 5 minutes) followed by IV liposomal doxorubicin (5 mg per rabbit, 1 mg per rat) or RF ablation alone (n = 5, each). Coagulation diameter and interstitial doxorubicin concentration (tissues were homogenized in acid alcohol, with doxorubicin extracted for 24 hours at 5 degrees C and quantified with fluorimetry) were measured 48 hours after treatment and compared. Multivariate analysis of variance and subsequent pairwise t tests (alpha = .05, two-tailed test) were performed. RESULTS Data are means +/- standard errors of the mean. A larger diameter of tumor destruction was observed in canine sarcomas treated with RF ablation-liposomal doxorubicin (3.7 cm +/- 0.6) compared with that in tumors treated with RF ablation (2.3 cm +/- 0.1) or liposomal doxorubicin (0.0 cm +/- 0.0) alone (P < .01). A new finding was a completely necrotic red zone (1.6 cm +/- 0.7) surrounding the central RF ablation-induced white coagulation zone. Greater but nonuniform drug uptake was observed particularly in this red zone (77.0 ng/g +/- 18.2) compared with uptake in the central zone (15.1 ng/g +/- 3.2), peripheral area of untreated tumor (38.9 ng/g +/- 8.0), and tumors treated with liposomal doxorubicin alone (43.9 ng/g +/- 6.7 for all regions) (P < .01 for all individual comparisons). In experiment 2, use of combined therapy led to increased coagulation in all tissues (liver: 17.6 mm +/- 3.1, P = .03; kidney: 11.0 mm +/- 3.1, P = .03; muscle: 13.1 mm +/- 1.3, P < .01) compared with use of RF ablation alone (liver, 13.4 mm +/- 1.5; kidney, 7.9 mm +/- 0.7; muscle, 8.6 mm +/- 0.5). Combined therapy, as compared with liposomal doxorubicin therapy alone, was also associated with increased doxorubicin accumulation in liver, kidney, and muscle (1.56 microg/g +/- 0.34, 4.36 microg/g +/- 1.78, and 3.63 microg/g +/- 1.43, respectively, vs 1.00 microg/g +/- 0.18, 1.23 microg/g +/- 0.32, and 0.87 microg/g +/- 0.53, respectively) (P < or = .01 for all individual comparisons). CONCLUSION Use of RF ablation combined with liposomal doxorubicin facilitates increased tissue coagulation and interstitial doxorubicin accumulation in multiple tissues and tumor types and may be useful for treatment of large tumors and achieving an ablative margin within the untreated tissue surrounding RF ablation-treated tumors.
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MESH Headings
- Animals
- Catheter Ablation
- Chemotherapy, Adjuvant
- Combined Modality Therapy
- Doxorubicin/administration & dosage
- Doxorubicin/pharmacokinetics
- Drug Synergism
- Extracellular Fluid/metabolism
- Injections, Intralesional
- Kidney/drug effects
- Kidney/metabolism
- Kidney/pathology
- Kidney/surgery
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- Liver/surgery
- Muscle, Skeletal/drug effects
- Muscle, Skeletal/metabolism
- Muscle, Skeletal/pathology
- Muscle, Skeletal/surgery
- Necrosis
- Neoplasm Transplantation
- Neoplasms, Multiple Primary/drug therapy
- Neoplasms, Multiple Primary/metabolism
- Neoplasms, Multiple Primary/pathology
- Neoplasms, Multiple Primary/surgery
- Rabbits
- Rats
- Rats, Inbred F344
- Sarcoma, Experimental/drug therapy
- Sarcoma, Experimental/metabolism
- Sarcoma, Experimental/pathology
- Sarcoma, Experimental/surgery
- Soft Tissue Neoplasms/drug therapy
- Soft Tissue Neoplasms/metabolism
- Soft Tissue Neoplasms/pathology
- Soft Tissue Neoplasms/surgery
- Tissue Distribution
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Affiliation(s)
- Muneeb Ahmed
- Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA
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15
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Nikfarjam M, Muralidharan V, Malcontenti-Wilson C, Christophi C. Progressive microvascular injury in liver and colorectal liver metastases following laser induced focal hyperthermia therapy. Lasers Surg Med 2005; 37:64-73. [PMID: 15954121 DOI: 10.1002/lsm.20194] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND AND OBJECTIVES Focal hyperthermia by laser or radiofrequency is currently the preferred method for local ablation of liver tumors. The underlying mechanism of action of focal hyperthermia, in particular the relationship between the microvascular and tissue effect is uncertain and was investigated in a murine model. STUDY DESIGN/MATERIALS AND METHODS Focal hyperthermia produced by a Neodymium-Yttrium-Aluminium-Garnet laser (wavelength 1,064 nm) was applied to the normal liver and colorectal cancer liver metastases in inbred male CBA strain mice at 2 W for 50 seconds (100 J). Tissue injury was assessed at 0, 24, 48, 72, 120, and 168 hours following therapy by measurements of necrosis in tissue sections stained for nicotinamide adenine dinucleotide (NADH) diaphorase activity. Characteristics of microvascular injury were assessed at the various time points by scanning electron microscopy (SEM) of vascular resin casts, Laser Doppler flowmetry, and confocal in vivo microscopy. RESULTS Focal hyperthermia produced progressive tissue and vascular injury. There was an initial reduction in blood flow and increased vascular permeability in the microcirculation of both tumor and liver tissue immediately following heat application as assessed by laser Doppler flowmetry and confocal in vivo microscopy, respectively. SEM of vascular casts showed heterogeneous regions of microvascular injury immediately following heat application. The extent of initial vascular disruption or occlusion on SEM of vascular resin casts (mean+/-SE) was significantly less than the tissue necrosis in liver (1.9+/-0.1 mm vs. 3.0 mm+/-0.2 mm P<0.001), but was equivalent to the tissue injury in tumor tissue (3.5 mm+/-0.2 mm vs. 3.6 mm+/-0.1 mm P = 0.907). This was followed by a progressive increase in both microvascular and tissue injury in liver and tumor that peaked by 72 hours following treatment. The peak microvascular injury and tissue damage in liver (6.6 mm+/-0.2 and 6.3 mm+/-0.2 mm, respectively) was significantly greater than the extent of microvascular and tissue damage in tumors (4.8 mm+/-0.2 mm and 4.5 mm+/-0.2 mm, respectively) (P<0.001). The progression of microvascular injury in liver and tumor at times preceded the tissue injury. CONCLUSION Focal hyperthermia produces both progressive microvascular and tissue damage in liver and colorectal liver metastases. An increase in tissue injury following focal hyperthermia may be a direct result of progressive microvascular damage. Tumor vessels appear more susceptible to direct focal hyperthermia destruction than liver sinusoids. The liver sinusoids are however more susceptible to progressive damage or occlusion following the initial laser thermal stimulus.
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Affiliation(s)
- Mehrdad Nikfarjam
- Department of Surgery, University of Melbourne, Austin Hospital, Lance Townsend Building Level 8, Studley Road, Heidelberg, Melbourne, Victoria 3084, Australia
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16
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Pilati P, Mocellin S, Rossi CR, Ori C, Innocente F, Scalerta R, Ceccherini M, Da Pian PP, Nitti D, Lise M. True versus mild hyperthermia during isolated hepatic perfusion: effects on melphalan pharmacokinetics and liver function. World J Surg 2004; 28:775-81. [PMID: 15457357 DOI: 10.1007/s00268-004-7430-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Hyperthermic antiblastic isolated hepatic perfusion (IHP) with melphalan has been recently proposed as an alternative therapeutic option for patients with unresectable liver tumors. Although melphalan-heat antiblastic synergism is at a maximum at temperatures higher than 41 degrees C, IHP has so far been performed in humans at lower temperatures. In this experimental work, we compared IHP under mild versus true hyperthermic conditions in terms of drug pharmacokinetics and liver function. Ten pigs were submitted to IHP with melphalan 1.5 mg/kg at a mean temperature of 40 degrees C (group A, n = 5) or 42 degrees C (group B, n = 5). After a 60-minute perfusion, a 15-minute washout was performed. Perfusate-to-plasma leakage was monitored using scintigraphy. Throughout perfusion, samples from the systemic blood, perfusate, and liver parenchyma were obtained to measure melphalan concentrations. Liver function was assessed using standard blood tests and the indocyanine green-based test. No deaths related to the IHP procedure were recorded. All animals had transient liver function impairment, with all liver function test results returning to normal within the observation period. At histologic examination, liver damage was similar under both hyperthermic conditions. Melphalan levels in the perfusate were not significantly different in the two study groups (the mean perfusate/plasma area under the curve from 0 to 60 minutes ratios were 463 and 501, respectively). These results correlated well with those obtained using the scintigraphic method. Liver drug concentrations remained unchanged after true hyperthermia IHP. Under true hyperthermic conditions, neither an increase in liver parenchyma toxicity nor changes in melphalan pharmacokinetics were observed. These findings support the use of true hyperthermia in the clinical setting to exploit fully the antitumor synergism between melphalan and heat.
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Affiliation(s)
- Pierluigi Pilati
- Surgery Branch, Department of Oncological and Surgical Sciences, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
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17
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Deraco M, Baratti D, Inglese MG, Allaria B, Andreola S, Gavazzi C, Kusamura S. Peritonectomy and intraperitoneal hyperthermic perfusion (IPHP): a strategy that has confirmed its efficacy in patients with pseudomyxoma peritonei. Ann Surg Oncol 2004; 11:393-8. [PMID: 15070599 DOI: 10.1245/aso.2004.07.002] [Citation(s) in RCA: 127] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Pseudomyxoma peritonei (PMP) is a rare disease with a poor prognosis characterized by a complete redistribution of mucin within the peritoneal cavity. The aim of this multicentric study was to evaluate the survival, morbidity, toxicity, and mortality of patients with PMP treated by cytoreductive surgery (CRS) with intraperitoneal hyperthermic perfusion (IPHP). METHODS Thirty-three patients with PMP (21 males and 12 females) were enrolled in a phase II clinical trial. One patient underwent surgery twice because of disease recurrence. CRS was performed with peritonectomy procedures. The closed abdomen technique was employed for IPHP with use of cisplatin (25 mg/m2/L) plus mitomycin-C (3.3 mg/m2/L) for 60 minutes under hyperthermic conditions (42.5 degrees C). RESULTS Thirty-one patients (92%) were optimally cytoreduced. Five-year overall survival, progression-free survival, and locoregional progression-free survival rates were 97%, 43%, and 59%, respectively. Grade II and grade III morbidity was observed in 5 patient (15%) and 6 patients (18%), respectively. There was one treatment-related death (3%), 21 days after treatment. CONCLUSIONS CRS associated with IPHP permitted complete tumor removal with an acceptable morbidity and mortality for patients with PMP. This study confirms the efficacy of the combined treatment in terms of long-term survival and local disease control.
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Affiliation(s)
- Marcello Deraco
- Department of Surgery, Melanoma and Sarcoma Unit, National Cancer Institute of Milan, Italy.
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18
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de Wilt JHW, van Etten B, Verhoef C, Eggermont AMM. Isolated hepatic perfusion: experimental evidence and clinical utility. Surg Clin North Am 2004; 84:627-41. [PMID: 15062665 DOI: 10.1016/s0039-6109(03)00233-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Many patients with tumors confined to the liver are not amenable for surgical resection, and an increasing number of these patients are treated by local ablation methods. Isolated hepatic perfusion is another treatment option especially suitable for patients with multiple or bulky primary or metastatic tumors. and can mediate clinical regression of advanced liver metastases. Experience with IHP is still limited to a few centers in the world because of its technical difficulties, surgery-related morbidity, and unproven efficacy. IHP remains an experimental modality restricted to specialized units dedicated to treating this difficult group of patients. Experimental animal IHP models have led us to explore new ways of improving efficacy, reducing technical difficulties, and minimizing regional and systemic toxicity. Future research should be directed to the identification of suitable biological or chemotherapeutic agents, defining clinical indications, and development of technical modifications to make it more generally applicable.
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Affiliation(s)
- Johannes H W de Wilt
- Erasmus MC (University Medical Center Rotterdam)-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands
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19
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Deraco M, Casali P, Inglese MG, Baratti D, Pennacchioli E, Bertulli R, Kusamura S. Peritoneal mesothelioma treated by induction chemotherapy, cytoreductive surgery, and intraperitoneal hyperthermic perfusion. J Surg Oncol 2003; 83:147-53. [PMID: 12827682 DOI: 10.1002/jso.10255] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND OBJECTIVES Peritoneal mesothelioma (PM) is a rare disease, with a poor prognosis. We decided to prospectively evaluate the prognostic impact of aggressive surgery followed by intraperitoneal chemotherapy with local hyperthermia. PATIENTS AND METHODS In this prospective study, 19 patients with PM were treated by cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP). Mean follow-up was 27 months (range: 1-65). Fifteen (68%) patients had malignant disease, two had well-differentiated papillary mesothelioma, and two had multicystic PM. Thirteen (65%) patients received preoperative chemotherapy. Fifteen cases (75%) underwent optimal cytoreduction (residual disease <2.5 mm). One patient underwent the procedure twice due to locoregional progression. IPHP was performed with closed abdomen technique, using a preheated polysaline perfusate (42.5 degrees C) containing cisplatin + mitomycin C or cisplatin + doxorubicin administered through a heart-lung pump for 60 or 90 min. RESULTS Three-year overall and progression-free survival was 69 and 66%, respectively. The operative morbidity (grade II/III), mortality, and overall toxicity (grade I-IV) rates were 25, 0, and 30%, respectively. Seventeen (94%) out of 18 patients had resolution of ascites. CONCLUSIONS This therapeutic strategy proved feasible and was well tolerated. Early results seem promising and consistent with a potentially major impact on survival in selected patients with PM.
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Affiliation(s)
- Marcello Deraco
- Department of Surgery, National Cancer Institute of Milan, Milan, Italy.
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20
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Monsky WL, Kruskal JB, Lukyanov AN, Girnun GD, Ahmed M, Gazelle GS, Huertas JC, Stuart KE, Torchilin VP, Goldberg SN. Radio-frequency ablation increases intratumoral liposomal doxorubicin accumulation in a rat breast tumor model. Radiology 2002; 224:823-9. [PMID: 12202721 DOI: 10.1148/radiol.2243011421] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
PURPOSE To determine whether intratumoral accumulation of liposomal doxorubicin or free unencapsulated doxorubicin is increased when combined with radio-frequency (RF) ablation. MATERIALS AND METHODS Two 1.2-1.5-cm R3230 mammary adenocarcinomas were grown within the mammary fat pads of 19 female Fischer rats. One tumor of each pair was treated with RF ablation (tip temperature, 70 degrees C +/- 2 [SD]; 120 mA +/- 75) for 5 minutes, whereas the other tumor was a control. Intravenous liposomal doxorubicin (1 mg in 500 micro L, n = 6) or intravenous free unencapsulated doxorubicin (n = 7) was administered immediately following RF ablation. Doxorubicin was extracted in acid alcohol from tumors 24 hours following RF ablation, and fluorescent spectrophotometry was used to quantify extracted doxorubicin. Comparisons of intratumoral doxorubicin accumulation in tumors treated with RF ablation and in untreated tumors were analyzed with parametric (paired Student t test) and nonparametric (Wilcoxon rank sum test) statistics. Findings at autoradiography with densitometry (six additional tumors) demonstrated the spatial distribution of the intratumoral accumulation of liposomal doxorubicin. RESULTS When RF ablation preceded administration of liposomal doxorubicin, mean intratumoral doxorubicin concentration was 5.6 micro g/g +/- 2.1 (range, 1.9-7.7 micro g/g), whereas 1.0 micro g/g +/- 0.4 (range, 0.5-1.5 micro g/g) was present in control tumors not treated with RF ablation (P <.05). Thus, there was a mean 7.1-fold +/- 4.9 increase in intratumoral doxorubicin accumulation following RF ablation (range, 2.1-14.5-fold) compared with the amount without RF pretreatment (P <.05). Increased intratumoral accumulation was not seen in animals receiving free doxorubicin with (mean, 0.4 micro g/g +/- 0.1) or without (mean, 0.8 micro g/g +/- 0.4) RF pretreatment (P =.07). Autoradiographic findings demonstrated accumulation of liposomal doxorubicin in a peripheral rim of tumor adjacent to the zone of coagulation. CONCLUSION RF ablation augments the delivery of systemic antineoplastic agents such as liposomal doxorubicin.
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Affiliation(s)
- Wayne L Monsky
- Dept of Radiology, Beth Israel Deaconess Med Ctr, Harvard Med School, 330 Brookline Ave, Boston, MA 02215, USA
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21
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Sato T, Kurokawa T, Kusano T, Kato T, Yasui O, Asanuma Y, Koyama K. Uptake of indocyanine green by hepatocytes under inflow occlusion of the liver. J Surg Res 2002; 105:81-5. [PMID: 12121691 DOI: 10.1006/jsre.2002.6378] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND It is not clear that hepatic venous backflow actually contributes to hepatic tissue oxygenation under inflow occlusion of the liver. In order to prove that substances delivered via the hepatic vein can be utilized and/or metabolized in hepatocytes during inflow occlusion, hepatic uptake in bile and excretion of indocyanine green (ICG) were investigated in pigs. MATERIALS AND METHODS Animals were divided into two groups: an inflow occlusion (IO) group (N = 6) and a total hepatic vascular exclusion (THVE) group (N = 3) using a bypass. One milligram of ICG per kilogram body weight was administered at the beginning of blood flow occlusion, the retention rate in the blood (ICG R) measured, and the ICG in the hepatic tissue measured by near-infrared (NIR) spectroscopy. Furthermore, the ICG concentration was measured in bile excreted by intermittent perfusion of the liver. RESULTS ICG R declined with time in both groups; however, ICG R in the IO group decreased much faster than in the THVE group. There were significant differences between the two groups after 30 min of occlusion (P < 0.05). ICG in the hepatic tissue could be detected as a peak at 805 nm 10 min after ICG injection, and the peak became steeper with time. On the other hand, ICG was not detected at all in the hepatic tissue after 180 min in the THVE group. ICG was excreted in the bile after 60 min under IO and increased with time. On the contrary, ICG was not excreted in the bile at all under THVE. There were significant differences between the two groups after 90 min (P < 0.05). CONCLUSION These results indicate that ICG can be extracted in hepatocytes and excreted in bile under IO of the liver. Consequently, substances such as oxygen and drugs, which are delivered via the hepatic vein, can be utilized and/or metabolized in hepatocytes under IO.
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Affiliation(s)
- Tsutomu Sato
- Department of Surgery, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
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22
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Schrump DS, Zhai S, Nguyen DM, Weiser TS, Fisher BA, Terrill RE, Flynn BM, Duray PH, Figg WD. Pharmacokinetics of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques. J Thorac Cardiovasc Surg 2002; 123:686-94. [PMID: 11986596 DOI: 10.1067/mtc.2002.120713] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Although paclitaxel is widely used as a systemic agent for the treatment of solid tumors, limited information is available concerning administration of this taxane by regional techniques. The present study was undertaken to evaluate the pharmacokinetics and acute toxicity of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques to ascertain its potential for the regional therapy of unresectable pulmonary neoplasms. METHODS Adult sheep underwent 90 minutes of retrograde isolated lung perfusion with escalating doses of paclitaxel and moderate hyperthermia using a protein-free, oxygenated extracorporeal circuit and a steady perfusion pressure of 14 to 16 mm Hg. An additional animal received paclitaxel by means of 1-hour central venous infusion. Paclitaxel concentrations in lung tissues, perfusates, and systemic circulation were determined by high-performance liquid chromotography techniques. Cytotoxicity of paclitaxel in cancer cells and in normal human bronchial epithelial cells was evaluated in vitro using 4, 5-dimethylthiazo-2-yl-25-dipagnyl tetrazolium bromide assays. Lung tissues were examined by hematoxylin-and-eosin techniques. RESULTS Paclitaxel concentrations (maximum concentration and area under the plasma concentration time curve) in perfused tissues increased with escalating perfusate doses. Uptake of drug into lung parenchyma appeared saturable at high paclitaxel exposure; a substantial pharmacokinetic advantage was observed. Paclitaxel concentrations in systemic circulation were undetectable or exceedingly low after perfusion. Histopathologic examination of lung tissues harvested 3 hours after completion of isolated lung perfusion revealed no immediate toxicity, even at a paclitaxel exposure 20-fold higher than that achievable after 1 hour of intravenous administration at the maximum tolerable dose in human subjects. Moderate hyperthermia enhanced paclitaxel-mediated cytotoxicity 5- to 100-fold in cultured cancer lines. No paclitaxel toxicity was observed in cultured normal human bronchial epithelial cells after exposure to paclitaxel under normothermic or hyperthermic conditions. CONCLUSIONS These data support further evaluation of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques for the treatment of unresectable malignant pulmonary tumors.
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MESH Headings
- Animals
- Antineoplastic Agents, Phytogenic/administration & dosage
- Antineoplastic Agents, Phytogenic/blood
- Antineoplastic Agents, Phytogenic/pharmacokinetics
- Area Under Curve
- Bronchi/cytology
- Chemotherapy, Cancer, Regional Perfusion
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Epithelial Cells/drug effects
- Humans
- Hyperthermia, Induced/adverse effects
- Infusions, Intravenous
- Lung Neoplasms/blood
- Lung Neoplasms/drug therapy
- Paclitaxel/administration & dosage
- Paclitaxel/blood
- Paclitaxel/pharmacokinetics
- Sheep
- Treatment Outcome
- Tumor Cells, Cultured/drug effects
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Affiliation(s)
- David S Schrump
- Thoracic Oncology Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1502, USA.
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23
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Ceelen WP, Hesse U, de Hemptinne B, Pattyn P. Hyperthermic intraperitoneal chemoperfusion in the treatment of locally advanced intra-abdominal cancer. Br J Surg 2000; 87:1006-15. [PMID: 10931042 DOI: 10.1046/j.1365-2168.2000.01538.x] [Citation(s) in RCA: 81] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Surgical treatment of intra-abdominal cancer is often followed by local recurrence. In a subgroup of patients, local recurrence is the sole site of disease, reflecting biologically low-grade malignancy. These patients might, therefore, benefit from local treatment. Recently, debulking surgery followed by hyperthermic chemoperfusion has been proposed in the treatment of locally advanced or recurrent intra-abdominal cancer. This paper reviews the rationale and assesses the currently accepted indications for and results of this novel treatment. METHODS A systematic web-based literature review was performed. Information was also retrieved from handbooks, congress abstracts and ongoing clinical trials. RESULTS A growing body of experimental evidence supports the use of hyperthermia combined with chemotherapy as an adjunct to cytoreductive surgery. Randomized clinical trials are available to support its use in the treatment and prevention of peritoneal carcinomatosis following resection of pathological tumour stage pT3 or pT4 gastric cancer; several other phase III trials are ongoing. Numerous phase I and II trials have reported good results for various other indications, with acceptable morbidity and mortality rates. Case mix, limited patient numbers and absence of a standardized technique are, however, a drawback in many of these series. CONCLUSION For a subgroup of patients with peritoneal cancer without distant disease, debulking surgery followed by hyperthermic chemoperfusion may offer a chance of cure or palliation in this otherwise untreatable condition. This novel therapy should, however, be considered experimental until further results from ongoing phase III trials become available.
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Affiliation(s)
- W P Ceelen
- Department of Abdominal Surgery 2P4, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium
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