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Nanohydroxyapatite-Mediated Imatinib Delivery for Specific Anticancer Applications. Molecules 2020; 25:molecules25204602. [PMID: 33050306 PMCID: PMC7587182 DOI: 10.3390/molecules25204602] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/02/2020] [Accepted: 10/07/2020] [Indexed: 12/19/2022] Open
Abstract
In the present study, a nanoapatite-mediated delivery system for imatinib has been proposed. Nanohydroxyapatite (nHAp) was obtained by co-precipitation method, and its physicochemical properties in combination with imatinib (IM) were studied by means of XRPD (X-ray Powder Diffraction), SEM-EDS (Scanning Electron Microscopy-Energy Dispersive X-ray Spectroscopy), FT-IR (Fourier-Transform Infrared Spectroscopy), absorption spectroscopy as well as DLS (Dynamic Light Scattering) techniques. The obtained hydroxyapatite was defined as nanosized rod-shaped particles with high crystallinity. The amorphous imatinib was obtained by conversion of its crystalline form. The beneficial effects of amorphous pharmaceutical agents have been manifested in the higher dissolution rate in body fluids improving their bioavailability. Imatinib-to-hydroxyapatite interactions on the surface were confirmed by SEM images as well as absorption and FT-IR spectroscopy. The cytotoxicity of the system was tested on NI-1, L929, and D17 cell lines. The effectiveness of imatinib was not affected by nHAp modification. The calculated IC50 values for drug-modified nHAp were similar to those for the drug itself. However, higher cytotoxicity was observed at higher concentrations of imatinib, in comparison with the drug alone.
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Ghosh S, Raju RSK, Ghosh N, Chaudhury K, Ghosh S, Banerjee I, Pramanik N. Development and physicochemical characterization of doxorubicin-encapsulated hydroxyapatite–polyvinyl alcohol nanocomposite for repair of osteosarcoma-affected bone tissues. CR CHIM 2019. [DOI: 10.1016/j.crci.2018.10.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Leelakanok N, Geary S, Salem A. Fabrication and Use of Poly(d,l-lactide-co-glycolide)-Based Formulations Designed for Modified Release of 5-Fluorouracil. J Pharm Sci 2017; 107:513-528. [PMID: 29045885 DOI: 10.1016/j.xphs.2017.10.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Revised: 10/03/2017] [Accepted: 10/06/2017] [Indexed: 12/14/2022]
Abstract
5-fluorouracil (5-FU) is a chemotherapeutic agent that has been used for the treatment of a variety of malignancies since its initial introduction to the clinic in 1957. Owing to its short biological half-life, multiple dosings are generally required to maintain effective 5-FU plasma concentrations throughout the therapeutic period. Clinical studies have shown that continuous 5-FU administration is generally superior to bolus injection as exhibited by lower toxicities and increased therapeutic efficacy. Optimal therapeutic efficacy, however, is often compromised by the limiting therapeutic index. Whilst oral formulations are also used, these suffer from the drawbacks of variable bioavailability and first-pass metabolism. As a result, sustained release formulations of 5-FU have been investigated in an effort to mimic the kinetics of continuous infusion particularly for situations where local delivery is considered appropriate. The biocompatible, biodegradable, and highly tunable synthetic polymer, poly(d,l-lactide-co-glycolide) (PLGA), is widely used as a vector for sustained drug delivery, however, issues such as insufficient loading and inappropriate burst release kinetics have dogged progress into the clinic for small hydrophilic drugs such as 5-FU. This review provides introductory information about the mechanism of action, pharmacokinetic and physicochemical properties, and clinical use of 5-FU that have contributed to the development of PLGA-based 5-FU release platforms. In addition, this review provides information on fabrication methods used for a range of 5-FU-loaded PLGA formulations and discusses factors affecting the release kinetics of 5-FU as well as the in vitro and in vivo antitumor or antiproliferative efficacy of these platforms.
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Affiliation(s)
- Nattawut Leelakanok
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, Iowa City, Iowa 52242
| | - Sean Geary
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, Iowa City, Iowa 52242
| | - Aliasger Salem
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, Iowa City, Iowa 52242.
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Khalid A, Mitropoulos AN, Marelli B, Tomljenovic-Hanic S, Omenetto FG. Doxorubicin loaded nanodiamond-silk spheres for fluorescence tracking and controlled drug release. BIOMEDICAL OPTICS EXPRESS 2016; 7:132-47. [PMID: 26819823 PMCID: PMC4722898 DOI: 10.1364/boe.7.000132] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 10/29/2015] [Accepted: 12/06/2015] [Indexed: 05/16/2023]
Abstract
Nanoparticle (NP) based technologies have proved to be considerably beneficial for advances in biomedicine especially in the areas of disease detection, drug delivery and bioimaging. Over the last few decades, NPs have garnered interest for their exemplary impacts on the detection, treatment, and prevention of cancer. The full potential of these technologies are yet to be employed for clinical use. The ongoing research and development in this field demands single multifunctional composite materials that can be employed simultaneously for drug delivery and biomedical imaging. In this manuscript, a unique combination of silk fibroin (SF) and nanodiamonds (NDs) in the form of nanospheres are fabricated and investigated. The spheres were loaded with the anthracyline Doxorubicin (DoX) and the drug release kinetics for these ND-SF-DoX (NDSX) spheres were studied. NDs provided the fluorescence modality for imaging while the degradable SF spheres stabilized and released the drug in a controlled manner. The emission and structural properties of the spheres were characterized during drug release. The degradability of SF and the subsequent release of DoX from the spheres were monitored through fluorescence of NDs inside the spheres. This research demonstrates the enormous potential of the ND-SF nanocomposite platforms for diagnostic and therapeutic purposes, which are both important for pharmaceutical research and clinical settings.
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Affiliation(s)
- Asma Khalid
- School of Physics, University of Melbourne, Melbourne, VIC 3010, Australia;
| | | | - Benedetto Marelli
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA
| | | | - Fiorenzo G Omenetto
- Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA;
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Ivić JT, Dimitrijević A, Milosavić N, Bezbradica D, Drakulić BJ, Jankulović MG, Pavlović M, Rogniaux H, Veličković D. Assessment of the interacting mechanism between Candida rugosa lipases and hydroxyapatite and identification of the hydroxyapatite-binding sequence through proteomics and molecular modelling. RSC Adv 2016. [DOI: 10.1039/c6ra07521e] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Hydroxyapatite (HAP), a calcium-phosphate bioactive ceramic, is actively employed in medical and separation sciences.
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Affiliation(s)
| | - Aleksandra Dimitrijević
- Department of Molecular Biology and Biochemistry
- University of California Irvine
- 92697 Irvine
- USA
| | - Nenad Milosavić
- Division of Experimental Therapeutics
- Department of Medicine
- Columbia University
- 10032 New York
- USA
| | - Dejan Bezbradica
- Department of Biochemical Engineering and Biotechnology
- Faculty of Technology and Metallurgy
- 11000 Belgrade
- Serbia
| | - Branko J. Drakulić
- Department of Chemistry
- Institute of Chemistry
- Technology and Metallurgy
- University of Belgrade
- Belgrade
| | | | - Marija Pavlović
- INRA
- UR1268
- Biopolymers Interactions Assembles
- 44316 Nantes
- France
| | - Helene Rogniaux
- INRA
- UR1268
- Biopolymers Interactions Assembles
- 44316 Nantes
- France
| | - Dušan Veličković
- Department of Biochemistry
- Faculty of Chemistry
- 11000 Belgrade
- Serbia
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Samantara AK, Maji S, Ghosh A, Bag B, Dash R, Jena BK. Good's buffer derived highly emissive carbon quantum dots: excellent biocompatible anticancer drug carrier. J Mater Chem B 2016; 4:2412-2420. [DOI: 10.1039/c6tb00081a] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A facile one-step approach has been developed for the synthesis of carbon quantum dots (CQDs) from Good’s buffer.
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Affiliation(s)
- Aneeya K. Samantara
- CSIR-Institute of Minerals and Materials Technology
- Bhubaneswar 751013
- India
- Academy of Scientific & Innovative Research (AcSIR)
- New Delhi-110 001
| | - Santanu Maji
- Institute of Life Sciences
- Bhubaneswar 751023
- India
- Manipal University
- India
| | | | - Bamaprasad Bag
- CSIR-Institute of Minerals and Materials Technology
- Bhubaneswar 751013
- India
- Academy of Scientific & Innovative Research (AcSIR)
- New Delhi-110 001
| | - Rupesh Dash
- Institute of Life Sciences
- Bhubaneswar 751023
- India
| | - Bikash Kumar Jena
- CSIR-Institute of Minerals and Materials Technology
- Bhubaneswar 751013
- India
- Academy of Scientific & Innovative Research (AcSIR)
- New Delhi-110 001
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Jassal M, Sengupta S, Bhowmick S. Functionalization of electrospun poly(caprolactone) fibers for pH-controlled delivery of doxorubicin hydrochloride. JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION 2015; 26:1425-38. [DOI: 10.1080/09205063.2015.1100495] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Li K, Wang S, Wen S, Tang Y, Li J, Shi X, Zhao Q. Enhanced in vivo antitumor efficacy of doxorubicin encapsulated within laponite nanodisks. ACS APPLIED MATERIALS & INTERFACES 2014; 6:12328-12334. [PMID: 25000274 DOI: 10.1021/am502094a] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Development of various nanoscale drug carriers for enhanced antitumor therapy still remains a great challenge. In this study, laponite (LAP) nanodisks encapsulated with anticancer drug doxorubicin (DOX) at an exceptionally high loading efficiency (98.3 ± 0.77%) were used for tumor therapy applications. The long-term in vivo antitumor efficacy and toxicology of the prepared LAP/DOX complexes were analyzed using a tumor-bearing mouse model. Long-term tumor appearance, normalized tumor volume, CD31 staining, and hematoxylin and eosin (H&E)-stained tumor sections were used to evaluate the tumor therapy efficacy, while long-term animal body weight changes and H&E-stained tissue sections of different major organs were used to evaluate the toxicology of LAP/DOX complexes. Finally, the in vivo biodistribution of magnesium ions and DOX in different organs was analyzed. We showed that under the same DOX concentration, LAP/DOX complexes displayed enhanced tumor inhibition efficacy and afforded the treated mice with dramatically prolonged survival time. In vivo biodistribution data revealed that the reticuloendothelial systems (especially liver) had significantly higher magnesium uptake than other major organs, and the LAP carrier was able to be cleared out of the body at 45 days post treatment. Furthermore, LAP/DOX afforded a higher DOX uptake in the tumor region than free DOX, presumably due to the known enhanced permeability and retention effect. The developed LAP-based drug delivery system with an exceptionally high DOX payload, enhanced in vivo antitumor efficacy, and low systemic toxicity may be used as a promising platform for enhanced tumor therapy.
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Affiliation(s)
- Kai Li
- Department of Orthopaedics, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200080, China
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Wang S, Wu Y, Guo R, Huang Y, Wen S, Shen M, Wang J, Shi X. Laponite nanodisks as an efficient platform for Doxorubicin delivery to cancer cells. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2013; 29:5030-5036. [PMID: 23419072 DOI: 10.1021/la4001363] [Citation(s) in RCA: 161] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
We report a facile approach to using laponite (LAP) nanodisks as a platform for efficient delivery of doxorubicin (DOX) to cancer cells. In this study, DOX was encapsulated into the interlayer space of LAP through an ionic exchange process with an exceptionally high loading efficiency of 98.3 ± 0.77%. The successful DOX loading was extensively characterized via different methods. In vitro drug release study shows that the release of DOX from LAP/DOX nanodisks is pH-dependent, and DOX is released at a quicker rate at acidic pH condition (pH = 5.4) than at physiological pH condition. Importantly, cell viability assay results reveal that LAP/DOX nanodisks display a much higher therapeutic efficacy in inhibiting the growth of a model cancer cell line (human epithelial carcinoma cells, KB cells) than free DOX drug at the same DOX concentration. The enhanced antitumor efficacy is primarily due to the much more cellular uptake of the LAP/DOX nanodisks than that of free DOX, which has been confirmed by confocal laser scanning microscope and flow cytometry analysis. The high DOX payload and enhanced antitumor efficacy render LAP nanodisks as a robust carrier system for different biomedical applications.
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Affiliation(s)
- Shige Wang
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Donghua University, Shanghai 201620, People's Republic of China
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Zheng F, Wang S, Shen M, Zhu M, Shi X. Antitumor efficacy of doxorubicin-loaded electrospun nano-hydroxyapatite–poly(lactic-co-glycolic acid) composite nanofibers. Polym Chem 2013; 4:933-941. [DOI: 10.1039/c2py20779f] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
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11
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Zhu Y, Shang F, Li B, Dong Y, Liu Y, Lohe MR, Hanagata N, Kaskel S. Magnetic mesoporous bioactive glass scaffolds: preparation, physicochemistry and biological properties. J Mater Chem B 2013; 1:1279-1288. [DOI: 10.1039/c2tb00262k] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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12
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Zamoume O, Thibault S, Regnié G, Mecherri MO, Fiallo M, Sharrock P. Macroporous calcium phosphate ceramic implants for sustained drug delivery. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2011. [DOI: 10.1016/j.msec.2011.04.020] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Pinto OA, Tabaković A, Goff TM, Liu Y, Adair JH. Calcium Phosphate and Calcium Phosphosilicate Mediated Drug Delivery and Imaging. INTRACELLULAR DELIVERY 2011. [DOI: 10.1007/978-94-007-1248-5_23] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Hu J, Liu ZS, Tang SL, He YM. Effect of hydroxyapatite nanoparticles on the growth and p53/c-Myc protein expression of implanted hepatic VX 2 tumor in rabbits by intravenous injection. World J Gastroenterol 2007; 13:2798-802. [PMID: 17569114 PMCID: PMC4395630 DOI: 10.3748/wjg.v13.i20.2798] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effect of hydroxyapatite nano-particles (Nano HAP) by intravenous injection on the inhibition of implanted hepatic VX2 tumor growth in rabbits and cell p53/c-Myc protein expression.
METHODS: 60 hepatic VX2 tumor-bearing rabbits was randomly divided into five groups. Nano HAP collosol 20 mg/kg, 40 mg/kg, 5-FU solutions 20 mg/mL, mixed liquor of 5-FU solution 20 mg/mL and Nano HAP collosol 20 mg/kg were infused by vein, normal saline conducted as the control. The general state, weight, liver function and gross tumor volume were detected dynamically. The expression of p53 and c-Myc gene protein in tumor tissue was detected by immunohistochemistry methods.
RESULTS: The growth of implanted hepatic VX2 tumors was significantly inhibited in all therapy groups, 3 wk after the injection, the tumor control rates in Nano HAP collosol groups were 25.5% and 32.5% respectively, and the gross tumor volumes were obviously less than that of control group. (24.81 ± 5.17 and 22.73 ± 4.23 vs 33.32 ± 5.26, P < 0.05). The tumor control rate of 5-FU group was 43.7% (18.74 ± 4.40 vs 33.32 ± 5.26, P < 0.05), but the general state of the animals after injection aggravated; and the adverse reaction in the drug combination group obviously decreased. Due to the effect of Nano HAP, the positive expression of tumor associated the mutated p53 and c-Myc in tumor tissue was decreased obviously compared with the control group.
CONCLUSION: Nano HAP has evident inhibitory action on rabbit implanted hepatic VX2 tumor in vivo, which may be the result of decreasing the expression of the mutated p53 and c-myc, and drug combination can obviously decrease the adverse reaction of 5-FU.
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Affiliation(s)
- Jun Hu
- Department of General Surgery, Zhongnan Hospital, Wuhan University, Wuhan 430071, Hubei Province, China
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15
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Sreedhar B, Aparna Y, Sairam M, Hebalkar N. Preparation and characterization of HAP/carboxymethyl chitosan nanocomposites. J Appl Polym Sci 2007. [DOI: 10.1002/app.26140] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Sunny MC, Ramesh P, Varma HK. Microstructured microspheres of hydroxyapatite bioceramic. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2002; 13:623-632. [PMID: 15348570 DOI: 10.1023/a:1015709705074] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Hydroxyapatite (HAP) particles having spherical geometry and 125-1000 microm in size range were prepared using a solid-in-water-in-oil (S/W/O) emulsion, cross-linking technique. An aqueous solution of chitosan containing different loading of HAP was dispersed as droplet in liquid paraffin using a stabilizing agent. Cross-linking of chitosan was induced by adding appropriate amount of glutaraldehyde saturated toluene. Chitosan microspheres containing HAP were sintered at 1150 degrees C to obtain pure HAP microspheres. The spheres thus produced were examined by scanning electron microscopy. The percentage yield and size distributions of the spheres were also determined.
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Affiliation(s)
- M C Sunny
- Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Poojappura, Thiruvananthapuram - 695 012, India.
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Gnant MF, Noll LA, Terrill RE, Wu PC, Berger AC, Nguyen HQ, Lans TE, Flynn BM, Libutti SK, Bartlett DL, Alexander HR. Isolated hepatic perfusion for lapine liver metastases: impact of hyperthermia on permeability of tumor neovasculature. Surgery 1999. [PMID: 10568189 DOI: 10.1016/s0039-6060(99)70030-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND Hyperthermic isolated hepatic perfusion (IHP) has been shown to cause significant regression of advanced unresectable liver metastases in patients. Although there are different agents and treatment modalities used in IHP, the contribution of perfusion hyperthermia is unknown. PURPOSE A large animal model of unresectable liver metastases and a technical standard for IHP in this model were established. This model was used to assess the effects of hyperthermia on vascular permeability of tumors and normal liver tissue during IHP. METHODS Sixty-five New Zealand White rabbits were used in a series of experiments. Disseminated liver tumors were established by direct injection of 1 x 10(6) VX-2 cells into the portal vein by laparotomy in anesthetized animals. Several surgical perfusion techniques were explored to determine a reliable and reproducible IHP model. Vascular permeability in tumor versus liver was then assessed with Evan's Blue labeled bovine albumin under normothermic (tissue temperature 36.5 degrees C +/- 0.5 degree C), moderate hyperthermic (39 degrees C +/- 0.5 degree C), or severe hyperthermic (41 degrees C +/- 0.5 degree C) conditions. RESULTS Tumor model and perfusion techniques were successfully established with inflow through the portal vein and outflow through an isolated segment of the inferior vena cava. A gravity driven perfusion circuit with stable perfusion parameters and complete vascular isolation was used. Vascular permeability was higher in tumor than in normal tissues (P = .03) at all time points during IHP. Hyperthermia resulted in a significant (up to 5-fold) increase in permeability of neovasculature; when severe hyperthermia was used, tumor vascular permeability was increased even more than normal liver permeability (P = .01). CONCLUSIONS The VX-2/New Zealand White rabbit system can be used as a reproducible large-animal model for IHP of unresectable liver metastases. It can be used to characterize the contribution and mechanism of action of different treatment parameters used in IHP. Hyperthermia preferentially increases vascular permeability in tumors compared with liver tissue in a dose-dependent fashion, thus providing a mechanism for its presumed benefit during isolated organ perfusion.
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Affiliation(s)
- M F Gnant
- Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Gnant MF, Noll LA, Irvine KR, Puhlmann M, Terrill RE, Alexander HR, Bartlett DL. Tumor-specific gene delivery using recombinant vaccinia virus in a rabbit model of liver metastases. J Natl Cancer Inst 1999; 91:1744-50. [PMID: 10528025 DOI: 10.1093/jnci/91.20.1744] [Citation(s) in RCA: 49] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Several approaches to gene therapy for cancer have yielded promising results in rodent models. The translation of these results to the clinical realm has been delayed by the lack of tumor models in large animals. We investigated the pattern of transgene (i. e., foreign or introduced gene) expression and virus vector elimination after systemic gene delivery using a thymidine kinase-negative vaccinia virus in a rabbit model of disseminated liver metastases. METHODS VX-2 rabbit carcinoma cells were maintained by serial transplantation in the thigh muscles of New Zealand White rabbits, and disseminated liver metastases were established by direct injection of tumor cells into the portal vein of the animals. Different doses of a recombinant thymidine kinase-negative vaccinia virus vector encoding the firefly luciferase reporter gene (i.e., transgene) were injected into tumor-bearing rabbits. Transgene activity in tumors and other organs was measured at multiple time points thereafter. The pattern of development of antibodies against the vaccinia virus vector was also examined. Two-tailed Student's paired t test was used for comparisons of transgene activity. RESULTS Transgene expression was increased in tumors by at least 16-fold in comparison with expression in other tissues by day 4 after vector injection (all P<. 001) and was maintained for approximately 1 week, providing evidence of tumor-specific gene delivery in this model. Rapid elimination of the circulating vector by the host immune system was observed. Anti-vector antibodies were detectable in serum as early as day 6 and were maintained for more than 3 months. CONCLUSIONS Tumor-specific gene delivery is possible after systemic injection of a thymidine kinase-negative vaccinia virus vector in a model of rabbit liver metastases. Although the period of transgene expression appears limited because of a rapid immune response, the therapeutic window might be sufficient for an enzyme/prodrug gene therapy approach in clinical application.
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Affiliation(s)
- M F Gnant
- Surgery Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD, USA
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Itokazu M, Kumazawa S, Wada E, Wenyi Y. Sustained release of adriamycin from implanted hydroxyapatite blocks for the treatment of experimental osteogenic sarcoma in mice. Cancer Lett 1996; 107:11-8. [PMID: 8913261 DOI: 10.1016/0304-3835(96)04337-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A sustained-release drug delivery system was developed using a hydroxyapatite (HA) block loaded with adriamycin (ADR) by cenrifugation. Release of ADR was sustained for 66 days in vitro and for 4 weeks in vivo following intramuscular implantation in mice. ADR concentrations in plasma, liver, and kidney were from 0.25% to 10% of that at the implantation site. ADR-HA blocks implanted into osteogenic sarcomas in mice markedly inhibited tumor growth. This drug delivery system provides sustained release of the cancer chemotherapeutic agent and may prove useful for treating malignant tumours while minimising systemic side effects.
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Affiliation(s)
- M Itokazu
- Department of Orthopaedic Surgery, Gifu University School of Medicine, Japan
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Anderson JH, Warren HW, McArdle CS. Clinical pharmacokinetic advantages of new drug delivery methods for the treatment of liver tumours. Clin Pharmacokinet 1994; 27:191-201. [PMID: 7988101 DOI: 10.2165/00003088-199427030-00003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Response rates following systemic chemotherapy for hepatic tumours are disappointing. The drugs used have a narrow therapeutic ratio, which limit the scope for dose escalation of these potentially toxic agents. Therefore, alternative delivery methods that optimise the efficacy of currently available cytotoxic agents have been explored. Several novel approaches have attempted to 'target' treatment so that it reaches the tumour whilst minimising systemic exposure. There is some evidence to suggest that certain agents, including monoclonal antibodies and liposomes, selectively lodge in tumours following intravenous administration. Alternatively, the route of administration may be modified to enhance targeting of the administered drug. Delivery via the hepatic arterial, portal venous, and peritoneal routes as well as drug delivery via direct implantation may provide certain pharmacokinetic advantages. Infusion rates may be adjusted to optimise the pharmacokinetic profile. Chemoembolisation with microspheres, microcapsules or macromolecules might enhance targeting further. Variations in particle characteristics or by modifying hepatic arterial blood flow with vasoactive substances may be used to further refine this technique. The ultimate 'magic bullet', which allows total delivery of treatment to malignant cells whilst eliminating exposure of healthy tissues to these toxic agents, has not been developed as yet. However, currently available techniques allow considerable dose escalation that, whilst not providing a significant survival advantage, certainly improves response rates.
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Affiliation(s)
- J H Anderson
- University Department of Surgery, Royal Infirmary, Glasgow, Scotland
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