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Biodistribution and Efficacy of Low Temperature-Sensitive Liposome Encapsulated Docetaxel Combined with Mild Hyperthermia in a Mouse Model of Prostate Cancer.

Abstract：

PURPOSE:Low temperature sensitive liposome (LTSL) encapsulated docetaxel were combined with mild hyperthermia (40-42°C) to investigate in vivo biodistribution and efficacy against a castrate resistant prostate cancer. METHOD:Female athymic nude mice with human prostate PC-3 M-luciferase cells grown subcutaneously into the right hind leg were randomized into six groups: saline (+/- heat), free docetaxel (+/- heat), and LTSL docetaxel (+/- heat). Treatment (15 mg docetaxel/kg) was administered via tail vein once tumors reached a size of 200-300 mm(3). Mice tumor volumes and body weights were recorded for up to 60 days. Docetaxel concentrations of harvested tumor and organ/tissue homogenates were determined by LC-MS. Histological evaluation (Mean vessel density, Ki67 proliferation, Caspase-3 apoptosis) of saline, free Docetaxel and LTSL docetaxel (+/- heat n = 3-5) was performed to determine molecular mechanism responsible for tumor cell killing. RESULT:LTSL/heat resulted in significantly higher tumor docetaxel concentrations (4.7-fold greater compared to free docetaxel). Adding heat to LTSL Docetaxel or free docetaxel treatment resulted in significantly greater survival and growth delay compared to other treatments (p < 0.05). Differences in body weight between all Docetaxel treatments were not reduced by >10% and were not statistically different from each other. Molecular markers such as caspase-3 were upregulated, and Ki67 expression was significantly decreased in the chemo-hyperthermia group. Vessel density was similar post treatment, but the heated group had reduced vessel area, suggesting thermal enhancement in efficacy by reduction in functional perfusion. CONCLUSION:This technique of hyperthermia sensitization and enhanced docetaxel delivery has potential for clinical translation for prostate cancer treatment.

journal_name

Pharm Res

journal_title

Pharmaceutical research

authors

Ranjan A,Benjamin CJ,Negussie AH,Chokshi S,Chung PH,Volkin D,Yeram N,Linehan WM,Dreher MR,Pinto PA,Wood BJ

doi

10.1007/s11095-016-1971-8

subject

Has Abstract

pub_date

2016-10-01 00:00:00

pages

2459-69

issue

eissn

0724-8741

issn

1573-904X

pii

10.1007/s11095-016-1971-8

journal_volume

pub_type

杂志文章

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Biodistribution and Efficacy of Low Temperature-Sensitive Liposome Encapsulated Docetaxel Combined with Mild Hyperthermia in a Mouse Model of Prostate Cancer.