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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

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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 mm3. 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.

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Abbreviations

DLS:

Dynamic light scattering

DPPC:

Dipalmitoylphosphatidylcholine

DSPE-PEG:

1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]

DSPG:

1,2-dioctadecanoyl-sn-glycero-3-phospho-(1′-rac-glycerol)

DTX:

Docetaxel

H&E:

Hematoxylin & Eosin

IVIS:

In vivo imaging system

LC/MS:

Liquid chromatography–mass spectrometry

LTSL:

Low temperature sensitive liposomes

MSPC:

1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine

PBS:

Phosphate buffered Saline

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ACKNOWLEDGMENTS AND DISCLOSURES

This research was supported by the Center for Interventional Oncology in the Intramural Research Program of the National Institutes of Health (NIH). NIH and Celsion Corp. have a Cooperative Research and Development Agreement. We are grateful for NCI pathology/histotechnology laboratory for their advice and useful discussions. We also thank Apredica inc. for their support and technical expertise in LC/MS.

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Authors and Affiliations

  1. Center for Interventional Oncology, Radiology & Imaging Sciences, Clinical Center, National Institutes of Health, MSC 1182- building 10- room 1c -341, 10 Center Drive, Bethesda, Maryland, 20892, USA

    Ashish Ranjan, Ayele H. Negussie, Matthew R. Dreher & Bradford J. Wood

  2. Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Compton J. Benjamin, Saurin Chokshi, Paul H. Chung, Dmitry Volkin, Nitin Yeram, W. Marston Linehan & Peter A. Pinto

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  1. Ashish Ranjan
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Correspondence to Bradford J. Wood.

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Ranjan, A., Benjamin, C.J., Negussie, A.H. et al. Biodistribution and Efficacy of Low Temperature-Sensitive Liposome Encapsulated Docetaxel Combined with Mild Hyperthermia in a Mouse Model of Prostate Cancer. Pharm Res 33, 2459–2469 (2016). https://doi.org/10.1007/s11095-016-1971-8

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  • DOI: https://doi.org/10.1007/s11095-016-1971-8

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