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Theranostics 2016; 6(10):1717-1731. doi:10.7150/thno.14960 This issue Cite

Research Paper

Investigation of Particle Accumulation, Chemosensitivity and Thermosensitivity for Effective Solid Tumor Therapy Using Thermosensitive Liposomes and Hyperthermia

Wouter J.M. Lokerse¹, Michiel Bolkestein¹, Timo L.M. ten Hagen¹, Marion de Jong², Alexander M.M. Eggermont³, Holger Grüll^4,5✉, Gerben A. Koning^{1† #}

1. Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC, Rotterdam, The Netherlands.
2. Departments of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, the Netherlands.
3. Gustave Roussy Cancer Campus Grand Paris, Villejuif Paris, France.
4. Eindhoven University of Technology, Department of Biomedical NMR, Eindhoven, The Netherlands.
5. Philips Research Eindhoven, Department of Oncology Solutions, Eindhoven, The Netherlands
† Deceased 29^th of December 2015.
# Dedicated to Gerben Koning, our friend, colleague and co-author, for his contribution to the field of hyperthermia and liposomal drug delivery. Sadly, much of his dreams remained unfinished.

✉ Corresponding author: Holger Grüll, Den Dolech 2, 5600 MB Eindhoven, Tel: +31 6129 32309 Email: h.gruellnl.

Abstract

Doxorubicin (Dox) loaded thermosensitive liposomes (TSLs) have shown promising results for hyperthermia-induced local drug delivery to solid tumors. Typically, the tumor is heated to hyperthermic temperatures (41-42 °C), which induced intravascular drug release from TSLs within the tumor tissue leading to high local drug concentrations (1-step delivery protocol). Next to providing a trigger for drug release, hyperthermia (HT) has been shown to be cytotoxic to tumor tissue, to enhance chemosensitivity and to increase particle extravasation from the vasculature into the tumor interstitial space. The latter can be exploited for a 2-step delivery protocol, where HT is applied prior to i.v. TSL injection to enhance tumor uptake, and after 4 hours waiting time for a second time to induce drug release. In this study, we compare the 1- and 2-step delivery protocols and investigate which factors are of importance for a therapeutic response. In murine B16 melanoma and BFS-1 sarcoma cell lines, HT induced an enhanced Dox uptake in 2D and 3D models, resulting in enhanced chemosensitivity. In vivo, therapeutic efficacy studies were performed for both tumor models, showing a therapeutic response for only the 1-step delivery protocol. SPECT/CT imaging allowed quantification of the liposomal accumulation in both tumor models at physiological temperatures and after a HT treatment. A simple two compartment model was used to derive respective rates for liposomal uptake, washout and retention, showing that the B16 model has a twofold higher liposomal uptake compared to the BFS-1 tumor. HT increases uptake and retention of liposomes in both tumors models by the same factor of 1.66 maintaining the absolute differences between the two models. Histology showed that HT induced apoptosis, blood vessel integrity and interstitial structures are important factors for TSL accumulation in the investigated tumor types. However, modeling data indicated that the intraliposomal Dox fraction did not reach therapeutic relevant concentrations in the tumor tissue in a 2-step delivery protocol due to the leaking of the drug from its liposomal carrier providing an explanation for the observed lack of efficacy.

Keywords: Drug delivery, hyperthermia, thermosensitive liposome, intravascular drug release, particle accumulation.

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