Tumor Drug Distribution after Local Drug Delivery by Hyperthermia, In Vivo.

Clemens Bos,Roel Deckers,Chrit Moonen,Kim Van Der Wurff-Jacobs,Angelique Barten-Van Rijbroek,Helena Besse

doi:10.3390/cancers11101512

Abstract

Tumor drug distribution and concentration are important factors for effective tumor treatment. A promising method to enhance the distribution and the concentration of the drug in the tumor is to encapsulate the drug in a temperature sensitive liposome. The aim of this study was to investigate the tumor drug distribution after treatment with various injected doses of different liposomal formulations of doxorubicin, ThermoDox (temperature sensitive liposomes) and DOXIL (non-temperature sensitive liposomes), and free doxorubicin at macroscopic and microscopic levels. Only ThermoDox treatment was combined with hyperthermia. Experiments were performed in mice bearing a human fibrosarcoma. At low and intermediate doses, the largest growth delay was obtained with ThermoDox, and at the largest dose, the largest growth delay was obtained with DOXIL. On histology, tumor areas with increased doxorubicin concentration correlated with decreased cell proliferation, and substantial variations in doxorubicin heterogeneity were observed. ThermoDox treatment resulted in higher tissue drug levels than DOXIL and free doxorubicin for the same dose. A relation with the distance to the vasculature was shown, but vessel perfusion was not always sufficient to determine doxorubicin delivery. Our results indicate that tumor drug distribution is an important factor for effective tumor treatment and that its dependence on delivery formulation merits further systemic investigation.

Highlights

Chemotherapy is one of the main treatment modalities of cancer
Survival was increased with respect to the controls in animals receiving DOX, DOXIL, and ThermoDox treatments, which was significant at doses of 5 and 10 mg/kg
A dose dependent increase in survival was observed after DOX, DOXIL, and ThermoDox treatments with the exception

Summary

Introduction

A commonly used chemotherapeutic agent is doxorubicin, which is used for the treatment of soft tissue sarcoma, among others [1,2,3,4]. Doxorubicin contributes to successful tumor treatment, but it causes serious toxicities in non-tumor tissue, especially in the heart [5,6,7]. These toxicities are a dose limiting factor for doxorubicin and could lead to suboptimal treatment of the tumor and to compromised efficacy [8]. After accumulation of the liposomes in the tumor, the chemotherapeutic agent diffuses from these liposomes over the course of days [13]

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