Abstract 2317: Mild hyperthermia and thermosensitive liposomes to improve chemotherapy delivery to solid tumors

Abstract

Abstract Long circulating liposomes are potent nanocarriers for the delivery of chemotherapeutic drugs to tumors. These liposomes can extravasate through leaky tumor microvasculature, and accumulate in the intratumoral space. However, inefficient drug release impairs efficacy, and hinders a successful application. Local hyperthermia (HT) can augment drug bioavailability and treatment efficacy by enhancing tumor vessel leakage for intratumoral liposomal drug accumulation, and triggering drug release from thermosensitive liposomes (TSL). Our study explored the thermal dose to maximize the permeability of tumor microvasculature for liposome extravasation and sequentially trigger drug release from the TSL in a two-step approach. We have optimized long-circulating TSL to improve content release efficiency under mild HT (Li et al. J Control Release 143(2):274-9, 2010). Doxorubicin (Dox) at a quenching concentration was encapsulated in TSL. In vitro temperature/time-dependent content release and TSL stability in serum were quantified by fluorometry. In vivo liposome extravasation was studied in dorsal skin flap window chamber models implanted with murine B16 melanoma, LLC carcinoma, BFS-1 sarcoma, and human BLM melanoma tumors in mice with constitutive vascular endothelial cell expression of an eNOS-Tag-GFP fusion protein using confocal microscopy. In vivo Dox release was observed in the same window chamber models. Mild HT induced a significant amount of liposome extravasation through tumor microvasculature, and intratumoral accumulation in the interstitial space in all tumor models. Minimum thermal dose of 41 °C for 30 min is required to open up tumor vessels. The permeability of tumor vessels increased over time with increasing thermal dose to 41 °C for 1 hr, and vasculature remained leaky for up to 8 hr post-HT. Increased permeability was not observed in heated normal vasculature or in non-heated tumor vasculature. Optimized Dox-TSL were stable at 37 °C and demonstrated efficient in vitro and in vivo drug release at 42 °C. Rapid intratumoral distribution of released Dox and delivery into tumor cells was observed, demonstrating strongly improved drug bioavailability. The superior application of TSL and mild HT will achieve both maximal intratumoral liposomal drug accumulation and rapid triggered drug release to aid liposomal chemotherapy in clinical practice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2317. doi:10.1158/1538-7445.AM2011-2317