Abstract
To elucidate the determinants of the in vivo anti-tumor efficacy of oxaliplatin-containing PEG-coated liposomes, we examined its anti-tumor activity using three different in vivo tumor models. We demonstrate that tumor vascular permeability varies significantly among the different tumor types and substantially affects the tumor accumulation of PEG-coated liposomes, consequently, affects the in vivo therapeutic efficacy of liposomal oxaliplatin.
The delivery of anticancer agents to solid tumors is problematic. Nanomolecular drug carriers represent an attractive alternative strategy for efficient anticancer drug delivery to tumor tissue, because they appear to target tumors and have limited toxicity in normal tissue. However, inadequate and heterogeneous distribution of nanocarriers in tumor tissue is a major impediment for their efficient use in clinical cancer therapy. In the present study, we examined the effect of tumor type on the intratumor accumulation and distribution of polyethylene glycol (PEG)-coated liposomes using in vivo mouse models of three cancer cell lines: colon adenocarcinoma (C26), Lewis lung carcinoma (LLC), and B16BL6 melanoma (B16BL6). The tumor growth inhibition and the apoptotic response of oxaliplatin (l-OHP) encapsulated in the PEG-coated liposomes were tumor type dependent and correlated with a tendency toward tumor accumulation and intratumor distribution of PEG-coated liposome, in contrast to in vitro cytotoxicity of l-OHP. A potent antitumor effect observed in both C26 and LLC tumor-bearing mice was attributed to the enhanced extravasation with subsequent preferential accumulation of PEG-coated liposomes through tumor vasculature with high permeability. Our results suggest that the permeability of tumor vasculature constitutes a potential impediment to tumor localization and thereby to the antitumor efficacy of PEG-coated liposomal anticancer drugs.