Tumor-stromal opening via S. typhimurium VNP20009 administration for complete inhibition of refractory tumor growth with liposomal anticancer drugs

Abstract

Many clinical tumors exhibit a vascular endothelium covered by mural cells and stroma with abundant collagen fibers, which greatly inhibit the penetration of nanoparticle drug delivery systems (DDS) formulations deep into the tumors. We previously found that Salmonella typhimurium VNP20009 attracting attention as live bacterial therapeutics, which is a novel pharmaceutical modality for cancer treatment, can grow within deep tumors with abundant stroma and tight vasculature. Because this finding interestingly indicates that VNP20009 administration disrupts vascular and stromal structures even in refractory tumors, we investigated the possibility that VNP20009 administration improves DDS formulations migrations into tumors in this study. VNP20009 co-administration drastically improved the translocation and diffusion of liposomes deep into the tumors, particularly in stroma-rich xenografted tumors, indicating its tumor stromal opening ability. Furthermore, this approach can completely inhibit tumors in various refractory tumor models, including pancreatic cancers, using liposomal doxorubicin (Doxil®) and liposomal irinotecan (Onivyde®). Notably, this remarkable anticancer effect is not simply attributed to the therapeutic effects of liposomal anticancer drugs and VNP20009, but it involves an additional effect, improving the intratumor pharmacokinetics of liposomal anticancer drugs following VNP20009 co-administration. The unique tumor stromal opening ability of VNP20009 demonstrated in this study is a promising strategy for resolving the major challenges faced by tumor DDS.