Targeted Nano Sized Drug Delivery to Heterogeneous Solid Tumor Microvasculatures: Implications for Immunoliposomes Exhibiting Bystander Killing Effect

Abstract

Targeted drug delivery to cancer cells utilizing antibodies against oncogenic cell-surface receptors is an emerging therapeutical approach. Here, we developed a computational framework to evaluate the treatment efficacy of free Doxorubicin (Dox) and immunoliposome at different stages of vascular solid tumors. Firstly, three stages of vascularized tumors with different microvascular densities (MVDs) are generated using mathematical modeling of tumor-induced angiogenesis. Secondly, the fluid flow in vascular and interstitial spaces is calculated. Ultimately, convection-diffusion-reaction equations governing on classical chemotherapy (stand-alone Dox) and immunochemotherapy (drug-loaded nanoparticles) are separately solved to calculate the spatiotemporal concentrations of different therapeutic agents. The present model considers the key processes in targeted drug delivery, including association/disassociation of payloads to cell receptors, cellular internalization, linker cleavage, intracellular drug release, and bystander-killing effect. Our results show that reducing MVD decreases the interstitial fluid pressure, allowing higher rates of the drug to enter the tumor microenvironment. Also, immunoliposomes exhibiting bystander-killing effect yield higher drug internalization, which supports a higher intracellular Dox concentration during immunochemotherapy. Bystander-killing effect alongside intracellular Dox release and persistence of immunoliposomes within tumor over a longer period lead to more homogeneous drug distribution and a much greater fraction of killed cancer cells than classical chemotherapy. Our findings also demonstrate drug transport at tumor microvascular networks is increased by decreasing MVD, leading to better treatment outcomes. Present results can be used to improve the treatment efficacy of drug delivery at different stages of vascular tumors.