Targeting tumor vasculature and microenvironment for nanomedicine

Targeting tumor vasculature and microenvironment for nanomedicine

Blood vessels in solid tumors have abnormal and heterogeneous organization, structure, and function resulting in abnormal microenvironment and hindrance of chemotherapeutic efficacy. One can exploit this aberrant microenvironment to enhance the delivery of nanotherapeutics. Unfortunately, relatively large nanotherapeutics cannot advance into tumor tissues after the extravasation from the blood vessels. To solve this problem, we have developed a multistage nanoparticle delivery system that can release small size nanoparticles upon exposure to enzymes uniquely present in tumor tissues and demonstrated superior intratumoral diffusion of these multistage nanoparticles.  We have also developed strategies to change the production and distribution of pro- and anti-angiogenic factors to “normalize” tumor vasculature and thus improve its function. Administration of nanomedicines during periods of vascular normalization potentiates their treatment efficacy. Furthermore, physical stress generated by growing tumor cells and fibrotic microenvironment – called desmoplasia – compresses blood vessels and hinders the drug distribution. Alleviating solid stress by targeting desmoplasia pathway would be a novel approach to enhance delivery and efficacy of nanomedicine.  Collectively, abnormal tumor vasculature and microenvironment form formidable barriers to anti-tumor therapies. Novel treatment approaches to exploit and/or tame such abnormalities would enhance delivery and efficacy of existing and future nanomedicine treatment strategies.