Injectable polypeptide micelles that form radiation crosslinked hydrogels in situ for intratumoral radiotherapy

Abstract

Intratumoral radiation therapy – ‘brachytherapy’ – is a highly effective treatment for solid tumors, particularly prostate cancer. Current titanium seed implants, however, are permanent and are limited in clinical application to indolent malignancies of low- to intermediate-risk. Attempts to develop polymeric alternatives, however, have been plagued by poor retention and off-target toxicity due to degradation. Herein, we report on a new approach whereby thermally sensitive micelles composed of an elastin-like polypeptide (ELP) are labeled with the radionuclide 131I to form an in situ hydrogel that is stabilized by two independent mechanisms: first, body heat triggers the radioactive ELP micelles to rapidly phase transition into an insoluble, viscous coacervate in under 2min; second, the high energy β-emissions of 131I further stabilize the depot by introducing crosslinks within the ELP depot over 24h. These injectable brachytherapy hydrogels were used to treat two aggressive orthotopic tumor models in athymic nude mice: a human PC-3 M-luc-C6 prostate tumor and a human BxPc3-luc2 pancreatic tumor model. The ELP depots retained greater than 52% and 70% of their radioactivity through 60days in the prostate and pancreatic tumors with no appreciable radioactive accumulation (≤0.1% ID) in off-target tissues after 72h. The 131I-ELP depots achieved >95% tumor regression in the prostate tumors (n=8); with a median survival of more than 60days compared to 12days for control mice. For the pancreatic tumors, ELP brachytherapy (n=6) induced significant growth inhibition (p=0.001, ANOVA) and enhanced median survival to 27days over controls.