Thermally-Responsive Biopolymer Depots for the Delivery of High-Dose, β-Radionuclide Brachytherapy in the Treatment of Prostate and Pancreatic Cancer
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 131-Iodine 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 2 minutes; second, the high energy β-emissions of 131-Iodine further stabilize the depot by introducing crosslinks within the ELP depot over 24 hours. These injectable brachytherapy hydrogels were used to treat two aggressive orthotopic tumor models in athymic nude mice: a human PC-3M-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 60 days in the prostate and pancreatic tumors with no appreciable radioactive accumulation (≤ 0.1% ID) in off-target tissues after 72 hours. The 131I-ELP depots achieved >95% tumor regression in the prostate tumors (n=8); with a median survival of more than 60 days compared to 12 days for control mice. For the pancreatic tumors, ELP brachytherapy (n=6) induced significant growth inhibition (p = 0.001, ANOVA) and enhanced median survival to 27 days over controls.
We then demonstrated that 131I-ELP brachytherapy can work synergistically with paclitaxel chemotherapy to overcome the intrinsic resistance found in pancreatic tumors. Treating tumors with an optimized radioactivity dose of 10.0 µCi/mg and systemically administered paclitaxel nanoparticles achieved complete regression in BxPc3-luc2, MIA PaCa-2, and AsPc-1 tumor models. Moreover, responses occurred irrespective of the paclitaxel dose (between 12.5-50 mg/kg) or the formulation (Abraxane or micelle formulation). A comparative study utilizing an aggressive 5x 5Gy hypofractionated X-ray radiation produced only minor growth inhibition, with or without paclitaxel.
The mechanistic underpinnings of this effect were explored in an orthotopic model to reveal the fundamental differences between 131I-ELP therapy and conventional radiotherapy. Continuous dose exposure was found to coordinate much more effectively with the temporal sensitization mechanisms of paclitaxel, as evidenced by TUNEL immunohistochemistry. Stromal collagen and cellular junctional proteins regulating interstitial permeability (Claudin-4, CD31, and VE-Cadherin) were dysregulated after 131I-ELP treatment. Fluorescent analysis of paclitaxel nanoparticles revealed significantly higher paclitaxel accumulation in brachytherapy tumors after treatment (p<0.01). These results show that 131I-ELP biopolymer brachytherapy offers a highly attractive alternative to current radiotherapy techniques and demonstrated negligible toxicity.
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