Abstract 5615: Evaluation of the antitumoral efficacy and toxicity of injectable, polymeric radionuclide seeds in a noninvasive preclinical prostate tumor model.
Authors: Schaal Jeffrey L. , Liu Wenge , Li Xinghai , Zalutsky Michael , Chilkoti Ashutosh 
Published: August 2014

Brachytherapy continues to be one of the predominant radiotherapy modalities for the treatment of prostate cancer. Depending on the stage of the cancer, it is employed either as a stand-alone treatment or as a neoadjuvant therapy to improve the success of surgical prostatectomy. Current clinical methods utilize titanium encased radioactive seeds, which must be permanently implanted within the prostate. The permanence of the titanium seed is problematic as it can lead to urinary and sexual discomfort; while rarer, migrating seeds can become entrapped in other tissues. To overcome these disadvantages, we have developed a new brachytherapy delivery depot from a genetically engineered elastin-like polypeptide (ELP). ELP exhibits an inverse transition behavior and has been designed to remain fluid at a refrigerated state (less than 21C) but aggregate to form a biocompatible and biodegradable intratumoral depot when injected into a tumor at body temperature.

Utilizing a previously developed ELP with a 7-tyrosine C-terminus tail, we examined the therapeutic efficacy of ELP labeled with the β-emitter 131I as a radioactive depot for treating prostate cancer in a preclinical, orthotopic model. The model was first established by xenografting a luciferase expressing human prostate cell line, Bioware® PC-3M-luc-C6, into immunoincompetent Balb/c nude mice. A non-invasive method for tracking tumor progression in vivo was developed by correlating the luminescence flux emitted from the tumor cells with the actual tumor size. The correlation between flux and tumor volume was determined as Volume = 7.234x10-9x - 18.54 (R2 = 0.7656), where x is the supine photon flux measured from a 10 second exposure taken 18 minutes after D-luciferin injection. This established a non-invasive approach for monitoring and quantifying the antitumor efficacy of the injectable ELP-radionuclide depot. ELP was labeled with 131I on constituent tyrosines by the IODO-GEN method, and mice were administered a single dose of 2 mCi per 40μl ELP per 150 mm3 of prostate tumor. Intratumoral deposition resulted in tumor regression in 91% of treated mice (n=11); 64% of which achieved tumor size reduction greater than 60% after 30 days. Radioactivity measurements demonstrated 90% ELP depot retention in tumor over 2 weeks. The local and systemic toxicity of this ELP-depot in this orthotopic tumor model was comparable to that in previous subcutaneous model studies. Further studies are currently under way to investigate the in vivo dissemination of the polypeptide after biodegradation of the polypeptide depot in a mouse model. Coupled with dietary iodine supplements, radionuclide accumulation in non-targeted tissues is expected to be negligible. We conclude that the injectable ELP-radionuclide depot is an attractive alternative to current radioactive seeds as a treatment of prostate cancer by brachytherapy.

Citation Format: Jeffrey L. Schaal, Wenge Liu, Xinghai Li, Michael Zalutsky, Ashutosh Chilkoti. Evaluation of the antitumoral efficacy and toxicity of injectable, polymeric radionuclide seeds in a noninvasive preclinical prostate tumor model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5615. doi:10.1158/1538-7445.AM2013-5615