Abstract 1809: Next-generation brachytherapy: a preclinical study of a thermally stabilized biopolymer gel for delivering intratumoral radionuclide therapy in a pancreatic tumor mouse model
Authors: Schaal Jeffrey Laurence , Liu Wenge , Chilkoti Ashutosh , Li Xinghai , Mastria Eric , Zalutsky Michael R. 
Published: August 2015

The intratumoral delivery of radioactive therapeutics, a clinical technique known as brachytherapy, has proven very successful in treating solid cancers and become a prevalent option for treating prostate, breast, and melanoma tumors. The method typically involves the permanent implantation of 80-120 titanium ‘seeds’ encapsulating radioactive isotopes and requires expert spatial placement to ensure full dose coverage. The disadvantages of the seeds include a complicated implantation process, the permanence of the implants, migration of seeds to off-target sites, and that the titanium shielding limits the application of radionuclides which could treat more aggressive forms of cancer. As such, we have developed a next-generation brachytherapy alternative to solid seeds using an injectable, biodegradable, biocompatible and thermosensitive elastin-like polypeptide (ELP). Through recombinant design and synthesis, ELP exhibits a thermal phase transition (soluble-to-insoluble) when heated above 21°C. This allows radionuclide-bearing ELP to be easily handled as a fluid at room temperature, but enables spontaneous self-assembly into a stable brachytherapy gel upon intratumoral injection at body temperature. Previously, we demonstrated the efficacy of ELP brachytherapy in treating both s.c. human hypopharyngeal tumors and orthotopic human prostate tumors xenografted in mice models.

Treatment options for pancreatic cancer remain limited due to a large proportion of patients presenting with advanced disease at the time of diagnosis. Trials investigating the use of brachytherapy as a neo-adjuvant for shrinking pancreatic tumors prior to surgery or as an adjuvant to inhibit recurrence have provided encouragement. By conjugating the more potent radionuclide 131-Iodine to ELP, we investigated the ability of ELP brachytherapy to treat more clinically aggressive pancreatic tumors. Utilizing a human CRL-1687 cell line transfected to express luciferase (BxPc3-luc2), human pancreatic tumors were xenografted into an orthotopic, athymic nu/nu mouse model. Upon reaching 150 mm^3 in size, mice were treated either with [131I]-ELP brachytherapy (n = 6), at a dose of 5.83 μCi/mm^3, or with an ELP-only control injection (n = 6). Tumor response was tracked non-invasively using luminescent imaging for 60 days. The ELP brachytherapy demonstrated significant tumor inhibition (p &lt; 0.05, one-way ANOVA) and no appreciable side effects as determined by weight loss. The therapy group experienced a significant survival benefit, with a median duration of 27 days (p &lt; 0.005, log-rank test), when compared to control mice. These results, while promising as a proof of concept, demonstrate that further development is required to determine the both the appropriate radiation dose and to intratumoral coverage for translational application.

Citation Format: Jeffrey Laurence Schaal, Wenge Liu, Ashutosh Chilkoti, Xinghai Li, Eric Mastria, Michael R. Zalutsky. Next-generation brachytherapy: a preclinical study of a thermally stabilized biopolymer gel for delivering intratumoral radionuclide therapy in a pancreatic tumor mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1809. doi:10.1158/1538-7445.AM2015-1809