Intratumoral (i.t.) drug delivery can circumvent the transport barriers_high intratumoral fluid pressure and irregular vascularization_of solid tumors that limit the effectiveness of systemically delivered therapeutics. Unfortunately, long tumor retention and tumor coverage are difficult to concurrently optimize in most i.t. delivery methodologies. One method to overcome this limitation is to design an i.t. delivery system where the initial dissemination of the delivery system_as a liquid_can be independently controlled from its liquid-solid transition by an external stimulus. Herein, we propose such a system in which a liquid can be converted to a solid by photo-oxidation within the tumor. This approach builds upon our previous work, wherein we successfully cross-linked elastin-like polypeptides (ELPs) within a tumor by mixing a cysteine containing ELP (cELP) with a low concentration of H2O2, a strong oxidant for the formation of disulfides. I.t. injection of the mixture led to quick (< 2min) crosslinking of the cELP that resulted in prolonged tumor retention of the cELP. However, we could not control the timing of the ELP crosslinking in this methodology. We hypothesized that the strong oxidative agent, singlet oxygen (O3), produced in photodynamic therapy (PDT) may provide the potential to trigger the in situ crosslinking of a cELP in solid tumor injected with a photosensitizer-loaded cELP and exposed to light to produce O3 within the tumor.We hypothesized that upon the i.t. injection, a soluble, photosensitizer (PS)-conjugated cELP (cELP-PS) will freely distribute within the tumor interstitium due to initial_injection driven_convection and subsequently by convection because of the intratumoral fluid pressure, and by diffusion driven by the concentration gradient. After dissemination within the tumor, its retention is ensured by photoirradiation (PR) of the tumor with light of a specific wavelength tuned to the absorbance maximum of the PS to generate O3 that triggers the cross-linking of cysteines in the cELP-PS. In this scenario, the cELP-PS is thus immobilized in the tumor after achieving sufficient tumor coverage without transport outside the tumor. Our results show that a conjugate of cELP with a PS, chlorine E6 (Ce6), exhibited in vitro cELP gelation after exposure to light at 660 nm (the peak absorbance wavelength). Exposure to the light also successfully triggered in situ hydrogel formation after i.t. infusion of the conjugate, resulting in significantly higher tumor retention than either cELP+Ce6 w/o PR or cELP with PR. The antitumor efficacy of this PS-cELP-PDT system for local radiotherapy is ongoing. The results suggest that in situ crosslinking of a cELP-Ce6 conjugate by PR of the tumor may provide a solution to maximizing tumor coverage and tumor retention. Furthermore, this system could provide a multi-functional platform for controlled release of additional antitumor agents within a solid tumor.

Citation Format: Wenge Liu, Ratul Mukerji, Xinghai Li, Jeff Schaal, Jayanta Bhattacharyya, Michael Zalutsky, Ashutosh Chilkoti. In situ photocontrolled intratumoral depot for combined photodynamic therapy and brachytherapy for solid tumor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4583. doi:10.1158/1538-7445.AM2014-4583