Abstract LB-240: Mechanism-based enhancement of ErbB2-targeted delivery of chemotherapeutics encapsulated in Trastuzumab-conjugated polymeric nanocarriers
Authors: Raja Srikumar M. , Kim Jong Oh , Desale Swapnil S. , Nukolova Natasha V. , Oberoi Hardeep S. , Williams Stetson H. , Luan Haitao , Band Vimla , Kabanov Alexander V. , Bronich Tatiana K. , Band Hamid 
Published: August 2012

Abstract
ErbB2-driven breast cancers account for 20-25% of Breast Cancer patients screened in the USA. The humanized monoclonal antibody, Trastuzumab (Herceptin™), in combination with chemotherapy is the current standard of treatment. However, newer agents to overcome challenges associated with de novo and acquired resistance to Trastuzumab therapy, are being explored. The HSP90 inhibitor, 17-allylaminodemethoxygeldanamycin (17-AAG), which recently completed phase II clinical trials, is an example. Despite the potent anti-cancer activity of 17-AAG, toxicities associated with current formulations remain a concern. Strategies for 17-AAG-encapsulation into biocompatible nanoparticle formulations (polymeric micelles, liposomes, nanoalbumins and dendrimers) are being pursued as an alternative. We have described nanogels composed of cross-linked polyanion and poly(ethylene glycol), PEG shell, which can be surface-functionalized with targeting ligands/antibodies for overexpressed cell-surface receptors, as novel polymeric nanocarriers for targeted delivery of anti-cancer agents. However, the slow endocytosis and rapid recycling of ErbB2-receptor, limits the efficacy of uptake of the targeted nanocarrier cargo. Since HSP90 inhibition can enhance the internalization and lysosomal routing of ErbB2 receptor, we hypothesize that, HSP90 inhibitors such as 17-AAG, can increase the efficiency of ErbB2-targeted delivery of nano-encapsulated drug cargo. We report our studies describing the preparation, characterization, endocytic uptake and anti-cancer activity of 17-AAG and Doxorubicin co-encapsulated in nanogels against ErbB2-overexpressing breast cancer models. 17-AAG and Doxorubicin were loaded into the cross-linked core of the nanogels at high total loading capacities. The drug-loaded nanogels had potent cytotoxic activity against ErbB2-overexpressing breast cancer cell lines, with 17-AAG potentiating the activity of Doxorubicin. Confocal immunofluorescence microscopy confirmed that the drug-loaded nanogels are efficiently internalized via the endocytic pathway. Analysis of ErbB2 degradation confirmed efficient 17-AAG release from nanogels with activities comparable to free 17-AAG. As proof-of-principle, we also demonstrate that the HSP90 inhibitors indeed facilitate the internalization of ErbB2-targeted nanogels into cancer cells. These studies demonstrate that nanogels could therefore serve as novel nanocarriers for synergistic combinations of 17-AAG with chemotherapeutics, providing an opportunity to overcome solubility issues associated with 17-AAG. Most importantly, we suggest a mechanism-based strategy to achieve the full potential of ErbB2-targeted delivery of chemotherapeutic payloads, by HSP90-inhibition-facilitated ErbB2-internalization and lysosomal routing of the nanogel cargo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-240. doi:1538-7445.AM2012-LB-240