Abstract 2618: Tumor multicomponent targeting nanoparticle for synergistic killing of drug resistant renal cell carcinoma

Abstract

Abstract Targeted therapy in renal cell carcinoma (RCC) has limited clinical response due to the development of drug resistance. Drug resistance can be acquired through multiple pathways including, impairment of apoptosis, overexpression of hypoxia promoting carbonic anhydrase 9 (CA9), and infiltration of folate receptor (FR) positive tumorigenic macrophages. Our hypothesis was to overcome the drug resistance by developing a tumor stimuli-responsive nanoparticle (NP) that can carry combination drugs, such as Cabozantinib (CB) and CFM 4.16 in RCC. The rationale of choosing the CB in combination with CFM4.16 was to induce synergistic anti-RCC effect by modulating the multiple tumor survival pathways, such as caspase 3, Akt/p-Akt, MET. One of the major challenges of the CB and CFM4.16 combination therapy is their poor water solubility and limited targetability to cancer. Thus, we came up with a smart strategy of developing dual folate receptor (FR) and carbonic anhydrase-9 (CA9) biomarker directed nanoparticles that can target the tumor stroma and hypoxia of RCC, respectively. In this proof of concept study, we synthesized SMA-TPGS and SMA polymer (PL) comprising of FR and CA9 dual targeting ligand, namely, FR-CA9-OL using reagent free ‘click' chemistry. FR-CA9-PL was encapsulated either with CFM4.16 or with CB to obtain nanoparticles, called FR-CA9-C4.16 and FR-CA9-CB respectively. The nanoparticles were prepared by using a co-solvent dialysis method that resulted in small-particle size with a range of 80-100 nm diameter, narrow polydispersity index of ∼ 0.15 and high drug loading of 30% (wt./wt.). The homogenous and high drug loading characteristics of nanoparticles are optimal for penetrating hypoxia of RCC. The IC50 of FR-CA9-C4.16 was improved by 60-fold as compared to CFM4.16 treatment and IC50 of FR-CA9-CB is improved by 16-fold compared to CB treatment in aggressive Everolimus-resistant (Evr-res) A498 RCC cells. The combination of FR-CA9-C4.16 with FR-CA9-CB demonstrated synergistic killing of Evr-res-A498 with CI value 0.1-0.5. The signature characteristic and superior anticancer effect of nanoparticles in Evr-resistant RCC provide a worthwhile strategy for overcoming drug resistance in RCC. Citation Format: Kushal Vanamala, Samaresh Sau, Shivani Naik, Arun K. Rishi, Arun Iyer. Tumor multicomponent targeting nanoparticle for synergistic killing of drug resistant renal cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2618.