Abstract 2006: A novel macromolecular platinum drug with potent efficacy to overcome cross-resistance in cancer therapy

Abstract

Abstract Background: Small molecular platinum (Pt)-based drugs such as cisplatin, carboplatin, and oxaliplatin have achieved great success in clinic over 40 years in cancer therapy. However, lack of tumor specificity leads to severe side effects. In addition, cancer cells frequently develop resistance to treatment through overexpressing cell surface multi-drug resistant proteins (MDRs). Therefore, it is desirable to develop novel Pt-based drugs with excellent anti-cancer efficacy and a minimal toxicity profile, as well as the capability to overcome drug resistance. We have previously demonstrated that poly(amino acid)-conjugated drugs can reduce toxicity and improve pharmacokinetics of chemotherapeutics and also overcome drug resistance by bypassing MDRs. Here we would like to apply this strategy on Pt drug development. Method: To address this question, we synthesized a L-aspartic acid-chelated Pt moieties (Asp-Pt), and then conjugated it to poly(L-glutamic acid/L-aspartic acid) to generate a polymeric-Pt macromolecule, namely carrier-platin. We next applied this drug on cancer cell lines including the therapeutic-resistant cancer cells in vitro, and tumor bearing murine models in vivo to evaluate its efficacy and toxicity. Result: We first tested the cytotoxicity of carrier-platin and compared with a current first-line chemotherapeutic oxaliplatin on colorectal cancer cell CT26 in vitro. Surprisingly, we found that carrier-platin effectively killed the CT26 cancer cells with hours while oxaliplatin slowly induced cell death after days. Importantly, carrier-platin was well-tolerated by non-cancerous cells. Furthermore, carrier-platin killed cancer cells that resistant to current chemotherapeutics in clinic, including cisplatin, oxaliplatin, doxorubicin and docetaxel, as effective as their parental cells. Next, we found that carrier-platin showed prolonged circulation time and high tumor accumulation compared with Pt-equivalent dosage of oxaliplatin. Treatment with 8 mg Pt/kg oxaliplatin caused severe body weight loss and intolerable hematotoxicity in mice, but even higher dose of carrier-platin (12 mg Pt/kg) can be tolerated by mice with stable body weight and did not induce any clinical symptoms. Finally, we revealed that carrier-platin potently inhibited mouse colorectal (CT26) and human ovarian (A2780) tumor growth over Pt-equivalent dosage of oxaliplatin. More importantly, carrier-platin was almost as effective on the cisplatin-resistant A2780 tumors (A2780-Cis) as on the parental A2780 tumors in vivo. Conclusion: We developed a novel macromolecular drug carrier-platin that overcome shortages of current small molecular Pt drugs. It displayed a satisfactory toxicity profile accompanied with excellent anti-tumor efficacy in vivo. Moreover, carrier-platin overcomes the cross-resistance problem of cancer cells to current chemotherapeutic drugs. Citation Format: Yongbin Liu, Dongfang Yu, Junhua Mai, Ping-Ying Pan, Shu-Hsia Chen, Haifa Shen. A novel macromolecular platinum drug with potent efficacy to overcome cross-resistance in cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2006.