Abstract 5734: Polymeric delivery with dual drug payloads for hepatocellular carcinoma (HCC) therapy

Abstract Background: The long-term survival of hepatocellular carcinoma (HCC) patients is hampered by high recurrence and drug resistance. Targeting sonic hedgehog (SHH) pathways can overcome drug resistance in HCC. In this study, we co-loaded SHH inhibitor, cyclopamine (CPA) and paclitaxel (PTX) in a novel polymeric nanomicellar drug delivery system (M-CPA/PTX), to overcome the drug resistance in HCC tumor models. Method: The combinational effect in vitro was studied by treating HCC with CPA and PTX. The combinational index was calculated using CalcuSyn Biosoft software to determine the additive or synergistic effect of the combination. Three formulations (F0, F5, and F16) were selected for further testing based on formulation optimization using central composition design (CCD). The storage stability of M-CPA/PTXs at room temperature and 4 °C was evaluated by measuring the changes in micelle size, PDI, and encapsulation efficiency (EE) over pre-determined periods. In the pharmacokinetics (PK) study, nude mice were IP-injected with 5 mg/kg of PTX equivalent F0 and F16. Additionally, the toxicity of F0 was investigated using healthy Sprague Dawley rats, in which rats were intravenously injected with a single F0 dose of 1, 2, and 4 mg/kg/drug of M-CPA/PTX. Results: Combinational effect study suggested that CPA and PTX, demonstrated synergistic effect in Hep3B and HepG2 cells compared to the mono-treatment, thus overcoming resistance. F0, F5, and F16 exhibited particle sizes of 75. 27 ± 1. 06, 54. 63 ± 0. 85, and 70. 63 ± 3. 39 nm, respectively. The release kinetics of both drugs from these micelles displayed significantly slow-release profiles from the micelles, with less than 10% cumulative release within 24 hours in plasma. The stability study indicated that both drugs' micelle size and EE were not appreciably changed over 6 weeks at room temperature and 4 °C. Notably, the biodistribution studies showed that F16 achieved significantly greater accumulations of CPA in the liver, kidney, and spleen compared to F0 (P 0. 05). Additionally, the maximal tolerable dose of F0 in rats was 4 mg/kg/drug for the M-CPA/PTX combination, which did not result in treatment-related mortality. Conclusion: The combination of CPA and PTX offered promising synergistic effects on HCC treatment. F0, F5, and F16 were developed and characterized with the desired physicochemical properties and demonstrated controlled release characteristics for both payloads, suggesting their potential for sustained drug delivery in HCC therapy. Enhanced liver accumulation of F16 suggested favorable biodistribution for the site of action. Lastly, the safe toxicity profile supports the first choice of F0 among other lead candidates for further pre-clinical efficacy studies. Citation Format: Lu Dai, Guodong Zhang, Fatima Dagher, Airong Li, Amir Mohammad Gholizadeh, Chun Li, Diana S- Chow. Polymeric delivery with dual drug payloads for hepatocellular carcinoma (HCC) therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5734.