Drug Design, Development and Therapy (Jan 2025)
Co-Delivery of Dacarbazine and miRNA 34a Combinations to Synergistically Improve Malignant Melanoma Treatments
Abstract
Baoyue Ding,1,2,* Mingjuan Li,2,* Jie Zhang,2,* Xiaojuan Zhang,2 Huan Gao,2 Jianqing Gao,3 Chunyan Shen,4 Yan Zhou,4 Fanzhu Li,5 Ailin Liu1 1Department of Pharmaceutical Analysis, Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, The School of Pharmacy, Fujian Medical University, Fuzhou, 350122, People’s Republic of China; 2Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, Jiaxing University College of Medicine, Jiaxing, Zhejiang, People’s Republic of China; 3Institute of Pharmaceutics, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058 People’s Republic of China; 4Jiaxing Institute for Food, Drug and Product Quality Control, Jiaxing, Zhejiang, People’s Republic of China; 5Zhejiang Chinese Medical University, School of Pharmaceutical Science, Hangzhou, 310053, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fanzhu Li; Ailin Liu, Email [email protected]; [email protected]: The incidence of malignant melanoma (MM) has risen over the past three decades, and despite advancements in treatment, there is still a need to improve treatment modalities. This study developed a promising strategy for tumor-targeted co-delivery of Dacarbazine (DTIC) and miRNA 34a-loaded PHRD micelles (Co-PHRD) for combination treatment of MM.Methods: To construct the dual drug-loaded delivery system Co-PHRD, poly (L-arginine)-poly (L-histidine)-polylactic acid (PLA) was employed as a building block. In this system, poly (L-arginine) and PLA function as hydrophilic and hydrophobic blocks, respectively, which self-assemble into micelles in aqueous solution. Poly(L-arginine) and poly(L-histidine) are efficiently taken up by cells and perform efficient gene condensation, which facilitate the release of encapsulated miRNA 34a into the cytoplasm. Due to its lipophilic properties, PLA can effectively encapsulate DTIC. The polypeptide aptamer DR5-TAT (D21) was used as a targeting ligand. The properties of Co-PHRD and its in vitro release behaviour were characterized. Additionally, the synergetic effects of DTIC and miRNA 34a in melanoma therapy were investigated in vitro and in vivo.Results: Compared to DTIC treatment alone, Co-PHRD treatment exhibited 1.84-fold greater cytotoxicity in A375 cells, demonstrating that miRNA 34a enhanced the efficacy of DTIC. The particle size of Co-PHRD at an N/P ratio of 10 was 164.1 ± 4.5 nm, and the zeta potential of Co-PHRD was 27.3 ± 1.38 mV. The flow cytometry and CLSM results revealed both DTIC and miRNA 34a were avidly taken up by A375 cells at 1 h and 4 h in PHRD. In addition, in vivo results indicated that Co-PHRD micelles can significantly inhibit tumor growth without causing significant damage to major organs.Conclusion: Co-delivery of DTIC and miRNA 34a via polypeptide micelles showed synergistic effects against MM, offering a new strategy for gene and chemotherapy.Keywords: nano micelle, DTIC, miRNA 34a, co-delivery, malignant melanoma
