Co-Delivery of Dacarbazine and miRNA 34a Combinations to Synergistically Improve Malignant Melanoma Treatments.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2025-01-24 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S497888

Baoyue Ding, Mingjuan Li, Jie Zhang, Xiaojuan Zhang, Huan Gao, Jianqing Gao, Chunyan Shen, Yan Zhou, Fanzhu Li, Ailin Liu

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Abstract

Purpose: 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.

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达卡巴嗪和miRNA 34a联合递送协同改善恶性黑色素瘤治疗

目的：在过去的三十年中，恶性黑色素瘤（MM）的发病率有所上升，尽管治疗取得了进步，但仍需要改进治疗方式。本研究为达卡巴嗪（DTIC）和携带miRNA 34a的PHRD胶束（Co-PHRD）联合治疗mm提供了一种有前景的肿瘤靶向共递送策略。方法：以聚l -精氨酸-聚l -组氨酸-聚乳酸（PLA）为主体构建双载药物递送体系Co-PHRD。在该体系中，聚l -精氨酸和聚乳酸分别作为亲水性和疏水性嵌段，在水溶液中自组装成胶束。聚（l -精氨酸）和聚（l -组氨酸）被细胞有效吸收并进行有效的基因凝聚，促进被包被的miRNA 34a释放到细胞质中。由于PLA的亲脂性，它可以有效地封装DTIC。多肽适体DR5-TAT （D21）作为靶向配体。研究了Co-PHRD的性质及其体外释放行为。此外，在体外和体内研究了DTIC和miRNA 34a在黑色素瘤治疗中的协同作用。结果：与单独DTIC治疗相比，Co-PHRD治疗对A375细胞的细胞毒性高1.84倍，表明miRNA 34a增强了DTIC的疗效。在N/P为10时，Co-PHRD的粒径为164.1±4.5 nm， zeta电位为27.3±1.38 mV。流式细胞术和CLSM结果显示，DTIC和miRNA 34a在PHRD 1 h和4 h时被A375细胞大量摄取。此外，体内实验结果表明，Co-PHRD胶束可以显著抑制肿瘤生长，而不会对主要器官造成明显损伤。结论：DTIC与miRNA 34a经多肽胶束共递送对MM具有协同作用，为基因和化疗提供了新的策略。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.