Xiao Xufeng, Zheng Yunuo, Wang Tianlong, Zhang Xiaoqing, Fang Gaochuan, Zhang Zhonghai, Zhang Zhengkui, Zhao Jiaojiao
Jiangsu Key Laboratory of Phylogenomics and Comparative Genomics, Jiangsu International Joint Center of Genomics, School of Life Sciences, Jiangsu Normal University Xuzhou 221116 Jiangsu China
Department of Obstetrics and Gynecology, Xuzhou Central Hospital Xuzhou 221009 Jiangsu China.
Nanoscale Adv. 2024 May 7;6(12):3135-3145. doi: 10.1039/d4na00079j. eCollection 2024 Jun 11.
The interplay between vascularization and macrophage-induced immune suppression plays a crucial role in melanoma treatment. In this study, we propose a novel combination approach to combat melanoma by simultaneously inhibiting tumor vascularization and enhancing macrophage-mediated anti-tumor responses. We investigate the potential of combining combretastatin A4 (CA4), a vascular-disrupting agent, with poly(I:C) (PIC), an immunostimulatory adjuvant. This combination approach effectively suppresses melanoma cell proliferation, disrupts vascularization, and promotes macrophage polarization towards the M1 phenotype for melanoma suppression. To facilitate efficient co-delivery of CA4 and PIC for enhanced anti-angiogenic immunotherapy, we develop an injectable metal-organic framework hydrogel using Zeolitic Imidazolate Framework-8 (ZIF-8) and hyaluronic acid (HA) (ZIF-8/HA). Our findings demonstrate that ZIF-8 enables efficient loading of CA4 and enhances the stability of PIC against RNAase degradation . Furthermore, the developed co-delivery hydrogel system, PIC/CA4@ZIF-8/HA, exhibits improved rheological properties, good injectability and prolonged drug retention. Importantly, experiments demonstrate that the PIC/CA4@ZIF-8/HA formulation significantly reduces the dosage and administration frequency while achieving a more pronounced therapeutic effect. It effectively inhibits melanoma growth by suppressing angiogenesis, destroying blood vessels, promoting M1 macrophage infiltration, and demonstrating excellent biocompatibility. In conclusion, our study advances anti-angiogenic immunotherapy for melanoma through the potent combination of PIC/CA4, particularly when administered using the PIC/CA4@ZIF-8/HA formulation. These findings provide a new perspective on clinical anti-angiogenic immunotherapy for melanoma, emphasizing the importance of targeting tumor vascularization and macrophage-mediated immune suppression simultaneously.
血管生成与巨噬细胞诱导的免疫抑制之间的相互作用在黑色素瘤治疗中起着关键作用。在本研究中，我们提出了一种新的联合方法来对抗黑色素瘤，即同时抑制肿瘤血管生成并增强巨噬细胞介导的抗肿瘤反应。我们研究了将血管破坏剂康普瑞汀A4（CA4）与免疫刺激佐剂聚肌胞苷酸（PIC）联合使用的潜力。这种联合方法有效地抑制了黑色素瘤细胞的增殖，破坏了血管生成，并促进巨噬细胞向抑制黑色素瘤的M1表型极化。为了促进CA4和PIC的高效共递送以增强抗血管生成免疫疗法，我们使用沸石咪唑酯骨架-8（ZIF-8）和透明质酸（HA）开发了一种可注射的金属有机骨架水凝胶（ZIF-8/HA）。我们的研究结果表明，ZIF-8能够有效负载CA4并增强PIC对核糖核酸酶降解的稳定性。此外，所开发的共递送水凝胶系统PIC/CA4@ZIF-8/HA具有改善的流变学性质、良好的可注射性和延长的药物保留时间。重要的是，实验表明，PIC/CA4@ZIF-8/HA制剂在实现更显著治疗效果的同时，显著降低了剂量和给药频率。它通过抑制血管生成、破坏血管、促进M1巨噬细胞浸润并表现出优异的生物相容性，有效抑制黑色素瘤生长。总之，我们的研究通过PIC/CA4的有效联合推进了黑色素瘤的抗血管生成免疫疗法，特别是当使用PIC/CA4@ZIF-8/HA制剂给药时。这些发现为黑色素瘤的临床抗血管生成免疫疗法提供了新的视角，强调了同时靶向肿瘤血管生成和巨噬细胞介导的免疫抑制的重要性。
