HASc-responsive dual-drug nano-particles for co-delivery of Pt(II) and BAI for combination therapy of tumors

IF 5.1 3区工程技术 Q1 CHEMISTRY, APPLIED Reactive & Functional Polymers Pub Date : 2025-03-01 Epub Date: 2025-01-13 DOI:10.1016/j.reactfunctpolym.2025.106165

Yifan Zhao , Tong Qiu , Chige Zhuang , Dan Li , Zimin Wan , Hua Zheng , Xueqiong Zhang

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Abstract

In this study, ascorbic acid (HASc)-responsive nano-particles were designed to co-deliver the ferroptosis inducer Baicalin (BAI) and the chemotherapeutic drug cisplatin (Pt(II)) to tumor sites, aiming for a synergistic effect of chemotherapy(CT) and ferroptosis. Using CMCS as the carrier, the small-molecule pro-drug cis-Pt(IV)-COOH was grafted onto the carrier to create an amphiphilic polymer pro-drug. Single-drug nano-particles M(Pt) and dual-drug nano-particles M(BAI/Pt) were obtained by ultrasonically self-assembling BAI encapsulated in hydrophobic cores. The M(BAI/Pt) exhibited an average diameter of 211.37

\pm

3.01 nm, a polydispersity index (PDI) of 0.196

\pm

0.015, and a surface charge of −14.93

\pm

0.72 mV, demonstrating excellent stability. Given that cis-Pt(IV)-COOH is sensitive to HASc, the nanoparticles could quickly release Pt(II) with 83.22 % efficiency in simulated tumor cells. Meanwhile, the nanoparticles disintegrated and released BAI with 84.35 % efficiency as well. BAI can induce the accumulation of lipid peroxides by down-regulating GPX4, while Pt(II) contributes to iron ion accumulation. The combined treatment strategy aims to achieve an effective synergistic approach between chemotherapy and ferroptosis. In vitro toxicity studies indicated that the M(BAI/Pt₁_–₁) exhibited significant cytotoxicity, synergistic impact (CI = 0.94) and strong selectivity (SI = 1.60) against 4 T1 cells. Mitochondrial membrane potential assessments and intracellular ROS and MDA analyses indicated that the M(BAI/Pt₁_–₁) generated substantial ROS, causing mitochondrial structural damage and lipid peroxidation in 4 T1 cells. The M(BAI/Pt₁_–₁) induced ferroptosis in 4 T1 cells by downregulating GPX4 expression and decreasing GSH levels, ultimately inhibiting in vitro tumor cell proliferation effectively. Consequently, these nano-particles provide fresh strategy to cancer treatment by combining chemotherapy with ferroptosis.

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用于联合治疗肿瘤的Pt（II）和BAI的hasc反应性双药纳米颗粒

本研究设计抗坏血酸（HASc）响应纳米颗粒，将铁衰亡诱导剂黄芩苷（Baicalin， BAI）和化疗药物顺铂（cisplatin, Pt(II)）共同递送至肿瘤部位，旨在实现化疗（CT）和铁衰亡的协同作用。以CMCS为载体，将小分子前药顺式pt (IV)-COOH接枝到载体上，制备了两亲性高分子前药。将BAI包埋在疏水核中，通过超声自组装得到单药纳米粒子M（Pt）和双药纳米粒子M（BAI/Pt）。M（BAI/Pt）的平均直径为211.37±3.01 nm，多分散性指数（PDI）为0.196±0.015，表面电荷为- 14.93±0.72 mV，具有良好的稳定性。考虑到顺式Pt(IV)-COOH对HASc敏感，纳米颗粒可以在模拟肿瘤细胞中以83.22%的效率快速释放Pt（II）。同时，纳米颗粒分解释放BAI的效率为84.35%。BAI通过下调GPX4诱导脂质过氧化物的积累，而Pt（II）促进铁离子的积累。联合治疗策略旨在实现化疗与铁下垂之间的有效协同途径。体外毒性研究表明，M（BAI/ Pt1-1）对4 T1细胞具有显著的细胞毒性、协同作用（CI = 0.94）和强选择性（SI = 1.60）。线粒体膜电位评估、细胞内ROS和MDA分析表明，M（BAI/ Pt1-1）产生大量ROS，导致4个T1细胞线粒体结构损伤和脂质过氧化。M（BAI/ Pt1-1）通过下调GPX4表达、降低GSH水平诱导4个T1细胞铁下垂，最终有效抑制体外肿瘤细胞增殖。因此，这些纳米颗粒通过联合化疗和铁下垂为癌症治疗提供了新的策略。

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来源期刊

Reactive & Functional Polymers 工程技术-高分子科学

CiteScore

8.90

自引率

5.90%

发文量

259

审稿时长

27 days

期刊介绍： Reactive & Functional Polymers provides a forum to disseminate original ideas, concepts and developments in the science and technology of polymers with functional groups, which impart specific chemical reactivity or physical, chemical, structural, biological, and pharmacological functionality. The scope covers organic polymers, acting for instance as reagents, catalysts, templates, ion-exchangers, selective sorbents, chelating or antimicrobial agents, drug carriers, sensors, membranes, and hydrogels. This also includes reactive cross-linkable prepolymers and high-performance thermosetting polymers, natural or degradable polymers, conducting polymers, and porous polymers. Original research articles must contain thorough molecular and material characterization data on synthesis of the above polymers in combination with their applications. Applications include but are not limited to catalysis, water or effluent treatment, separations and recovery, electronics and information storage, energy conversion, encapsulation, or adhesion.