Que 和 BCL-2 siRNA 与脂质-共聚物杂化纳米复合物的共同传递可实现有效的肿瘤消退,ACS Biomaterials Science & Engineering

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Que 和 BCL-2 siRNA 与脂质-共聚物杂化纳米复合物的共同传递可实现有效的肿瘤消退
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2023-07-18 , DOI: 10.1021/acsbiomaterials.3c00489
Kangkang Li ₁ , Xiaohua Cai ₂ , Yong Fan ₃ , Meng Jin ₄ , Yi Xie ₁ , Zhenghui Jing ₁ , Xinlong Zang ₁ , Yantao Han ₁

Affiliation

化疗的疗效常常因肿瘤细胞的化疗耐药性而降低，这通常是由基因异常过度表达引起的。在此，开发了多功能纳米复合物（Que/siBCL2@BioMICs）来传递槲皮素（Que）和BCL-2 siRNA（siBCL2）以协同抑制肿瘤生长。该纳米复合物由聚乙二醇甲醚甲基丙烯酸酯-聚[2-(二甲氨基)丙烯酸乙酯]-聚己内酯(PEGMA-PDMAEA-PCL)和1,2-二硬脂酰-sn-甘油-3的两亲性三嵌段共聚物组成。-磷酸乙醇胺-聚乙二醇-生物素（DSPE-PEG-生物素）。Que 通过疏水相互作用被封装到核心中，而带负电荷的 siBCL2 通过静电相互作用被加载。纳米复合物可以通过生物素介导的主动靶向有效促进细胞摄取，并通过 PDMAEA 的“质子海绵效应”在胞质中释放货物。由于 Que 和 siBCL2 的体外协同作用，Que/siBCL2@BioMICs 实现了增强的细胞毒性和抗转移活性。更重要的是，在原发肿瘤负荷和肺转移结节减少的原位4T1荷瘤小鼠中观察到优异的抗肿瘤功效，同时未观察到对主要器官的明显副作用。总之，具有化疗药物和核苷酸药物包埋的生物素靶向纳米复合物为有效的三阴性乳腺癌（TNBC）治疗提供了一种有前途的策略。

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Codelivery of Que and BCL-2 siRNA with Lipid–Copolymer Hybrid Nanocomplexes for Efficient Tumor Regression

The efficacy of chemotherapy is often reduced due to the chemotherapy resistance of tumor cells, which is usually caused by abnormal gene overexpression. Herein, multifunctional nanocomplexes (Que/siBCL2@BioMICs) were developed to deliver quercetin (Que) and BCL-2 siRNA (siBCL2) to synergistically inhibit tumor growth. The nanocomplexes were composed of an amphiphilic triblock copolymer of poly(ethylene glycol) methyl ether methacrylate–poly[2-(dimethylamino) ethyl acrylate]–polycaprolactone (PEGMA–PDMAEA–PCL) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-biotin (DSPE–PEG–biotin). Que was encapsulated into the cores through hydrophobic interactions, while negatively charged siBCL2 was loaded through electrostatic interactions. The nanocomplexes could effectively facilitate cellular uptake via biotin-mediated active targeting and cytosolic release of cargos by the “proton sponge effect” of PDMAEA. Que/siBCL2@BioMICs achieved enhanced cytotoxicity and anti-metastasis activity due to a synergistic effect of Que and siBCL2 in vitro. More importantly, superior anti-tumor efficacy was observed in orthotopic 4T1 tumor-bearing mice with reduced primary tumor burden and lung metastatic nodules, while no obvious side effects to major organs were observed. In conclusion, the biotin-targeted nanocomplexes with chemotherapeutic and nucleotide agent entrapment provide a promising strategy for efficient triple-negative breast cancer (TNBC) therapy.

更新日期：2023-07-18

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