School of Life Sciences, Anhui Medical University, Hefei 230032, China.
School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China.
Carbohydr Polym. 2022 Sep 1;291:119554. doi: 10.1016/j.carbpol.2022.119554. Epub 2022 May 2.
Efficient delivery systems for co-delivery of P-glycoprotein (P-gp) inhibitors and chemotherapeutic drugs are essential for inhibiting multi-drug resistance (MDR) breast cancers. Herein, we present a multi-functional carboxymethyl chitosan (CMC) based core-shell nanoplatform to co-deliver MDR1 gene-silenced small interfering RNA (siMDR1) and doxorubicin (DOX) for optimal combinatorial therapy. DOX is linked to CMC through a disulfide bond to model redox-responsive prodrug (CMC-DOX) as the inner core. siMDR1 is encapsulated in oligoethylenimine (OEI), which is electrostatically adsorbed on CMC-DOX as the pH-responsive sheddable shielding shell. AS1411 aptamer and GALA peptide functionalised hyaluronic acid (AHA/GHA) are provided on the surface for tumour-targeting and endo/lysosomal escape. The nanoplatform could stepwise release payloads with acid/redox triggered fashion. AHA effectively improves nanoplatform intracellular uptake and tumour accumulation. GHA facilitates cargos escape from endo/lysosomes to cytoplasm. The multi-functional nanoplatform provides 86.3 ± 2.2% siMDR1 gene silencing and significantly downregulates P-gp expression. Moreover, it ensures 55.7 ± 1.6% MCF-7/ADR cell apoptosis at a low concentration of DOX (30 μg/mL) in vitro and performs synergistic therapeutic effects suppressing tumour growth in vivo. Overall, the multi-functional CMC-based biopolymers can be efficient siRNA/drug co-delivery carriers for cancer chemotherapy.
高效的共递药系统对于克服多药耐药（MDR）乳腺癌至关重要，该系统能同时递送 P-糖蛋白（P-gp）抑制剂和化疗药物。在此，我们构建了一种多功能羧甲基壳聚糖（CMC）基核壳纳米平台，用于共递送沉默 MDR1 基因的小干扰 RNA（siMDR1）和多柔比星（DOX），以实现最佳联合治疗。通过二硫键将 DOX 连接到 CMC 上，以构建模型还原响应性前药（CMC-DOX）作为内核。将 siMDR1 包裹在聚乙二烯亚胺（OEI）中，通过静电吸附在 CMC-DOX 上作为 pH 响应性可脱落的屏蔽壳。AS1411 适配体和 GALA 肽功能化透明质酸（AHA/GHA）被提供在表面上用于肿瘤靶向和内体/溶酶体逃逸。纳米平台可以以酸/还原触发的方式逐步释放有效载荷。AHA 可有效提高纳米平台的细胞内摄取和肿瘤积累。GHA 有助于货物从内体/溶酶体逃逸到细胞质。多功能纳米平台提供 86.3 ± 2.2%的 siMDR1 基因沉默，并显著下调 P-gp 表达。此外，它确保在体外低浓度 DOX（30 μg/mL）下 MCF-7/ADR 细胞凋亡率达到 55.7 ± 1.6%，并在体内发挥协同治疗作用抑制肿瘤生长。总之，基于多功能 CMC 的生物聚合物可以作为有效的 siRNA/药物共递药载体用于癌症化疗。
