Erlotinib-functionalized dextran derivatives enable self-assembly of redox-responsive paclitaxel dimers for lung Cancer treatment after intratracheal delivery

IF 10.7 1区化学 Q1 CHEMISTRY, APPLIED

Carbohydrate Polymers Pub Date : 2025-06-15 DOI:10.1016/j.carbpol.2025.123899

Lan Wu , Yingchao Han , Yuzhu Liu , Yingkai Ning , Fangyan Zuo , Xinhe Wang , Xing Zhao , Yu Zhang , Hriday Bera , Dongmei Cun , Mingshi Yang

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引用次数: 0

Abstract

The intratracheal route enables an enhanced drug accumulation within the lungs together with reduced systemic exposure, making it a promising approach for treating epidermal growth factor receptor (EGFR)-overexpressed non-small cell lung cancer (NSCLC). In this study, dextran-PEG-erlotinib co-polymers (DPE), novel amphiphilic conjugates with outstanding therapeutic activities against EGFR-overexpressed NSCLC and stabilizing effects were synthesized and facilitated self-assembly of redox-sensitive paclitaxel dimers. The obtained nanoassemblies (DPE dimer NPs) exhibited high drug loading efficiency, satisfactory stability and optimal redox responsive paclitaxel release profile comparable with control nanoassemblies (TPGS dimer NPs), where paclitaxel dimers were assembled in the presence of TPGS, a therapeutically inert stabilizer. The DPE dimer NPs evidenced an enhanced cellular uptake efficiency and cytotoxicity in EGFR-overexpressed HCC827 cells as compared to TPGS dimer NPs. These also demonstrated superior tumor penetration ability and inhibition potential in HCC827 3D tumor spheroid. Compared to TPGS dimer NPs and Taxol® intravenous injection, the DPE dimer NPs illustrated an improved anticancer effect with reduced systemic toxicity and excellent biocompatibility after intratracheal administration to the HCC827 metastatic lung cancer mouse model. These results revealed a great potential of DPE as a stabilizer to synergistically improve the therapeutic efficacy of paclitaxel dimers against EGFR-overexpressed NSCLC after intratracheal administration.

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厄洛替尼功能化的葡聚糖衍生物能够自组装氧化还原反应紫杉醇二聚体，用于肺癌气管内输送后的治疗

气管内途径能够增强药物在肺内的积累，同时减少全身暴露，使其成为治疗表皮生长因子受体（EGFR）过表达的非小细胞肺癌（NSCLC）的一种有希望的方法。本研究合成了右旋糖酐- peg -厄洛替尼共聚物（DPE），这是一种新型两亲性偶联物，对egfr过表达的NSCLC具有突出的治疗活性和稳定作用，并促进了氧化还原敏感紫杉醇二聚体的自组装。与对照纳米组件（TPGS二聚体NPs）相比，所获得的纳米组件（DPE二聚体NPs）具有较高的载药效率，令人满意的稳定性和最佳的氧化还原响应性紫杉醇释放谱，其中紫杉醇二聚体是在治疗惰性稳定剂TPGS的存在下组装的。与TPGS二聚体NPs相比，DPE二聚体NPs在egfr过表达的HCC827细胞中具有更高的细胞摄取效率和细胞毒性。这些也显示了HCC827 3D肿瘤球体优越的肿瘤穿透能力和抑制潜力。与TPGS二聚体NPs和紫杉醇®静脉注射相比，DPE二聚体NPs在气管内给药HCC827转移性肺癌小鼠模型后显示出更好的抗癌效果，降低了全身毒性和良好的生物相容性。这些结果揭示了DPE作为稳定剂的巨大潜力，在气管内给药后协同提高紫杉醇二聚体对egfr过表达的NSCLC的治疗效果。

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来源期刊

Carbohydrate Polymers 化学-高分子科学

CiteScore

22.40

自引率

8.00%

发文量

1286

审稿时长

47 days

期刊介绍： Carbohydrate Polymers stands as a prominent journal in the glycoscience field, dedicated to exploring and harnessing the potential of polysaccharides with applications spanning bioenergy, bioplastics, biomaterials, biorefining, chemistry, drug delivery, food, health, nanotechnology, packaging, paper, pharmaceuticals, medicine, oil recovery, textiles, tissue engineering, wood, and various aspects of glycoscience. The journal emphasizes the central role of well-characterized carbohydrate polymers, highlighting their significance as the primary focus rather than a peripheral topic. Each paper must prominently feature at least one named carbohydrate polymer, evident in both citation and title, with a commitment to innovative research that advances scientific knowledge.