双级作用树枝状聚合物纳米粒子用于加深对肿瘤细胞的化疗药物输送。

IF 3.1 Q2 PHARMACOLOGY & PHARMACY
Advanced pharmaceutical bulletin Pub Date : 2024-10-01 Epub Date: 2024-06-29 DOI:10.34172/apb.2024.054
Mohammad Shahpouri, Mohammad Amin Adili-Aghdam, Hossein Mahmudi, Saeedeh Ghiasvand, Hamed Dadashi, Aysan Salemi, Sajjad Alimohammadvand, Leila Roshangar, Abolfazl Barzegari, Mehdi Jaymand, Rana Jahanban-Esfahlan
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引用次数: 0

摘要

目的:我们报告了缺氧诱导双级作用树枝状分子纳米颗粒(NPs)的设计,用于体外选择性递送两种化疗模型药物多柔比星(DOX)和替拉帕嗪(TPZ),以加深缺氧肿瘤的药物递送:方法:PAMAM G5树枝状聚合物与低氧偶氮连接剂交联,并与mPEG连接,在树枝状聚合物表面形成可分离的电晕(PAP NPs)。研究人员通过 Zeta 分析仪、透射电子显微镜(TEM)、傅立叶变换红外光谱(FTIR)和药物释放动力学对 NPs 进行了表征。通过在二维和三维培养的 MDA-MB-231 乳腺癌细胞中进行多项测试,评估了 PAPs 的抗癌性能:MTT试验表明,PAP与PAMAMG5在生物相容性方面存在显著差异,在缺氧条件下,PAP@DOX的效果明显高于游离DOX。DAPI和Annexin V-FITC/PI细胞染色结果也证实了药物的均匀渗透,球形细胞中90%的细胞凋亡诱导和缺氧条件下PAP@DOX诱导的高水平ROS生成也验证了这一点。从机理上讲,与对照组相比,PAP@DOX 能明显降低 mTOR 和 Notch1 的表达,而 Bax 和 Caspase3 的表达则明显不受调控。重要的是,缺氧反应性解体和缺氧诱导的HAP药物激活协同作用,促进了HAP在整个微小肿瘤区域的深层和均匀分布,从而有效消除残留的肿瘤细胞:我们的研究结果表明,PAP 系统用于化疗药物的靶向给药具有安全性和高治疗潜力,尤其是 HAPs 对缺氧性实体瘤具有最大的抗癌活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Dual-stage Acting Dendrimeric Nanoparticle for Deepened Chemotherapeutic Drug Delivery to Tumor Cells.

Purpose: We report on the design of hypoxia-induced dual-stage acting dendrimeric nanoparticles (NPs) for selective delivery of two chemotherapeutic model drugs doxorubicin (DOX) and tirapazamin (TPZ) for deepened drug delivery into hypoxic tumors in vitro.

Methods: PAMAM G5 dendrimers were crosslinked with a hypoxic azo linker, attached to a mPEG to form a detachable corona on the dendrimer surface (PAP NPs). NPs were characterized by Zeta sizer, transmission electron microscope (TEM), Fourier transforms infrared (FTIR) and drug release kinetics. The anti-cancer performance of PAPs was evaluated by numerous tests in 2D and 3D cultured MDA-MB-231 breast cancer cells.

Results: MTT assay showed a significant difference between PAP and PAMAMG5 in terms of biocompatibility, and the effect of PAP@DOX was significantly greater than free DOX in hypoxic conditions. The results of DAPI and Annexin V-FITC/PI cell staining also confirmed uniform drug penetration as validated by induction of 90% cell apoptosis in spheroids and a high level of PAP@DOX-induced ROS generation under hypoxia conditions. Mechanistically, PAP@DOX significantly reduced the expression of mTOR, and Notch1, while the expression of Bax and Caspase3 was considerably unregulated, compared to the controls. Importantly, hypoxia-responsive disintegration and hypoxia-induced activation of HAP drug were synergized to promote deep and homogenous HAP distribution in whole microtumor regions to efficiently eliminate residual tumor cells.

Conclusion: Our results indicate the safety and high therapeutic potential of PAP system for targeted drug delivery of chemotherapeutics in particular HAPs which show maximum anti-cancer activity against hypoxic solid tumors.

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来源期刊
Advanced pharmaceutical bulletin
Advanced pharmaceutical bulletin PHARMACOLOGY & PHARMACY-
CiteScore
6.80
自引率
2.80%
发文量
51
审稿时长
12 weeks
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