Crosslinked hydroxypropyl-β-cyclodextrin nanoparticles for improved efficacy of venetoclax against triple negative breast cancer

IF 5.2 2区医学 Q1 PHARMACOLOGY & PHARMACY International Journal of Pharmaceutics Pub Date : 2025-02-25 Epub Date: 2025-01-28 DOI:10.1016/j.ijpharm.2025.125296

Simran Chandani , Sayali Dighe , Oly Katari , Vivek Yadav , Sanyog Jain

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Abstract

Bcl-2 protein plays an integral role in hijacking apoptosis and triggering chemoresistance in triple negative breast cancer (TNBC). The present study explored the therapeutic efficacy of Bcl-2 inhibitor i.e., venetoclax (VTX) loaded HP-β-CD NPs (VTX/HP-β-CD NPs) against TNBC. VTX/HP-β-CD NPs were prepared using nanoprecipitation method. The prepared nanoparticles had optimal size (∼217 ± 4.32 nm), narrow PDI (∼0.23 ± 0.01), higher drug loading (∼15.7 ± 1.94 %) and % entrapment efficiency (∼78.5 ± 1.09 %). Morphology assessment revealed a spherical shape. In-vitro release studies displayed sustained release for up to 72h. Moreover, VTX/HP-β-CD NPs exhibited higher cellular uptake, cytotoxicity, and apoptosis index than free drug. Furthermore, the IC₅₀ values for VTX/HP-β-CD NPs were significantly reduced in 4T1 (∼3.96-fold) and MDA-MB-231 (∼5.23-fold) cells. Additionally, VTX/HP-β-CD NPs showed remarkable potential to induce “mixed cell death” by reducing the glutathione (GSH) levels and increasing ROS in TNBC cells. The pharmacokinetic studies showed a marked increase in the AUC_0-∞ (∼2.12-fold), C_max (∼1.05-fold), and t_1/2 (∼1.66-fold). Also, anti-cancer efficacy studies in 4T1-based model revealed improved therapeutic efficacy of VTX when delivered via HP-β-CD NPs. Safety evaluation revealed no signs of toxicity. Overall, the prepared nanocarrier holds significant promise in enhancing the payload and efficacy of VTX.

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交联羟丙基-β-环糊精纳米颗粒提高venetoclax抗三阴性乳腺癌的疗效。

Bcl-2蛋白在三阴性乳腺癌（TNBC）中劫持细胞凋亡和引发化疗耐药中起着不可或缺的作用。本研究探讨了Bcl-2抑制剂即载HP-β-CD NPs （VTX/HP-β-CD NPs）的venetoclax （VTX）对TNBC的治疗效果。采用纳米沉淀法制备了VTX/HP-β-CD NPs。准备的纳米粒子有最佳大小(217∼ ±4.32  海里),窄PDI(0.23∼ ±0.01 ),更高的药物加载(15.7∼ ±1.94  %)和%截留效率(78.5∼ ±1.09  %)。形态学鉴定显示为球形。体外释放研究显示缓释长达72 h。此外，与游离药物相比，VTX/HP-β-CD NPs表现出更高的细胞摄取、细胞毒性和凋亡指数。此外，VTX/HP-β-CD NPs的IC50值在4个 T1（~ 3.96倍）和MDA-MB-231（~ 5.23倍）细胞中显著降低。此外，VTX/HP-β-CD NPs通过降低TNBC细胞中的谷胱甘肽（GSH）水平和增加ROS，显示出显著的诱导“混合性细胞死亡”的潜力。药代动力学研究显示，AUC0-∞（~ 2.12倍）、Cmax（~ 1.05倍）和t1/2（~ 1.66倍）显著增加。此外，4个 t1模型的抗癌疗效研究显示，通过HP-β-CD NPs给药可以提高VTX的治疗效果。安全性评估显示没有毒性迹象。总的来说，所制备的纳米载体在提高VTX的有效载荷和效能方面具有重要的前景。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International Journal of Pharmaceutics 医学-药学

CiteScore

10.70

自引率

8.60%

发文量

951

审稿时长

72 days

期刊介绍： The International Journal of Pharmaceutics is the third most cited journal in the "Pharmacy & Pharmacology" category out of 366 journals, being the true home for pharmaceutical scientists concerned with the physical, chemical and biological properties of devices and delivery systems for drugs, vaccines and biologicals, including their design, manufacture and evaluation. This includes evaluation of the properties of drugs, excipients such as surfactants and polymers and novel materials. The journal has special sections on pharmaceutical nanotechnology and personalized medicines, and publishes research papers, reviews, commentaries and letters to the editor as well as special issues.