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创新型肿瘤细胞间质液触发的碳点-多西他赛纳米组装体用于 HER2 阳性乳腺癌的靶向药物递送和成像。

Innovative tumor interstitial fluid-triggered carbon dot-docetaxel nanoassemblies for targeted drug delivery and imaging of HER2-positive breast cancer.

机构信息

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Shaanxi Engineering Research Center of Cardiovascular Drugs Screening & Analysis, Xi'an 710061, China.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Shaanxi Engineering Research Center of Cardiovascular Drugs Screening & Analysis, Xi'an 710061, China.

出版信息

Int J Pharm. 2024 May 25;657:124145. doi: 10.1016/j.ijpharm.2024.124145. Epub 2024 Apr 26.

Abstract

In this study, we have developed an innovative pH-triggered nanomedicine delivery system, targeting HER2-positive breast cancer cells for effective low-cost, imaging-guided drug delivery and precise therapy. The key feature of this system lies in its unique tumor interstitial fluid microenvironment-responsive drug release behavior which achieved tumor site-specific drug delivery. Our in vitro experiments demonstrated that the carbon dot-integrated material achieves more efficient DTX release (96.13 % at 72 h) in the tumor interstitial fluid microenvironment (pH 6.5), thereby boosting drug concentration at the tumor site and enhancing therapeutic efficacy. Further cell experiments confirmed the system's significant inhibitory effect on HER2-positive tumor cells SKBR3 in a pH 6.5 environment, and apoptosis assays indicating a notable increase in early cell apoptosis (from 8.39 % to 24.61 % compared with pH 7.4). Furthermore, the integration of HER2 aptamer within the carbon dot-based system enables targeted recognition and binding to tumor cells, ensuring more precise delivery of DTX while minimizing potential side effects. Crucially, the carbon dots in this system emit superior red fluorescence (the QY = 47.64 % excited at 535 nm compared with Rodamine 6G), enabling real-time visualization of the drug delivery process. This feature provides valuable feedback on treatment effectiveness, facilitating necessary adjustments. The small size (1.88 ± 0.48 nm) of carbon dots significantly improved their ability to penetrate biological barriers, while their low toxicity (no significant cell toxicity under 350 μg/mL) contributed to the formulation's outstanding biocompatibility. Overall, this carbon dot-enhanced drug delivery system offers immense potential for enhancing drug efficacy, minimizing side effects, and providing real-time treatment monitoring, thus proposing a innovate strategy for breast cancer therapy.

摘要

在这项研究中,我们开发了一种创新的 pH 触发型纳米医学递药系统,针对 HER2 阳性乳腺癌细胞,实现了经济高效、成像引导的药物递药和精准治疗。该系统的关键特点在于其独特的肿瘤间质液微环境响应性药物释放行为,实现了肿瘤部位的特异性药物递药。我们的体外实验表明,碳点整合材料在肿瘤间质液微环境(pH 6.5)中实现了更有效的 DTX 释放(72 h 时达到 96.13%),从而提高了肿瘤部位的药物浓度,增强了治疗效果。进一步的细胞实验证实,该系统在 pH 6.5 环境下对 HER2 阳性肿瘤细胞 SKBR3 具有显著的抑制作用,细胞凋亡实验表明早期细胞凋亡显著增加(与 pH 7.4 相比,从 8.39%增加到 24.61%)。此外,HER2 适体整合在基于碳点的系统中,能够实现对肿瘤细胞的靶向识别和结合,确保更精确地递药,同时最小化潜在的副作用。关键的是,该系统中的碳点发出优异的红色荧光(在 535 nm 激发时的 QY 为 47.64%,与罗丹明 6G 相比),能够实时可视化药物递药过程。这一特性为治疗效果提供了有价值的反馈,便于进行必要的调整。碳点的小尺寸(1.88±0.48nm)显著提高了其穿透生物屏障的能力,而其低毒性(在 350μg/mL 以下没有明显的细胞毒性)有助于提高制剂的出色生物相容性。总体而言,这种碳点增强的药物递药系统为提高药物疗效、最小化副作用和提供实时治疗监测提供了巨大的潜力,为乳腺癌治疗提出了一种创新策略。

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