Docetaxel-tethered di-Carboxylic Acid Derivatised Fullerenes: A Promising Drug Delivery Approach for Breast Cancer

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech Pub Date : 2024-10-02 DOI:10.1208/s12249-024-02955-y

Charu Misra, Jasleen Kaur, Manish Kumar, Lokesh Kaushik, Deepak Chitkara, Simran Preet, Muhammad Wahajuddin, Kaisar Raza

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Abstract

Docetaxel (DTX) has become widely accepted as a first-line treatment for metastatic breast cancer; however, the frequent development of resistance provides challenges in treating the disease.C₆₀ fullerene introduces a unique molecular form of carbon, exhibiting attractive chemical and physical properties. Our study aimed to develop dicarboxylic acid-derivatized C₆₀ fullerenes as a novel DTX delivery carrier. This study investigated the potential of water-soluble fullerenes to deliver the anti-cancer drug DTX through a hydrophilic linker. The synthesis was carried out using the Prato reaction. The spectroscopic analysis confirmed the successful conjugation of DTX molecules over fullerenes. The particle size of nanoconjugate was reported to be 122.13 ± 1.63 nm with a conjugation efficiency of 76.7 ± 0.14%. The designed conjugate offers pH-dependent release with significantly less plasma pH, ensuring maximum release at the target site. In-vitro cell viability studies demonstrated the enhanced cytotoxic nature of the developed nanoconjugate compared to DTX. These synthesized nanoscaffolds were highly compatible with erythrocytes, indicating the safer intravenous route administration. Pharmacokinetic studies confirmed the higher bioavailability (~ 6 times) and decreased drug clearance from the system vis-à-vis plain drug. The histological studies reveal that nanoconjugate-treated tumour cells exhibit similar morphology to normal cells. Therefore, it was concluded that this developed formulation would be a valuable option for clinical use.

Graphical Abstract

Abstract Image

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多西他赛系链二羧酸衍生富勒烯：一种治疗乳腺癌的有效给药方法。

多西他赛（DTX）已被广泛接受为转移性乳腺癌的一线治疗药物，然而，耐药性的频繁产生给该疾病的治疗带来了挑战。C60富勒烯是一种独特的碳分子形式，具有诱人的化学和物理特性。我们的研究旨在开发二羧酸衍生化 C60 富勒烯作为新型 DTX 递送载体。本研究探讨了水溶性富勒烯通过亲水连接体递送抗癌药物 DTX 的潜力。合成采用了普拉托反应。光谱分析证实了 DTX 分子与富勒烯的成功结合。据报道，纳米共轭物的粒径为 122.13 ± 1.63 nm，共轭效率为 76.7 ± 0.14%。所设计的共轭物可根据血浆 pH 值进行释放，大大降低了血浆 pH 值，确保在目标部位的最大释放量。体外细胞活力研究表明，与 DTX 相比，所开发的纳米共轭物具有更强的细胞毒性。这些合成的纳米支架与红细胞高度相容，表明通过静脉途径给药更为安全。药代动力学研究证实，与普通药物相比，纳米缀合物的生物利用度更高（约为普通药物的 6 倍），药物从体内清除率更低。组织学研究表明，纳米共轭物处理过的肿瘤细胞与正常细胞形态相似。因此，该制剂将成为临床使用的重要选择。

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

AAPS PharmSciTech 医学-药学

CiteScore

6.80

自引率

3.00%

发文量

264

审稿时长

2.4 months

期刊介绍： AAPS PharmSciTech is a peer-reviewed, online-only journal committed to serving those pharmaceutical scientists and engineers interested in the research, development, and evaluation of pharmaceutical dosage forms and delivery systems, including drugs derived from biotechnology and the manufacturing science pertaining to the commercialization of such dosage forms. Because of its electronic nature, AAPS PharmSciTech aspires to utilize evolving electronic technology to enable faster and diverse mechanisms of information delivery to its readership. Submission of uninvited expert reviews and research articles are welcomed.