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pH 响应性透明质酸纳米粒增强三阴性乳腺癌治疗

pH-Responsive Hyaluronic Acid Nanoparticles for Enhanced Triple Negative Breast Cancer Therapy.

机构信息

School of Pharmacy, Bengbu Medical College, Bengbu, 233030, People's Republic of China.

出版信息

Int J Nanomedicine. 2022 Mar 25;17:1437-1457. doi: 10.2147/IJN.S360500. eCollection 2022.

DOI:10.2147/IJN.S360500
PMID:35369031
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8965017/
Abstract

PURPOSE

This study emphasized that dasatinib (DAS) and olaparib (OLA) have synergistic effects on triple negative breast cancer, by inducing DNA damage and inhibiting DNA damage repair. However, poor water solubility, short half-life of drugs, and low drug concentration in tumor tissue limit the clinical application.

METHODS

In this research, acid-sensitive ester bonds were used to connect hydrophobic DAS and hydrophilic hyaluronic acid (HA) to form the amphiphilic polymer prodrug HA-DAS, and then OLA was added as the core, the HA-DAS was used as the carrier to form nanomicelles (HDO-NPs) in aqueous. The characterization and drug release of HDO-NPs were studied, and the cytotoxicity, targeting effect, and intracellular transport behavior of HDO-NPs were evaluated in MDA-MB-231. In addition, the pharmacokinetic and therapeutic effect of HDO-NPs were further verified in vivo.

RESULTS

In vitro characterizations showed that HDO-NPs were spherical with uniform particle size, good stability and anti-dilution ability, and displayed favorable pH-responsive drug release behavior. In addition, the cell experiments showed that HDO-NPs could be effectively taken up by binding to the overexpressed CD44 proteins of MDA-MB-231 cells, resulting in increased intracellular drug concentration. In vivo experiments showed that HDO-NPs can effectively target tumor tissues, have excellent therapeutic effects on tumor, significantly prolong the circulation time of drugs in vivo, and effectively improved the bioavailability of drugs.

CONCLUSION

DAS and OLA were designed into micelles, the efficacy of HDO-NPs was higher than that of free drugs. Therefore, HDO-NPs have good application prospects in the treatment of triple negative breast cancer.

摘要

目的

本研究强调达沙替尼（DAS）和奥拉帕利（OLA）通过诱导 DNA 损伤和抑制 DNA 损伤修复对三阴性乳腺癌具有协同作用。然而，较差的水溶性、药物半衰期短以及肿瘤组织中药物浓度低限制了其临床应用。

方法

在这项研究中，使用酸敏感酯键将疏水性 DAS 与亲水性透明质酸（HA）连接，形成两亲聚合物前药 HA-DAS，然后加入 OLA 作为核心，将 HA-DAS 用作载体在水中形成纳米胶束（HDO-NPs）。研究了 HDO-NPs 的表征和药物释放，并在 MDA-MB-231 中评价了 HDO-NPs 的细胞毒性、靶向作用和细胞内转运行为。此外，还进一步在体内验证了 HDO-NPs 的药代动力学和治疗效果。

结果

体外特性表明 HDO-NPs 呈球形，具有均匀的粒径、良好的稳定性和抗稀释能力，并表现出良好的 pH 响应性药物释放行为。此外，细胞实验表明 HDO-NPs 可以通过与 MDA-MB-231 细胞过度表达的 CD44 蛋白结合而被有效摄取，从而导致细胞内药物浓度增加。体内实验表明 HDO-NPs 可以有效地靶向肿瘤组织，对肿瘤具有优异的治疗效果，显著延长药物在体内的循环时间，并有效提高药物的生物利用度。

结论

将 DAS 和 OLA 设计成胶束，HDO-NPs 的疗效高于游离药物。因此，HDO-NPs 在治疗三阴性乳腺癌方面具有良好的应用前景。

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