The Affiliated Nanhua Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, 421001, People's Republic of China.
Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, People's Republic of China.
Int J Nanomedicine. 2024 Oct 9;19:10247-10262. doi: 10.2147/IJN.S459047. eCollection 2024.
Breast cancer treatment has been a global puzzle, and targeted strategies based on the hypoxic tumor microenvironment (TME) have attracted extensive attention. As a signature transcription factor overexpressed in hypoxia tumor, hypoxia-inducible factor-1 (HIF-1) contribute to cancer progression. Compound 7-(3-(2-chloro-1H-benzo[d]1midazole-1-yl) propoxy)-2-(3,4,5-trime-thoxyphenyl)-4H-chromen-4-one, synthesized and named FB15 in our earlier research, a potential inhibitor of HIF-1α signaling pathway, has been proved a promising drug candidate for many kinds of cancer chemotherapy. However, the poor solubility and undesirable pharmacokinetics of FB15 leads to limited treatment efficacy of tumor, which ultimately restricts its potential clinical applications. Carbonic anhydrase IX (CAIX), a tumor cell transmembrane protein, was overexpressed in hypoxia tumor site. Acetazolamide (AZA), a highly selective ligand targeting CAIX, can be utilized to delivery FB15 to hypoxia tumor site.
In this study, we prepared and characterized FB15 loaded nano-mixed micelles with the AZA conjugated poloxamer 188 (AZA-P188) and D-a-Tocopherol Polyethylene 1000 Glycol Succinate (TPGS), denoted as, AZA-P188/TPGS@FB15. Its delivery efficiency in vitro and in vivo was assessed by in vitro drug release, cytotoxicity assay, cellular uptake, and in vivo pharmacokinetics and fluorescence imaging. Finally, therapeutic effect of AZA-P188/TPGS@FB15 was investigated using a preclinical breast cancer subcutaneous graft model in vivo.
In vitro studies revealed that AZA-P188/TPGS@FB15 could efficiently target breast cancer cells mediated by CAIX receptor, trigger FB15 release in response to acidic condition, and enhance cellular uptake and cytotoxicity against breast cancer cells. The pharmacokinetic studies showed that FB15-loaded AZA-functionalized micelles exhibited significantly increased AUC over free FB15. In vivo imaging demonstrated that AZA-functionalized micelles significantly increased the drug distribution in the tumor site. In vivo experiments confirmed that AZA-P188/TPGS@FB15 exhibited superior inhibition of tumor growth in nude mice with good biosafety.
AZA-P188/TPGS@FB15 hold promise as a potentially effective therapeutic way for breast cancer. Its targeted delivery system utilizing AZA as a carrier shows potential for improving the efficacy of FB15 in cancer therapy.
乳腺癌的治疗一直是一个全球性的难题，基于缺氧肿瘤微环境（TME）的靶向策略引起了广泛关注。作为缺氧肿瘤中过度表达的特征转录因子，缺氧诱导因子-1（HIF-1）有助于癌症的进展。我们在早期研究中合成并命名为 FB15 的 7-(3-(2-氯-1H-苯并[d]1 咪唑-1-基)丙氧基)-2-(3,4,5-三甲氧基苯基)-4H-色烯-4-酮是一种潜在的 HIF-1α信号通路抑制剂，已被证明是许多种癌症化疗的有前途的药物候选物。然而，FB15 的溶解度差和不理想的药代动力学导致肿瘤的治疗效果有限，最终限制了其潜在的临床应用。碳酸酐酶 IX（CAIX）是一种肿瘤细胞跨膜蛋白，在缺氧肿瘤部位过度表达。作为高度靶向 CAIX 的配体，乙酰唑胺（AZA）可用于将 FB15 递送到缺氧肿瘤部位。
在这项研究中，我们制备并表征了用 AZA 修饰的泊洛沙姆 188（AZA-P188）和 D-a-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）负载 FB15 的纳米混合胶束，命名为 AZA-P188/TPGS@FB15。通过体外药物释放、细胞毒性测定、细胞摄取和体内药代动力学和荧光成像评估其体外和体内递药效率。最后，通过体内乳腺癌皮下移植模型研究了 AZA-P188/TPGS@FB15 的治疗效果。
体外研究表明，AZA-P188/TPGS@FB15 可以通过 CAIX 受体有效靶向乳腺癌细胞，响应酸性条件触发 FB15 释放，并增强对乳腺癌细胞的细胞摄取和细胞毒性。药代动力学研究表明，负载 FB15 的 AZA 功能化胶束的 AUC 显著高于游离 FB15。体内成像显示，AZA 功能化胶束显著增加了药物在肿瘤部位的分布。体内实验证实，AZA-P188/TPGS@FB15 在裸鼠体内表现出优异的抑制肿瘤生长作用，且具有良好的生物安全性。
AZA-P188/TPGS@FB15 有望成为治疗乳腺癌的一种潜在有效方法。它利用 AZA 作为载体的靶向递药系统显示出提高 FB15 在癌症治疗中的疗效的潜力。
