Triple negative breast cancer (TNBC) represents the most aggressive and heterogenous disease, and combination therapy holds promising potential. Here, an enzyme-responsive polymeric prodrug with self-assembly properties was synthesized for targeted co-delivery of paclitaxel (PTX) and ursolic acid (UA). Hyaluronic acid (HA) was conjugated with UA, yielding an amphiphilic prodrug with 13.85 mol% UA and a CMC of 32.3 μg/mL. The HA-UA conjugate exhibited ∼14 % and 47 % hydrolysis at pH 7.4 and in tumor cell lysate. HA-UA/PTX NPs exhibited a spherical structure with 173 nm particle size, and 0.15 PDI. The nanoparticles showed high drug loading (11.58 %) and entrapment efficiency (76.87 %) of PTX. Release experiments revealed accelerated drug release (∼78 %) in the presence of hyaluronidase enzyme. Cellular uptake in MDA-MB-231 cells showed enhanced uptake of HA-UA/PTX NPs through CD44 receptor-mediated endocytosis. , HA-UA/PTX NPs exhibited higher cytotoxicity, apoptosis, and mitochondrial depolarization compared to PTX alone. , HA-UA/PTX NPs demonstrated improved pharmacokinetic properties, with 2.18, 2.40, and 2.35-fold higher AUC, t, and MRT compared to free PTX. Notably, HA-UA/PTX NPs exhibited superior antitumor efficacy with a 90 % tumor inhibition rate in 4T1 tumor model and low systemic toxicity, showcasing their significant potential as carriers for TNBC combination therapy.

中文翻译：

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揭示熊果酸修饰的透明质酸盐纳米颗粒用于三阴性乳腺癌联合药物治疗的潜力


三阴性乳腺癌（TNBC）是最具侵袭性和异质性的疾病，联合治疗具有广阔的前景。在这里，合成了一种具有自组装特性的酶响应性聚合物前药，用于紫杉醇（PTX）和熊果酸（UA）的靶向共递送。透明质酸 (HA) 与 UA 缀合，产生 UA 含量为 13.85 mol%、CMC 为 32.3 μg/mL 的两亲性前药。 HA-UA 缀合物在 pH 7.4 和肿瘤细胞裂解液中表现出 ~14% 和 47% 的水解。 HA-UA/PTX NPs 呈现球形结构，粒径为 173 nm，PDI 为 0.15。纳米颗粒对 PTX 具有较高的载药量 (11.58%) 和包封率 (76.87%)。释放实验表明，在透明质酸酶存在下，药物释放加速（∼78%）。 MDA-MB-231 细胞的细胞摄取显示通过 CD44 受体介导的内吞作用增强了 HA-UA/PTX NP 的摄取。与单独的 PTX 相比，HA-UA/PTX NPs 表现出更高的细胞毒性、细胞凋亡和线粒体去极化。 ，HA-UA/PTX NPs 表现出改善的药代动力学特性，与游离 PTX 相比，AUC、t 和 MRT 高出 2.18、2.40 和 2.35 倍。值得注意的是，HA-UA/PTX NPs 在 4T1 肿瘤模型中表现出优异的抗肿瘤功效，肿瘤抑制率为 90%，且全身毒性低，显示出其作为 TNBC 联合治疗载体的巨大潜力。