The paper presents the results of the experimental and analytical study of targeted drug-loaded polymer-based microspheres made from blend polymer of polylactic-co-glycolic acid and polycaprolactone (PLGA-PCL) for targeted and localized cancer drug delivery. In vitro sustained release with detailed thermodynamically driven drug release kinetics, over a period of three months using encapsulated targeted drugs (prodigiosin-EphA2 or paclitaxel-EphA2) and control drugs [Prodigiosin (PGS), and paclitaxel (PTX)] were studied. Results from in vitro study showed a sustained and localized drug release that is well-characterized by non-Fickian Korsmeyer–Peppas kinetics model over the range of temperatures of 37 °C (body temperature), 41 °C, and 44 °C (hyperthermic temperatures). The in vitro alamar blue, and flow cytometry assays in the presence of the different drug-loaded polymer formulations resulted to cell death and cytotoxicity that was evidence through cell inhibition and late apoptosis on triple negative breast cancer (TNBC) cells (MDA-MB 231). In vivo studies carried out on groups of 4-week-old athymic nude mice that were induced with subcutaneous TNBC, showed that the localized release of the EphA2-conjugated drugs was effective in complete elimination of residual tumor after local surgical resection. Finally, ex vivo histopathological analysis carried out on the euthanized mice revealed no cytotoxicity and absence of breast cancer metastases in the liver, kidney, and lungs 12 weeks after treatment. The implications of the results are then discussed for the development of encapsulated EphA2-conjugated drugs formulation in the specific targeting, localized, and sustain drug release for the elimination of local recurred TNBC tumors after surgical resection.

Graphical Abstract

中文翻译：

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靶向载药PLGA-PCL微球用于三阴性乳腺癌的特异性和局部治疗

本文介绍了由聚乳酸-乙醇酸和聚己内酯共混聚合物（PLGA-PCL）制成的靶向载药聚合物微球用于靶向和局部癌症药物递送的实验和分析研究结果。使用封装的靶向药物（灵菌红-EphA2 或紫杉醇-EphA2）和对照药物[灵菌红 (PGS) 和紫杉​​醇 (PTX)] 在三个月的时间内研究了具有详细热力学驱动的药物释放动力学的体外缓释。体外研究结果显示，在 37 °C（体温）、41 °C 和 44 °C（高温）温度范围内，药物持续且局部释放，这一点通过非 Fickian Korsmeyer-Peppas 动力学模型得到了很好的表征。温度）。在存在不同载药聚合物制剂的情况下进行的体外阿尔玛蓝和流式细胞术测定导致细胞死亡和细胞毒性，这通过三阴性乳腺癌 (TNBC) 细胞 (MDA-MB 231) 的细胞抑制和晚期凋亡得到证明。 ）。对皮下 TNBC 诱导的 4 周龄无胸腺裸鼠组进行的体内研究表明，EphA2 结合药物的局部释放可有效完全消除局部手术切除后残留的肿瘤。最后，对安乐死小鼠进行的离体组织病理学分析显示，治疗 12 周后，没有细胞毒性，并且肝脏、肾脏和肺部不存在乳腺癌转移。然后讨论了这些结果对开发封装的 EphA2 缀合药物制剂的影响，该制剂可用于特异性靶向、局部和持续药物释放，以消除手术切除后局部复发的 TNBC 肿瘤。

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