Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
J Cell Physiol. 2020 May;235(5):4618-4630. doi: 10.1002/jcp.29339. Epub 2019 Oct 31.
Prostate cancer (PCa) is one of the most prevalent non-drug delivery system cutaneous malignancies. Undoubtedly, introducing novel treatment options to achieve higher therapeutic index will be worthwhile. In this study, we report for the first time, a novel targeted self-assembled based on PEG-PLA nanoparticles (PEG-PLA NPs) containing galbanic acid (GBA) and docetaxel, which was targeted using ((S)-2-(3-((S)-5-amino-1-carboxypentyl) ureido) pentanedioic acid (ACUPA), a small molecule inhibitor targeting prostate-specific membrane antigen (PSMA), in prostate cancer cell line. The prepared NPs were characterized by different analytical methods. The MTT assay was used to compare the anti-proliferation of drugs-loaded PEG-PLA NPs and ACUPA-PEG-PLA against LNCaP (PSMA ) and PC3 (PSMA ) cells. PEG-PLA NPs with an average size of 130-140 nm had an enhanced release of GBA and docetaxel at pH 5.5 compared with pH 7.5. Spectrofluorometric analysis suggested that ACUPA-modified PEG-PLA could effectively enhance the drug uptake in PSMA prostate cancer cells. Cytotoxicity studies showed that the targeted NPs loaded with different concentrations of GBA and fixed concentration of docetaxel (4 nM) have shown higher toxicity (IC 30 ± 3 µM) than both free GBA (80 ± 4.5 µM) and nontargeted NPs (IC 40 ± 4.6 µM) in LNCaP cells. Collectively, these findings suggest that ACUPA-conjugated PEG-PLA nanosystem containing GBA and docetaxel is a viable delivery carrier for various cancer-targeting PSMA that suffer from short circulation half-life and limited therapeutic efficacy.
前列腺癌 (PCa) 是最常见的非药物递送系统皮肤恶性肿瘤之一。毫无疑问，引入新的治疗方案以实现更高的治疗指数将是值得的。在这项研究中，我们首次报道了一种新型靶向自组装基于聚乙二醇-聚乳酸纳米粒（PEG-PLA NPs）的载药系统，其中包含了钩藤碱（GBA）和多西他赛，并使用（S）-2-（3-（（S）-5-氨基-1-羧基戊基）脲基）戊二酸（ACUPA）作为靶向物，ACUPA 是一种针对前列腺特异性膜抗原（PSMA）的小分子抑制剂，用于前列腺癌细胞系。所制备的 NPs 通过不同的分析方法进行了表征。MTT 法用于比较载药 PEG-PLA NPs 和 ACUPA-PEG-PLA 对 LNCaP（PSMA+）和 PC3（PSMA-）细胞的抗增殖作用。PEG-PLA NPs 的平均粒径为 130-140nm，在 pH5.5 下比在 pH7.5 下具有更高的 GBA 和多西他赛释放率。荧光光谱分析表明，ACUPA 修饰的 PEG-PLA 可以有效增强 PSMA 前列腺癌细胞对药物的摄取。细胞毒性研究表明，载有不同浓度 GBA 和固定浓度多西他赛（4nM）的靶向 NPs 在 LNCaP 细胞中的毒性（IC30±3µM）高于游离 GBA（80±4.5µM）和非靶向 NPs（IC40±4.6µM）。综上所述，这些发现表明，载有 GBA 和多西他赛的 ACUPA 缀合 PEG-PLA 纳米系统是一种有前途的用于各种癌症靶向 PSMA 的递送载体，这些载体存在半衰期短和治疗效果有限的问题。
