Department of Chemistry and Pharmacy, Laboratory of Nanomedicine, University of Sassari, 07100 Sassari, Italy.
School of Medicine and Public Health, Department of Dermatology, University of Wisconsin-Madison, Madison WI 53706, USA.
Sci Rep. 2017 Feb 1;7:41573. doi: 10.1038/srep41573.
Earlier we introduced the concept of 'nanochemoprevention' i.e. the use of nanotechnology to improve the outcome of cancer chemoprevention. Here, we extended our work and developed polymeric EGCG-encapsulated nanoparticles (NPs) targeted with small molecular entities, able to bind to prostate specific membrane antigen (PSMA), a transmembrane protein that is overexpressed in prostate cancer (PCa), and evaluated their efficacy in preclinical studies. First, we performed a molecular recognition of DCL- and AG-PEGylation on ligand binding on PSMA active site. Next, the biocompatible polymers PLGA-PEG-A were synthesized and used as base to conjugate DCL or AG to obtain the respective copolymers, needed for the preparation of targeted NPs. The resulting EGCG encapsulating NPs led to an enhanced anti-proliferative activity in PCa cell lines compared to the free EGCG. The behavior of EGCG encapsulated in NPs in modulating apoptosis and cell-cycle, was also determined. Then, in vivo experiments, in mouse xenograft model of prostatic tumor, using EGCG-loaded NPs, with a model of targeted nanosystems, were conducted. The obtained data supported our hypothesis of target-specific enhanced bioavailability and limited unwanted toxicity, thus leading to a significant potential for probable clinical outcome.
早前，我们介绍了“纳米化学预防”的概念，即利用纳米技术来改善癌症化学预防的效果。在这里，我们扩展了我们的工作，开发了靶向前列腺特异性膜抗原（PSMA）的聚合物 EGCG 包封纳米颗粒（NPs），小分子实体能够与 PSMA 结合，PSMA 是一种在前列腺癌（PCa）中过度表达的跨膜蛋白，并在临床前研究中评估了它们的疗效。首先，我们在 PSMA 活性位点上进行了 DCL 和 AG-PEG 化的分子识别，以实现配体结合。接下来，合成了生物相容性聚合物 PLGA-PEG-A，并将其用作基础，将 DCL 或 AG 连接起来，得到用于制备靶向 NPs 的相应共聚物。与游离 EGCG 相比，包封在 NPs 中的 EGCG 导致 PCa 细胞系的增殖活性增强。还确定了 EGCG 包封在 NPs 中对细胞凋亡和细胞周期的调节作用。然后，在前列腺肿瘤的小鼠异种移植模型中进行了体内实验，使用载有 EGCG 的 NPs，作为靶向纳米系统的模型。获得的数据支持了我们的假设，即靶向特异性增强的生物利用度和有限的不必要毒性，从而为可能的临床结果提供了显著的潜力。
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