Department of Pharmaceutical Chemistry, The University of Kansas , Simons Laboratories, 2095 Constant Ave. Rm. 136B, Lawrence, Kansas 66047, United States.
Mol Pharm. 2012 Jun 4;9(6):1705-16. doi: 10.1021/mp3000309. Epub 2012 May 1.
TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110β catalytic subunit. Recent studies showed that TGX-221 has antiproliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles was significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than that of the naked drug, and the drug clearance rate was 6.16-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment.
TGX-221 是一种有效的、选择性的、细胞膜通透性的 PI3K p110β 催化亚基抑制剂。最近的研究表明，TGX-221 对包括前列腺癌在内的 PTEN 缺失的肿瘤细胞系具有抗增殖活性。本研究的目的是开发一种封装系统，通过前列腺特异性膜适体（PSMAa10）将 TGX-221 递送至靶组织，同时几乎没有或没有副作用。在这项研究中，制备了 PEG-PCL 胶束来包裹药物，并采用前药策略来提高载体系统的稳定性。荧光成像研究表明，在 PSMA 阳性细胞系中，靶向胶束显著提高了药物和纳米颗粒的细胞摄取。裸鼠体内胶束制剂的血浆浓度时间曲线下面积是裸药的 2.27 倍，药物清除率慢 6.16 倍。这些发现为提高针对特定部位的分子靶向前列腺癌治疗药物的递送提供了一种新的制剂方法。
