Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, TX, United States; Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China; Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, TX, United States.
Nanomedicine. 2019 Jul;19:71-80. doi: 10.1016/j.nano.2019.03.012. Epub 2019 Apr 17.
Low tumor specificity and multidrug resistance (MDR) remain challenging for many anticancer drugs. In this study, the micelles assembled by a matrix metalloproteinase 2 (MMP2)-sensitive self-assembling efflux inhibitor (PEG2k-pp-PE) were developed and evaluated in various cancer models. In vitro, the PEG2k-pp-PE micelles enhanced the cellular uptake and tissue penetration and sensitized the cancers to drug treatments in MDR cancer cells and their three-dimensional multicellular spheroids. Their efflux inhibitory capability was comparable to those of the well-known small-molecule P-glycoprotein (P-gp) inhibitor and polymeric P-gp inhibitor. In vivo, the PEG2k-pp-PE micelles could specifically and effectively deliver the loaded cargoes to the tumor, as evidenced by the enhanced drug accumulation and prolonged drug retention in the tumor tissue, resulting in the improved anticancer activity. Our results suggest that the PEG2k-pp-PE micelles may have great potential to be a simple but multifunctional nanocarrier for concurrent tumor-targeted drug delivery and sensitization of resistant cancers.
低肿瘤特异性和多药耐药性（MDR）仍然是许多抗癌药物面临的挑战。在这项研究中，开发了由基质金属蛋白酶 2（MMP2）敏感自组装外排抑制剂（PEG2k-pp-PE）组装的胶束，并在各种癌症模型中进行了评估。在体外，PEG2k-pp-PE 胶束增强了细胞摄取和组织穿透能力，并使耐药性癌症及其三维多细胞球体对药物治疗敏感。其外排抑制能力可与著名的小分子 P 糖蛋白（P-gp）抑制剂和聚合物 P-gp 抑制剂相媲美。在体内，PEG2k-pp-PE 胶束可以特异性和有效地将负载的货物递送到肿瘤部位，这可以通过增强药物在肿瘤组织中的积累和延长药物保留时间来证明，从而提高了抗癌活性。我们的结果表明，PEG2k-pp-PE 胶束可能具有巨大的潜力成为一种简单但多功能的纳米载体，用于同时进行肿瘤靶向药物递送和耐药性癌症的增敏。
