BWH-HST Center for Biomedical Engineering, Harvard Medical School, Cambridge, MA 02139, USA.
Nanotechnology. 2011 Jul 1;22(26):265101. doi: 10.1088/0957-4484/22/26/265101. Epub 2011 May 17.
The use of cisplatin, a first line chemotherapy for most cancers, is dose-limited due to nephrotoxicity. While this toxicity can be addressed through nanotechnology, previous attempts at engineering cisplatin nanoparticles have been limited by the impact on the potency of cisplatin. Here we report the rational engineering of a novel cisplatin nanoparticle by harnessing a novel polyethylene glycol-functionalized poly-isobutylene-maleic acid (PEG-PIMA) copolymer, which can complex with cis-platinum (II) through a monocarboxylato and a coordinate bond. We show that this complex self-assembles into a nanoparticle, and exhibits an IC(50) = 0.77 ± 0.11 µM comparable to that of free cisplatin (IC(50) = 0.44 ± 0.09 µM). The nanoparticles are internalized into the endolysosomal compartment of cancer cells, and release cisplatin in a pH-dependent manner. Furthermore, the nanoparticles exhibit significantly improved antitumor efficacy in a 4T1 breast cancer model in vivo, with limited nephrotoxicity, which can be explained by preferential biodistribution in the tumor with reduced kidney concentrations. Our results suggest that the PEG-PIMA-cisplatin nanoparticle can emerge as an attractive solution to the challenges in cisplatin chemotherapy.
顺铂是大多数癌症的一线化疗药物，但由于肾毒性，其使用剂量受到限制。虽然纳米技术可以解决这种毒性问题，但以前在工程化顺铂纳米粒子方面的尝试受到了对顺铂效力的影响的限制。在这里，我们通过利用一种新型的聚乙二醇功能化聚异丁烯-马来酸（PEG-PIMA）共聚物来合理地设计了一种新型的顺铂纳米粒子，该共聚物可以通过单羧酸盐和配位键与顺铂（II）络合。我们表明，这种复合物可以自组装成纳米粒子，并表现出与游离顺铂（IC（50）= 0.44 ± 0.09 μM）相当的 IC（50）= 0.77 ± 0.11 μM。纳米粒子被内吞到癌细胞的内溶酶体区室中，并以 pH 依赖性的方式释放顺铂。此外，这些纳米粒子在体内 4T1 乳腺癌模型中表现出显著提高的抗肿瘤疗效，同时肾毒性有限，这可以通过在肿瘤中优先分布而减少肾脏浓度来解释。我们的结果表明，PEG-PIMA-顺铂纳米粒子可能成为顺铂化疗面临的挑战的一种有吸引力的解决方案。
