Department of Medicine, Brigham and Women's Hospital, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12435-40. doi: 10.1073/pnas.1007026107. Epub 2010 Jun 23.
Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O --> Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 +/- 0.16 microM) comparable to that of free cisplatin (3.87 +/- 0.37 microM), and superior to carboplatin (14.75 +/- 0.38 microM). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-ras(LSL/+)/Pten(fl/fl) ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer.
顺铂是大多数类型癌症的一线化疗药物。然而，由于严重的肾毒性，其使用受到剂量限制。在这里，我们报告了一种受顺铂生物活化机制启发的新型纳米铂酸盐的合理工程设计。我们设计了一种新型聚合物，即葡糖胺官能化聚异丁烯-马来酸，其中铂 (Pt) 可以使用单羧酸盐和 O --> Pt 配位键与单体单元络合。我们表明，在独特的铂与聚合物比例下，该复合物自组装成纳米颗粒，以 pH 依赖性方式释放顺铂。这些纳米颗粒迅速被内化到癌细胞的内溶酶体隔间中，并表现出与游离顺铂（3.87 +/- 0.37 microM）相当的 IC50（4.25 +/- 0.16 microM），优于卡铂（14.75 +/- 0.38 microM）。这些纳米颗粒在乳腺癌和肺癌的肿瘤生长延迟以及 K-ras(LSL/+)/Pten(fl/fl)卵巢癌模型中的肿瘤消退方面表现出显著改善的抗肿瘤疗效。此外，纳米颗粒治疗导致全身和肾毒性降低，这通过使用电感耦合等离子体光谱法定量测量铂向肾脏的生物分布减少得到验证。鉴于对更好的铂酸盐的普遍需求，我们预计这种纳米技术和结构-活性关系的结合可以在癌症的临床治疗方面在全球范围内产生重大影响。
