Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy
Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy
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DOI：
10.1073/pnas.1007026107
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发表时间：
2010-07-13
影响因子：
11.1
通讯作者：
Sengupta, Shiladitya
中科院分区：
文献类型：
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作者：
Paraskar, Abhimanyu S.;Soni, Shivani;Sengupta, Shiladitya
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，我们报告的合理工程的一种新的nanoplatinate灵感的机制，顺铂的生物活化。我们设计了一种新的聚合物，葡糖胺官能化的聚异丁烯-马来酸，其中铂（Pt）可以使用单羧基和O -> Pt配位键络合到单体单元。我们表明，在一个独特的铂聚合物的比例，这种复杂的自组装成纳米粒子，释放顺铂在pH值依赖性的方式。纳米颗粒被迅速内化到癌细胞的内溶酶体区室中，并且表现出与游离顺铂（3.87 +/-0.37 μ M）相当的IC 50（4.25 + 0.16 μ M），并且上级于卡铂（14.75 +/-0.38 μ M）。在乳腺癌和肺癌中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，纳米颗粒表现出显著改善的抗肿瘤功效。此外，纳米颗粒治疗导致全身毒性和肾毒性降低，通过使用电感耦合等离子体光谱法定量的铂到肾脏的生物分布降低来验证。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-活性关系的耦合，以合理地重新设计顺铂，可能会在全球范围内对癌症的临床治疗产生重大影响。
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 mu M) comparable to that of free cisplatin (3.87 +/- 0.37 mu M), and superior to carboplatin (14.75 +/- 0.38 mu M). 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.