Margiotta Nicola, Savino Salvatore, Denora Nunzio, Marzano Cristina, Laquintana Valentino, Cutrignelli Annalisa, Hoeschele James D, Gandin Valentina, Natile Giovanni
Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy.
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy.
Dalton Trans. 2016 Aug 16;45(33):13070-81. doi: 10.1039/c6dt00763e.
Biodegradable, PEG-coated, nanoparticles (NPs) have gained therapeutic application as injectable colloidal systems for the controlled and site-specific release of drugs. In this paper, encapsulation in PLGA-PEG polymer NPs has been exploited to lower the toxicity and to increase the antitumor activity of kiteplatin ([PtCl2(cis-1,4-DACH)]). Kiteplatin contains an isomeric form of the diamine ligand present in oxaliplatin and proved to be particularly active against ovarian and colon cancers. To favor encapsulation of the platinum drug in the hydrophobic core of the polymeric micelles, Pt(iv) prodrugs having hydrophobic carboxylic ligands at the axial positions were used in place of hydrophilic Pt(ii) complexes (compounds 1-4). The size, size distribution, and zeta potential (ZP) were measured by dynamic light scattering (DLS) and laser Doppler velocimetry (LDV), and drug encapsulation efficiency (EE) correlated to the alkyl chain length of the different Pt(iv) prodrugs. The number of the Pt atoms per NP (in the range of 1.3-2.4 × 10(6)) is comparable to that of polysilsesquioxane-based NPs and higher than that found for other nanoparticle platforms. The platinum-loaded PLGA-PEG NPs, tested in vivo in a syngeneic murine solid tumor (LLC), had a higher antitumor effect and, most importantly, were markedly less toxic than kiteplatin.
可生物降解的聚乙二醇包被纳米颗粒（NPs）作为用于药物控释和位点特异性释放的可注射胶体系统已获得治疗应用。在本文中，利用将其包封于聚乳酸-羟基乙酸共聚物-聚乙二醇（PLGA-PEG）聚合物纳米颗粒中来降低毒性并提高卡铂（[PtCl2(cis-1,4-DACH)]）的抗肿瘤活性。卡铂含有奥沙利铂中存在的二胺配体的异构体形式，并被证明对卵巢癌和结肠癌特别有效。为了有利于铂类药物包封在聚合物胶束的疏水核心中，使用了在轴向位置具有疏水羧酸配体的铂（IV）前药来代替亲水性铂（II）配合物（化合物1-4）。通过动态光散射（DLS）和激光多普勒测速法（LDV）测量粒径、粒径分布和zeta电位（ZP），并将药物包封效率（EE）与不同铂（IV）前药的烷基链长度相关联。每个纳米颗粒中铂原子的数量（在1.3 - 2.4×10⁶范围内）与基于聚倍半硅氧烷的纳米颗粒相当，且高于其他纳米颗粒平台。负载铂的PLGA-PEG纳米颗粒在同基因小鼠实体瘤（LLC）中进行体内测试时，具有更高的抗肿瘤效果，最重要的是，其毒性明显低于卡铂。
