Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Cambridge, MA 02139, USA.
Nanotechnology. 2012 Feb 24;23(7):075103. doi: 10.1088/0957-4484/23/7/075103.
Nanoscale drug delivery vehicles have been extensively studied as carriers for cancer chemotherapeutics. However, the formulation of platinum chemotherapeutics in nanoparticles has been a challenge arising from their physicochemical properties. There are only a few reports describing oxaliplatin nanoparticles. In this study, we derivatized the monomeric units of a polyisobutylene maleic acid copolymer with glucosamine, which chelates trans-1,2-diaminocyclohexane (DACH) platinum (II) through a novel monocarboxylato and O --> Pt coordination linkage. At a specific polymer to platinum ratio, the complex self-assembled into a nanoparticle, where the polymeric units act as the leaving group, releasing DACH-platinum in a sustained pH-dependent manner. Sizing was done using dynamic light scatter and electron microscopy. The nanoparticles were evaluated for efficacy in vitro and in vivo. Biodistribution was quantified using inductively coupled plasma atomic absorption spectroscopy (ICP-AAS). The PIMA-GA-DACH-platinum nanoparticle was found to be more active than free oxaliplatin in vitro. In vivo, the nanoparticles resulted in greater tumor inhibition than oxaliplatin (equivalent to 5 mg kg⁻¹ platinum dose) with minimal nephrotoxicity or body weight loss. ICP-AAS revealed significant preferential tumor accumulation of platinum with reduced biodistribution to the kidney or liver following PIMA-GA-DACH-platinum nanoparticle administration as compared with free oxaliplatin. These results indicate that the rational engineering of a novel polymeric nanoparticle inspired by the bioactivation of oxaliplatin results in increased antitumor potency with reduced systemic toxicity compared with the parent cytotoxic. Rational design can emerge as an exciting strategy in the synthesis of nanomedicines for cancer chemotherapy.
纳米级药物输送载体已被广泛研究作为癌症化疗药物的载体。然而，由于其物理化学性质，铂类化疗药物在纳米颗粒中的制剂一直是一个挑战。仅有少数报道描述了奥沙利铂纳米颗粒。在这项研究中，我们用葡糖胺衍生了聚异丁烯马来酸共聚物的单体单元，该共聚物通过新颖的单羧酸盐和 O --> Pt 配位键螯合顺式-1,2-二氨基环己烷（DACH）铂（II）。在特定的聚合物与铂的比例下，该复合物自组装成纳米颗粒，其中聚合物单元作为离去基团，以持续依赖 pH 的方式释放 DACH-铂。通过动态光散射和电子显微镜进行了粒径测定。评估了纳米颗粒的体外和体内疗效。使用电感耦合等离子体原子吸收光谱法（ICP-AAS）定量测定生物分布。发现 PIMA-GA-DACH-铂纳米颗粒在体外比游离奥沙利铂更有效。在体内，纳米颗粒导致的肿瘤抑制作用大于奥沙利铂（相当于 5mgkg⁻¹铂剂量），同时肾毒性或体重减轻最小。与游离奥沙利铂相比，ICP-AAS 显示出铂在肿瘤中的显著优先积累，而在 PIMA-GA-DACH-铂纳米颗粒给药后，铂在肾脏或肝脏中的生物分布减少。这些结果表明，受奥沙利铂生物活化启发的新型聚合物纳米颗粒的合理设计可提高抗肿瘤效力，同时降低全身毒性，优于亲代细胞毒性药物。合理设计可能成为癌症化疗纳米医学合成的令人兴奋的策略。
