Rationally designed oxaliplatin-nanoparticle for enhanced antitumor efficacy.
Rationally designed oxaliplatin-nanoparticle for enhanced antitumor efficacy.
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DOI：
10.1088/0957-4484/23/7/075103
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发表时间：
2012-02-24
期刊：
影响因子：
3.5
通讯作者：
Sengupta S
中科院分区：
文献类型：
--
作者：
Paraskar A;Soni S;Roy B;Papa AL;Sengupta S
纳米级药物载体作为癌症化疗药物的载体已被广泛研究。然而，由于纳米粒子的物理化学性质，铂类化疗药物在纳米粒子中的配方一直是一个挑战。描述奥沙利铂纳米粒的报道很少。在这项研究中，我们衍生化了一种聚异丁烯马来酸与氨基葡萄糖共聚的单体单元，它通过一种新的单羧基和O-→铂配位键来螯合反式-1，2-二氨基环己烷铂(II)。在特定的聚合物与铂的比例下，络合物自组装成纳米颗粒，其中聚合单元充当离开基团，以持续的pH依赖方式释放DACH-铂。用动态光散射法和电子显微镜进行施胶。对纳米粒的体外和体内疗效进行了评估。生物分布采用电感耦合等离子体原子吸收光谱分析(ICP-AAS)。PIMA-GA-DACH-铂纳米粒体外活性高于游离奥沙利铂。在体内，纳米粒比奥沙利铂(相当于5 mg/kg铂剂量)对肿瘤的抑制作用更强，肾毒性或体重减轻最小。与游离奥沙利铂相比，PIMA-GA-DACH-铂纳米粒给药后，铂在肿瘤中的蓄积明显优先，肾或肝的生物分布减少。这些结果表明，受奥沙利铂生物激活的启发，合理设计一种新型聚合物纳米颗粒，与母体细胞毒性相比，可以提高抗肿瘤活性，降低全身毒性。在用于癌症化疗的纳米药物的合成中，合理的设计可以成为一种令人兴奋的策略。
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 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 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 inductive-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 5mg/kg 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.
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影响因子：
15
作者：
Brown, Sarah D.;Nativo, Paola;Smith, Jo-Ann;Stirling, David;Edwards, Paul R.;Venugopal, Balaji;Flint, David J.;Plumb, Jane A.;Graham, Duncan;Wheate, Nial J.
通讯作者：
Wheate, Nial J.
影响因子：
14
作者：
LEE, KY;HA, WS;PARK, WH
通讯作者：
PARK, WH
DOI：
10.1073/pnas.1007026107
发表时间：
2010-07-13
影响因子：
11.1
作者：
Paraskar, Abhimanyu S.;Soni, Shivani;Sengupta, Shiladitya
通讯作者：
Sengupta, Shiladitya
DOI：
10.1111/j.1365-2613.2009.00684.x
发表时间：
2010-02-01
影响因子：
3
作者：
Shen, Fang-Zhen;Wang, Jing;Wang, Yan-Tao
通讯作者：
Wang, Yan-Tao
影响因子：
8.4
作者：
Gianasi, E;Wasil, M;Duncan, R
通讯作者：
Duncan, R