Targeted delivery of a cisplatin prodrug for safer and more effective prostate cancer therapy in vivo
Targeted delivery of a cisplatin prodrug for safer and more effective prostate cancer therapy in vivo
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DOI：
10.1073/pnas.1011379108
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发表时间：
2011-02-01
影响因子：
11.1
通讯作者：
Farokhzad, Omid C.
中科院分区：
文献类型：
--
作者：
Dhar, Shanta;Kolishetti, Nagesh;Farokhzad, Omid C.
非活性铂（Pt）前药的靶向递送和控释可能提供一种新的方法来改善Pt家族药物的疗效和耐受性，这些药物目前用于治疗50%的癌症。使用前列腺癌（PCa）作为模型疾病，我们先前描述了适体（Apt）靶向多聚核苷酸的工程化，（D，L-乳酸-羟基乙酸共聚物）-b-聚（乙二醇）（PLGA-b-PEG）纳米颗粒（NP），其包封Pt（IV）前药c，t，c[ Pt（NH3）（2）-（O2 CCH 2CH 2CH 2CH 2CH 3）（2）Cl-2]（1）（Pt-PLGA-b-PEG-Apt-NP），其靶向前列腺特异性膜抗原（PSMA）的细胞外结构域，用于增强体外细胞毒性。在此，我们分别在正常Sprague道利大鼠、Swiss白化病小鼠和表达PSMA的LNCaP皮下异种移植PCa小鼠模型中，证明了与以其常规形式给药的顺铂相比，Pt-PLGA-b-PEG-Apt-NP（150 +/- 15 nm封装，类似于5% wt/wt Pt（IV）前药）的体内药代动力学（PK）、生物分布、耐受性和疗效增强。大鼠和小鼠单次静脉注射Pt-PLGA-b-PEG-NP后的10天最大耐受剂量分别为40 mg/kg和5 mg/kg。Pt-PLGA-b-PEG-NP的PK研究显示，铂在全身血液循环中的持久性延长，铂在肾脏（顺铂毒性的主要靶部位）中的蓄积减少。Pt-PLGA-b-PEG-Apt-NP进一步显示出药物的显著剂量节省特征，在LNCaP异种移植物中，以其常规形式施用的顺铂的1/3剂量（0.3 mg/kg vs. 1 mg/kg）具有等同的抗肿瘤功效。当考虑耐受性和疗效的同时改善时，Pt-PLGA-b-PEG-Apt NP提供了药物治疗指数的显著改善。
Targeted delivery and controlled release of inactive platinum (Pt) prodrugs may offer a new approach to improve the efficacy and tolerability of the Pt family of drugs, which are used to treat 50% of all cancers today. Using prostate cancer (PCa) as a model disease, we previously described the engineering of aptamer (Apt)targeted poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles (NPs) encapsulating a Pt(IV) prodrug c,t,c[ Pt(NH3)(2)-(O2CCH2CH2CH2CH2CH3)(2)Cl-2] (1) (Pt-PLGA-b-PEG-Apt-NP), which target the extracellular domain of the prostate specific membrane antigen (PSMA), for enhanced in vitro cytotoxicity. Here we demonstrate enhanced in vivo pharmacokinetics (PK), biodistribution, tolerability, and efficacy of Pt-PLGA-b-PEG-Apt-NP (150 +/- 15 nm encapsulating similar to 5% wt/wt Pt(IV) prodrug) when compared to cisplatin administered in its conventional form in normal Sprague Dawley rats, Swiss Albino mice, and the PSMA-expressing LNCaP subcutaneous xenograft mouse model of PCa, respectively. The 10-d maximum tolerated dose following a single i.v. injection of Pt-PLGA-b-PEG-NP in rats and mice was determined at 40 mg/kg and 5 mg/kg, respectively. PK studies with Pt-PLGA-b-PEG-NP revealed prolonged Pt persistence in systemic blood circulation and decreased accumulation of Pt in the kidneys, a major target site of cisplatin toxicity. Pt-PLGA-b-PEG-Apt-NPs further displayed the significant dose-sparing characteristics of the drug, with equivalent antitumor efficacy in LNCaP xenografts at 1/3 the dose of cisplatin administered in its conventional form (0.3 mg/kg vs. 1 mg/kg). When considering the simultaneous improvement in tolerability and efficacy, the Pt-PLGA-b-PEG-Apt NP provides a remarkable improvement in the drug therapeutic index.