Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles
Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles
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DOI：
10.1073/pnas.0809154105
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发表时间：
2008-11-11
影响因子：
11.1
通讯作者：
Lippard, Stephen J.
中科院分区：
文献类型：
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作者：
Dhar, Shanta;Gu, Frank X.;Lippard, Stephen J.
顺铂用于治疗多种肿瘤，但剂量限制性毒性或内在和获得性耐药性限制了其在许多类型的癌症（包括前列腺癌）中的应用。我们报告了一种独特的策略，通过构建Pt（IV）封装的前列腺特异性膜抗原（PSMA）靶向聚（D，L-乳酸-共-乙醇酸）（PLGA）-聚（乙二醇）（PEG）-功能化控释聚合物的纳米粒子（NP），将顺铂递送到前列腺癌细胞。通过使用表面上具有PSMA靶向适体（Apt）的PLGA-b-PEG纳米颗粒作为铂（IV）化合物c，t，c-[Pt（NH3）（2）（O2 CCH 2CH 2CH 2CH 3）（2）Cl-2]（1）的载体，将致死剂量的顺铂特异性地递送至前列腺癌细胞。使用荧光显微镜，通过绿色荧光标记的胆固醇包封的NP和早期内体标记物EEA-1的共定位，证明了通过纳米颗粒载体的内吞作用将Pt（IV）货物靶向递送至PSMA（+）LNCaP前列腺癌细胞。1中线性己基链的选择是系统研究的结果，以优化包封和从聚合物中的受控释放，而不损害任一特征。通过使用单克隆抗体的加合物，从聚合物纳米颗粒释放顺铂后，1和顺铂1，2-链内d（GpG）的核DNA上的交联的形成。在表面上具有PSMA适体的Pt（IV）包封的PLGA-b-PEG NP（Pt-NP-Apt）、顺铂和非靶向Pt（IV）包封的NP（Pt-NP）对人前列腺PSMA过表达的LNCaP和PSMA（-）PC 3癌细胞的细胞毒性活性之间的比较显示出显著差异。靶向PSMA的Pt-NP-Apt纳米颗粒对PSMA（+）LNCaP细胞的有效性比游离顺铂的有效性大约大一个数量级。
Cisplatin is used to treat a variety of tumors, but dose limiting toxicities or intrinsic and acquired resistance limit its application in many types of cancer including prostate. We report a unique strategy to deliver cisplatin to prostate cancer cells by constructing Pt(IV)-encapsulated prostate-specific membrane antigen (PSMA) targeted nanoparticles (NPs) of poly(D,L-lactic-co-glycolic acid) (PLGA)-poly(ethylene glycol) (PEG)-functionalized controlled release polymers. By using PLGA-b-PEG nanoparticles with PSMA targeting aptamers (Apt) on the surface as a vehicle for the platinum(IV) compound c,t,c-[Pt(NH3)(2)(O2CCH2CH2CH2CH2CH3)(2)Cl-2] (1), a lethal dose of cisplatin was delivered specifically to prostate cancer cells. PSMA aptamer targeted delivery of Pt(IV) cargos to PSMA(+) LNCaP prostate cancer cells by endocytosis of the nanoparticle vehicles was demonstrated using fluorescence microscopy by colocalization of green fluorescent labeled cholesterol-encapsulated NPs and early endosome marker EEA-1. The choice of linear hexyl chains in 1 was the result of a systematic study to optimize encapsulation and controlled release from the polymer without compromising either feature. Release of cisplatin from the polymeric nanoparticles after reduction of 1 and formation of cisplatin 1,2-intrastrand d(GpG) cross-links on nuclear DNA was confirmed by using a monoclonal antibody for the adduct. A comparison between the cytotoxic activities of Pt(IV)-encapsulated PLGA-b-PEG NPs with the PSMA aptamer on the surface (Pt-NP-Apt), cisplatin, and the nontargeted Pt(IV)-encapsulated NPs (Pt-NP) against human prostate PSMA-overexpressing LNCaP and PSMA(-)PC3 cancer cells revealed significant differences. The effectiveness of PSMA targeted Pt-NP-Apt nanoparticles against the PSMA(+) LNCaP cells is approximately an order of magnitude greater than that of free cisplatin.