Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy
Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy
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DOI：
10.1073/pnas.1011368107
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发表时间：
2010-10-19
影响因子：
11.1
通讯作者：
Farokhzad, Omid C.
中科院分区：
文献类型：
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作者：
Kolishetti, Nagesh;Dhar, Shanta;Farokhzad, Omid C.
基因组革命已经确定了许多疾病的治疗靶点，因此需要开发强大的联合药物治疗技术。在目前的工作中，我们描述了一种自组装的聚合物纳米颗粒（NP）平台，以精确地靶向和控制具有不同物理化学性质的药物向癌细胞的共递送。作为概念的证明，我们将顺铂和多西他赛（Dtxl）编码为具有协同细胞毒性的前列腺癌细胞。制备了侧羟基聚乳酸（PLA）衍生物并将其与铂（IV）[Pt（IV）]前药c，t，c-[Pt（NH3）（2）（O2 CCH 2CH 2COOH）（OH）Cl-2] [PLA=Pt（IV）]缀合。在存在或不存在Dtxl的情况下，PLA-Pt（IV）官能化聚合物和羧基封端的聚（D，L-乳酸-共-乙醇酸）-嵌段-聚（乙二醇）共聚物的共混物在微流体通道中转化为直径接近的NP 100纳米。该方法产生了优异的包封效率（EE）和亲水性铂前药和疏水性Dtxl两者的高负载，具有可再现的EE和负载。纳米颗粒的表面用A10适体衍生化，其结合前列腺癌细胞上的前列腺特异性膜抗原（PSMA）。这些NP在48-72小时内经历两种药物的受控释放。靶向的NP通过胞吞作用被表达PSMA的LNCaP细胞内化，并验证了顺铂1，2-d（GpG）链内交联在核DNA上的形成。体外毒性证明靶向双药组合NP优于单药NP或非靶向NP。这项工作揭示了一个单一的，可编程的纳米粒子混合和提供癌症治疗药物组合的潜力。
The genomic revolution has identified therapeutic targets for a plethora of diseases, creating a need to develop robust technologies for combination drug therapy. In the present work, we describe a self-assembled polymeric nanoparticle (NP) platform to target and control precisely the codelivery of drugs with varying physicochemical properties to cancer cells. As proof of concept, we code-livered cisplatin and docetaxel (Dtxl) to prostate cancer cells with synergistic cytotoxicity. A polylactide (PLA) derivative with pendant hydroxyl groups was prepared and conjugated to a platinum(IV) [Pt(IV)] prodrug, c,t,c-[Pt(NH3)(2)(O2CCH2CH2COOH)(OH)Cl-2] [PLA=Pt(IV)]. A blend of PLA-Pt(IV) functionalized polymer and carboxylterminated poly(D, L-lactic-co-glycolic acid)-block-poly(ethylene glycol) copolymer in the presence or absence of Dtxl, was converted, in microfluidic channels, to NPs with a diameter of similar to 100 nm. This process resulted in excellent encapsulation efficiency (EE) and high loading of both hydrophilic platinum prodrug and hydrophobic Dtxl with reproducible EEs and loadings. The surface of the NPs was derivatized with the A10 aptamer, which binds to the prostate-specific membrane antigen (PSMA) on prostate cancer cells. These NPs undergo controlled release of both drugs over a period of 48-72 h. Targeted NPs were internalized by the PSMA-expressing LNCaP cells via endocytosis, and formation of cisplatin 1,2-d(GpG) intrastrand cross-links on nuclear DNA was verified. In vitro toxicities demonstrated superiority of the targeted dual-drug combination NPs over NPs with single drug or nontargeted NPs. This work reveals the potential of a single, programmable nanoparticle to blend and deliver a combination of drugs for cancer treatment.