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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Targeted delivery of a cisplatin prodrug for safer and more effective prostate cancer therapy in vivo
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Targeted delivery of a cisplatin prodrug for safer and more effective prostate cancer therapy in vivo

机译:靶向递送顺铂前药,可在体内进行更安全,更有效的前列腺癌治疗

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摘要

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(NH_3)2-(O_2CCH_2CH_2CH_2CH_2CH_3)_2CI_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), bio-distribution, tolerability, and efficacy of Pt-PLGA-b-PEG-Apt-NP (150±15 nm encapsulating~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.
机译:靶向释放和控制释放非活性铂(Pt)前药可能会提供一种新的方法来提高Pt系列药物的功效和耐受性,该药物可用于治疗当今所有癌症的50%。使用前列腺癌(PCa)作为模型疾病,我们之前描述了以适体(Apt)为靶标的聚(D,L-乳酸-乙醇酸)-b-聚乙二醇(PLGA-b-PEG)的工程设计)封装了Pt(IV)前药c,t,c [Pt(NH_3)2-(O_2CCH_2CH_2CH_2CH_2CH_2CH_3)_2CI_2](1)(Pt-PLGA-b-PEG-Apt-NP)的纳米颗粒(NPs)前列腺特异性膜抗原(PSMA)的结构域,可增强体外细胞毒性。在这里,我们证明了Pt-PLGA-b-PEG-Apt-NP(150±15 nm封装〜5%wt / wt Pt(IV)前药)的体内药代动力学(PK),生物分布,耐受性和功效增强分别与正常Sprague Dawley大鼠,Swiss Albino小鼠和表达PSMA的LNCaP皮下异种移植PCa小鼠模型中常规形式的顺铂相比。一次静脉注射后的10天最大耐受剂量。将大鼠和小鼠中Pt-PLGA-b-PEG-NP的注射剂量分别确定为40 mg / kg和5 mg / kg。用Pt-PLGA-b-PEG-NP进行的PK研究表明,Pt在全身血液循环中的持久性延长,并且Pt在肾脏中的蓄积减少,肾脏是顺铂毒性的主要靶点。 Pt-PLGA-b-PEG-Apt-NPs进一步显示出该药物的明显减量特性,在LNCaP异种移植物中,以传统形式顺铂剂量的1/3(0.3 mg / kg vs. 1 mg / kg)。当考虑到耐受性和功效的同时改善时,Pt-PLGA-b-PEG-Apt NP可显着改善药物治疗指数。

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  • 作者单位

    Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139;

    Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital (BWH), Harvard Medical School, 75 Francis Street, Boston, MA 02115,Massachusetts Institute of Technology (MIT)-Harvard Center for Cancer Nanotechnology Excellence, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge,MA 02139;

    Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139,Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139;

    Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital (BWH), Harvard Medical School, 75 Francis Street, Boston, MA 02115,Massachusetts Institute of Technology (MIT)-Harvard Center for Cancer Nanotechnology Excellence, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge,MA 02139;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    chemotherapy; metals in medicine; biodegradable polymer; nanomedicine;

    机译:化学疗法;药物中的金属;可生物降解的聚合物;纳米药物;

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