Polymeric Engineering of Aptamer-Drug Conjugates for Targeted Cancer Therapy.,Bioconjugate Chemistry

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Polymeric Engineering of Aptamer-Drug Conjugates for Targeted Cancer Therapy.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2019-12-16 , DOI: 10.1021/acs.bioconjchem.9b00715
Zhengyu Deng ₁ , Qiuxia Yang ₁ , Yongbo Peng ₁ , Jiaxuan He ₁ , Shujuan Xu _{1,

2} , Dan Wang ₁ , Tianhuan Peng ₁ , Ruowen Wang ₃ , Xue-Qiang Wang ₁ , Weihong Tan _{1,

2,

3,

4}

Affiliation

Nucleic acid aptamers, also known as "chemical antibodies", have been widely employed in targeted cancer therapy and diagnosis. For example, aptamer-drug conjugates (ApDCs), through covalent conjugation of cytotoxic warheads to aptamers, have demonstrated anticancer efficacy both in vitro and in vivo. However, a general strategy to endow ApDCs with enhanced biostability, prolonged circulation half-life, and high drug loading content remained elusive. Herein, we present a polymeric approach to engineer ApDCs via conjugation of cell-targeting aptamers with water-soluble polyprodrugs containing a reductive environmentally sensitive prodrug and biocompatible brush-like backbone. The resultant high-drug loading Aptamer-PolyproDrug Conjugates (ApPDCs) exhibited high nuclease resistance, extended in vivo circulation time, specific recognition, and cellular uptake to target cells, reduction-triggered and fluorescent-reporting drug release, and effective cytotoxicity. We could also further expand this design principle toward combination therapy by using two kinds of therapeutic drugs with distinct pharmacological mechanisms.

中文翻译：

适体-药物缀合物的聚合物工程用于靶向癌症治疗。

核酸适体，也称为“化学抗体”，已广泛用于靶向癌症的治疗和诊断。例如，通过细胞毒性弹头与适体的共价缀合，适体-药物缀合物（ApDC）已在体外和体内均显示出抗癌功效。但是，赋予ApDC更高的生物稳定性，延长的循环半衰期和较高的药物载量的一般策略仍然遥不可及。在这里，我们提出了一种聚合方法，可通过将靶向细胞的适体与含有还原性环境敏感型前药和生物相容性刷状骨架的水溶性多药前药缀合来工程化ApDC。所得高载药量的适体-PolyproDrug共轭物（ApPDC）表现出高核酸酶抗性，延长了体内循环时间，特异性识别，以及细胞对靶细胞的吸收，减少触发和荧光报告的药物释放以及有效的细胞毒性。我们还可以通过使用两种具有不同药理机制的治疗药物，进一步将这种设计原理扩展到组合治疗。

更新日期：2019-12-17

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