Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China.
Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China.
Int J Pharm. 2022 Nov 25;628:122330. doi: 10.1016/j.ijpharm.2022.122330. Epub 2022 Oct 22.
Nucleic acid aptamers (Apt) are RNA or DNA fragments that can bind specifically to a target molecule or to a target substrate with great affinity, thus has attracted great attention for diagnosis and treatment of various malignant diseases. Two primary strategies reported for efficient incorporation of Apt into a nanocarrier include physical encapsulation via electrostatic interactions and chemical conjugation via covalent bonds. Generally, physical encapsulation offers an easier approach for Apt functionalization than covalent bonding that involves sophisticated chemical design as well as synthesis and purification procedures. However, the effect of Apt's incorporation strategies on the property and performance of Apt-functionalized nanocarriers, to our knowledge, remains unclear, which clearly hampers the biomedical applications and potential clinical translations of Apt-decorated delivery systems. To clarify this critical issue toward better performance of Apt for biomedical applications, an Apt moiety with a specific targeting property to liver cancer cells was introduced to a previously fabricated polymeric prodrug, chitosan-5-fluorouracil-1-acetic acid (CS-FU) via either an amide link or electrostatic interactions to afford two types of Apt-functionalized polymeric prodrugs, i.e., Apt/CS-FU and Apt-CS-FU with an equivalent amount of incorporated Apt, respectively. The in vivo and in vitro anti-tumor efficacy and targeting properties of these two Apt-functionalized polymeric prodrugs were investigated and further compared in detail. Interestingly, the two self-assembled micelles showed almost identical in vitro targeting and antitumor efficiency, but Apt-CS-FU mediated 1.5-fold greater tumor inhibition rate (TIR) than Apt/CS-FU in murine tumor models. The better performance of Apt-CS-FU than that of Apt/CS-FU was substantially attributed to the smaller size of Apt-CS-FU than that of Apt/CS-FU in the presence of serum for prolonged in vivo circulation. The first disclosed Apt incorporation strategy effects on the performance and property of Apt-decorated nanocarriers is believed to promote rational design and future clinical translations of Apt-functionalized nanoplatforms with greater therapeutic efficiency.
核酸适体（Apt）是能够与靶分子或靶底物特异性结合的 RNA 或 DNA 片段，具有很高的亲和力，因此引起了人们对各种恶性疾病的诊断和治疗的极大关注。目前报道的两种将 Apt 有效整合到纳米载体中的主要策略包括通过静电相互作用的物理包封和通过共价键的化学偶联。通常，与涉及复杂化学设计以及合成和纯化步骤的共价键结合相比，物理包封为 Apt 功能化提供了一种更容易的方法。然而，据我们所知，Apt 掺入策略对 Apt 功能化纳米载体的性质和性能的影响尚不清楚，这显然阻碍了 Apt 修饰的递药系统的生物医学应用和潜在的临床转化。为了阐明这个关键问题，以提高 Apt 在生物医学应用中的性能，将具有特定肝癌细胞靶向性的 Apt 部分通过酰胺键或静电相互作用引入到先前制备的聚合物前药壳聚糖-5-氟尿嘧啶-1-乙酸（CS-FU）中，得到两种类型的 Apt 功能化聚合物前药，即 Apt/CS-FU 和 Apt-CS-FU，其掺入的 Apt 量相等。研究了这两种 Apt 功能化聚合物前药的体内和体外抗肿瘤功效和靶向特性，并进一步进行了详细比较。有趣的是，这两种自组装胶束在体外显示出几乎相同的靶向性和抗肿瘤效率，但 Apt-CS-FU 在小鼠肿瘤模型中比 Apt/CS-FU 介导的肿瘤抑制率（TIR）高 1.5 倍。与 Apt/CS-FU 相比，Apt-CS-FU 的性能更好，主要归因于在存在血清的情况下，Apt-CS-FU 的尺寸比 Apt/CS-FU 小，从而延长了体内循环时间。相信首次揭示的 Apt 掺入策略对 Apt 修饰纳米载体的性能和性质的影响将促进具有更高治疗效率的 Apt 功能化纳米平台的合理设计和未来临床转化。
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