Sustained Intracellular Raltegravir Depots Generated with Prodrugs Designed for Nanoparticle Delivery.
Sustained Intracellular Raltegravir Depots Generated with Prodrugs Designed for Nanoparticle Delivery.
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持续的细胞内Raltegravir仓库由设计用于纳米颗粒递送的前药产生。
DOI：
10.1021/acsbiomaterials.9b00658
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发表时间：
2019-08-12
影响因子：
5.8
通讯作者：
Woodrow KA
中科院分区：
文献类型：
--
作者：
Creighton RL;Suydam IT;Ebner ME;Afunugo WE;Bever AM;Cao S;Jiang Y;Woodrow KA
高分子纳米载体已被广泛用于改善疏水药物的递送，但往往提供低封装效率和百分比负载亲水化合物。特别是，亲水抗逆转录病毒药物如整合酶抑制剂雷替格拉韦（raltegravir， RAL）的负荷不足限制了针对HIV的缓释疗法或预防策略的发展。为了解决这个问题，我们开发了一种通用的前药策略，使用RAL作为模型，其中加载，释放和随后的水解可以通过启动子选择来调节。与RAL相比，具有大分割系数的前药将包封效率提高了25倍，导致抗病毒活性测定的剂量显著降低。这些前药的不同水解率导致了RAL可用性和观察到的抗病毒活性的不同模式。我们还开发了一种方法来监测游离前药或前药nps处理的细胞中前药和RAL的时间分布。这些研究结果表明，前药nps在细胞内创造了一个能够持续释放细胞内药物的药物库。总之，我们的研究结果表明，为特定的聚合物纳米载体系统设计前药可以为制定具有许多生物医学应用的物理化学多样性的亲水药物提供更广泛的策略。
Polymeric nanocarriers have been extensively used to improve the delivery of hydrophobic drugs, but often provide low encapsulation efficiency and percent loading for hydrophilic compounds. In particular, insufficient loading of hydrophilic antiretroviral drugs such as the integrase inhibitor raltegravir (RAL) has limited the development of sustained-release therapeutics or prevention strategies against HIV. To address this, we developed a generalizable prodrug strategy using RAL as a model where loading, release and subsequent hydrolysis can be tuned by promoiety selection. Prodrugs with large partition coefficients increased the encapsulation efficiency up to 25-fold relative to RAL, leading to significant dose reductions in antiviral activity assays. The differential hydrolysis rates of these prodrugs led to distinct patterns of RAL availability and observed antiviral activity. We also developed a method to monitor the temporal distribution of both prodrug and RAL in cells treated with free prodrug or prodrug-NPs. Results of these studies indicated that prodrug-NPs create an intracellular drug reservoir capable of sustained intracellular drug release. Overall, our results suggest that the design of prodrugs for specific polymeric nanocarrier systems could provide a more generalized strategy to formulate physicochemically diverse hydrophilic drugs with a number of biomedical applications.
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