Synthesis, nanosizing and in vitro drug release of a novel anti-HIV polymeric prodrug: chitosan-O-isopropyl-5'-O-d4T monophosphate conjugate.
Synthesis, nanosizing and in vitro drug release of a novel anti-HIV polymeric prodrug: chitosan-O-isopropyl-5'-O-d4T monophosphate conjugate.
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DOI：
10.1016/j.bmc.2009.11.013
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发表时间：
2010
影响因子：
3.5
通讯作者：
Lin Yang;Liqiang Chen;R. Zeng;Chao Li;R. Qiao;Liming Hu;Ze-Ling Li
中科院分区：
文献类型：
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作者：
Lin Yang;Liqiang Chen;R. Zeng;Chao Li;R. Qiao;Liming Hu;Ze-Ling Li
以d4 T为模型核苷类逆转录酶抑制剂（NRTI），构建了一种纳米级NRTI单磷酸酯-聚合物偶联物。首先，通过Atherton-Todd反应，在温和条件下高效合成了一种新型的壳聚糖-O-异丙基-5 ′-O-d4 T单磷酸酯偶联物。在MT4细胞系中评价聚合物缀合物的抗HIV活性和细胞毒性。然后通过离子型凝胶法将TPP与chitosan-d4 T偶联物制备成偶联纳米粒，并利用透射电镜（TEM）、动态光散射（DLS）和X射线衍射（XRD）等技术对偶联纳米粒的理化性质进行表征。pH1.1和pH7.4条件下的体外药物释放研究表明，壳聚糖-d4 T偶联物及其纳米粒在较长时间内更倾向于释放d4 T 5′-（O-异丙基）单磷酸，这导致聚合偶联物相对于游离d4 T的抗HIV选择性增强，这是由于绕过了单磷酸化的代谢瓶颈。此外，交联的缀合物纳米颗粒可以防止偶联的药物在进入靶病毒储库之前从纳米颗粒中泄漏，并且提供d4 T 5′-（O-异丙基）单磷酸的温和持续释放而没有突释。结果表明，壳聚糖-O-异丙基-5 ′-O-d4 T单磷酸酯偶联物纳米前药可作为一种靶向、缓释的高分子前药，用于抗逆转录病毒治疗，提高疗效，减少毒副作用。
A novel approach to improve the antiviral efficacy of nucleoside reverse transcriptase inhibitors (NRTIs) and reduce their side effects was developed by constructing a nanosized NRTI monophosphate-polymer conjugate using d4T as a model NRTI. Firstly, a novel chitosan-O-isopropyl-5′-O-d4T monophosphate conjugate with a phosphoramidate linkage was efficiently synthesized through Atherton–Todd reaction under mild conditions. The anti-HIV activity and cytotoxicity of the polymeric conjugate were evaluated in MT4 cell line. Then the conjugate nanoparticles were prepared by the process of ionotropic gelation between TPP and chitosan-d4T conjugate to improve their delivery to viral reservoirs, and their physicochemical properties were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) techniques and X-ray diffraction (XRD). In vitro drug release studies in pH 1.1 and pH 7.4 suggested that both chitosan-d4T conjugate and its nanoparticles prefer to release d4T 5′-(O-isopropyl) monophosphate than free d4T for prolonged periods, which resulted in the enhancement of anti-HIV selectivity of the polymeric conjugate relative to free d4T due to bypassing the metabolic bottleneck of monophosphorylation. Additionally, the crosslinked conjugate nanoparticles can prevent the coupled drug from leaking out of the nanoparticles before entering the target viral reservoirs and provide a mild sustained release of d4T 5′-(O-isopropyl) monophosphate without the burst release. The results suggested that this kind of chitosan-O-isopropyl-5′-O-d4T monophosphate conjugate nano-prodrugs may be used as a targeting and sustained polymeric prodrugs for improving therapy efficacy and reducing side effects in antiretroviral treatment.