State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, Beijing University of Chemical Technology, Beijing 100029, PR China.
Bioorg Med Chem. 2010 Jan 1;18(1):117-23. doi: 10.1016/j.bmc.2009.11.013. Epub 2009 Nov 10.
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.
一种提高核苷逆转录酶抑制剂（NRTIs）抗病毒疗效、降低其副作用的新方法是通过构建一种纳米大小的 NRTI 单磷酸-聚合物缀合物来实现的，该缀合物以 d4T 为模型 NRTI。首先，通过温和条件下的 Atherton-Todd 反应，高效合成了具有磷酰胺键的新型壳聚糖-O-异丙基-5'-O-d4T 单磷酸缀合物。在 MT4 细胞系中评价了聚合缀合物的抗 HIV 活性和细胞毒性。然后，通过 TPP 与壳聚糖-d4T 缀合物之间的离子凝胶化过程制备缀合物纳米粒子，以提高其向病毒储存库的递送，并用透射电子显微镜（TEM）、动态光散射（DLS）技术和 X 射线衍射（XRD）对其理化性质进行了表征。在 pH1.1 和 pH7.4 中的体外药物释放研究表明，壳聚糖-d4T 缀合物及其纳米粒子都更倾向于释放 d4T 5'-(O-异丙基）单磷酸，而不是游离的 d4T，从而延长了时间，这导致聚合缀合物相对于游离 d4T 提高了抗 HIV 的选择性，因为它绕过了单磷酸化的代谢瓶颈。此外，交联的缀合物纳米粒子可以防止偶联药物在进入靶病毒储存库之前从纳米粒子中泄漏出来，并提供温和的 d4T 5'-(O-异丙基）单磷酸持续释放，而没有突释。结果表明，这种壳聚糖-O-异丙基-5'-O-d4T 单磷酸缀合物纳米前药可作为一种靶向和持续的聚合物前药，用于提高抗逆转录病毒治疗的疗效和降低副作用。
