Facial Solid-Phase Synthesis of Well-Defined Zwitterionic Amphiphiles for Enhanced Anticancer Drug Delivery.
Facial Solid-Phase Synthesis of Well-Defined Zwitterionic Amphiphiles for Enhanced Anticancer Drug Delivery.
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DOI：
10.1021/acs.molpharmaceut.1c00163
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发表时间：
2021-05
影响因子：
4.9
通讯作者：
Lili Wang;Xiaotian Ji;Dandan Guo;Changying Shi;Juntao Luo
中科院分区：
文献类型：
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作者：
Lili Wang;Xiaotian Ji;Dandan Guo;Changying Shi;Juntao Luo
血清蛋白在纳米颗粒表面的吸附决定了高分子纳米载体的生物学特性，并对静脉注射后的体内稳定性产生重要影响。为了减少血清蛋白冠的形成，延长药物的药代动力学，提高纳米治疗药物的体内性能，在递送系统中需要超亲水性表面。两性离子聚合物已被探索作为生物医学应用的替代隐身材料。在本研究中，我们采用固相肽化学（SPPC）合成了多功能两性离子两亲体作为药物传递载体。SPPC促进了树状两亲分子的合成和纯化，得到了高纯度和精确的结构。选择两性离子甘油酰磷胆碱（GPC）作为构建超亲水性树突的表面片段，并利用多个大黄酸（Rh）分子作为药物结合片段（DBMs）通过pi-pi堆叠和氢键在固相上偶联到疏水树突上，用于加载阿霉素（DOX）。与具有聚乙二醇（PEG）表面的类似物（PEG5k-Rh4）相比，得到的两性离子两亲性Janus树状大分子（标记为GPC8-Rh4）具有更好的稳定性和持续的药物释放。异种移植小鼠肿瘤模型的体内研究表明，与DOX-PEG5k-Rh4相比，DOX-GPC8-Rh4纳米制剂由于改善了体内药代动力学和增加了肿瘤积累，显著提高了抗癌效果。
Serum protein adsorption on the nanoparticle surface determines the biological identity of polymeric nanocarriers and critically impacts the in vivo stability following intravenous injection. Ultrahydrophilic surfaces are desired in delivery systems to reduce the serum protein corona formation, prolong drug pharmacokinetics, and improve the in vivo performance of nanotherapeutics. Zwitterionic polymers have been explored as alternative stealth materials for biomedical applications. In this study, we employed facial solid-phase peptide chemistry (SPPC) to synthesize multifunctional zwitterionic amphiphiles for application as a drug delivery vehicle. SPPC facilitates synthesis and purification of the well-defined dendritic amphiphiles, yielding high-purity and precise architecture. Zwitterionic glycerylphosphorylcholine (GPC) was selected as a surface moiety for the construction of a ultrahydrophilic dendron, which was coupled on solid phase to a hydrophobic dendron using multiple rhein (Rh) molecules as drug-binding moieties (DBMs) for doxorubicin (DOX) loading via pi-pi stacking and hydrogen bonding. The resulting zwitterionic amphiphilic Janus dendrimer (denoted as GPC8-Rh4) showed improved stabilities and sustained drug release compared to the analogue with poly(ethylene glycol) (PEG) surface (PEG5k-Rh4). In vivo studies in xenograft mouse tumor models demonstrated that the DOX-GPC8-Rh4 nanoformulation significantly improved anticancer effects compared to DOX-PEG5k-Rh4, owing to the improved in vivo pharmacokinetics and increased tumor accumulation.