Department of Chemistry and §Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal , Bhauri, Bhopal By-pass Road, Bhopal 462 066, India.
Biomacromolecules. 2016 Jul 11;17(7):2375-83. doi: 10.1021/acs.biomac.6b00417. Epub 2016 Jun 7.
Many hydrophobic drugs encounter severe bioavailability issues owing to their low aqueous solubility and limited cellular uptake. We have designed a series of amphiphilic polyaspartamide polyelectrolytes (PEs) that solubilize such hydrophobic drugs in aqueous medium and enhance their cellular uptake. These PEs were synthesized through controlled (∼20 mol %) derivatization of polysuccinimide (PSI) precursor polymer with hydrophobic amines (of varying alkyl chain lengths, viz. hexyl, octyl, dodecyl, and oleyl), while the remaining succinimide residues of PSI were opened using a protonable and hydrophilic amine, 2-(2-amino-ethyl amino) ethanol (AE). Curcumin (Cur) was employed as a representative hydrophobic drug to explore the drug-delivery potential of the resulting PEs. Unprecedented enhancement in the aqueous solubility of Cur was achieved by employing these PEs through a rather simple protocol. In the case of PEs containing oleyl/dodecyl residues, up to >65000× increment in the solubility of Cur in aqueous medium could be achieved without requiring any organic solvent at all. The resulting suspensions were physically and chemically stable for at least 2 weeks. Stable nanosized polyelectrolyte complexes (PECs) with average hydrodynamic diameters (DH) of 150-170 nm (without Cur) and 220-270 nm (after Cur loading) were obtained by using submolar sodium polyaspartate (SPA) counter polyelectrolyte. The zeta potential of these PECs ranged from +36 to +43 mV. The PEC-formation significantly improved the cytocompatibility of the PEs while affording reconstitutable nanoformulations having up to 40 wt % drug-loading. The Cur-loaded PECs were readily internalized by mammalian cells (HEK-293T, MDA-MB-231, and U2OS), majorly through clathrin-mediated endocytosis (CME). Cellular uptake of Cur was directly correlated with the length of the alkyl chain present in the PECs. Further, the PECs significantly improved nuclear transport of Cur in cancer cells, resulting in their death by apoptosis. Noncancerous cells were completely unaffected under this treatment.
许多疏水性药物由于其低水溶性和有限的细胞摄取而遇到严重的生物利用度问题。我们设计了一系列两亲性聚天冬酰胺聚电解质（PEs），可将这些疏水性药物溶解在水性介质中并增强其细胞摄取。这些 PEs 是通过用疏水性胺（具有不同烷基链长度，即己基、辛基、十二烷基和油基）对聚琥珀酰亚胺（PSI）前体聚合物进行控制（约 20 mol％）衍生化而合成的，而 PSI 的其余琥珀酰亚胺残基则使用质子化和亲水胺 2-（2-氨基乙基氨基）乙醇（AE）打开。姜黄素（Cur）被用作代表性疏水性药物来探索所得 PEs 的药物传递潜力。通过采用这些 PEs 可以通过相当简单的方案实现 Cur 的水溶性的空前提高。在含有油基/十二烷基残基的 PEs 的情况下，无需使用任何有机溶剂，就可以在水性介质中使 Cur 的溶解度增加高达 >65000×。所得悬浮液在物理和化学上稳定至少 2 周。通过使用亚摩尔量的聚天冬氨酸（SPA）作为抗衡聚电解质，获得了平均水动力直径（DH）为 150-170nm（无 Cur）和 220-270nm（负载 Cur 后）的稳定纳米尺寸聚电解质复合物（PECs）。这些 PEC 的 zeta 电位范围为+36 至+43 mV。PECs 的形成显着提高了 PEs 的细胞相容性，同时提供了具有高达 40wt％载药量的可重构纳米制剂。负载 Cur 的 PEC 很容易被哺乳动物细胞（HEK-293T、MDA-MB-231 和 U2OS）内化，主要通过网格蛋白介导的内吞作用（CME）。Cur 的细胞摄取与 PEC 中存在的烷基链的长度直接相关。此外，PECs 显着改善了 Cur 在癌细胞中的核转运，导致其通过细胞凋亡死亡。在这种治疗下，非癌细胞完全不受影响。
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