Department of Chemistry, China Pharmaceutical University, Nanjing 211198, Jiangsu, China.
State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China.
Acta Biomater. 2020 Apr 1;106:278-288. doi: 10.1016/j.actbio.2020.02.021. Epub 2020 Feb 18.
Temporal control of drug dosing is indispensable for a successful combination therapy that utilizes cisplatin (CDDP) and irinotecan (IRN), with clinical evidence supporting a higher response rate when CDDP was administered prior to IRN. Herein, a peptide-based nanocomposite hydrogel (CDDP/Pept-AlgNP/IRN) was designed for differential release of CDDP and IRN to maximize synergism of two drugs. First, a double-crosslinking strategy was exploited for structural reinforcement of hydrogel, with integration of coordination interactions between CDDP and hydrogelator (Pept) as well as electrostatic interactions between Pept and alginate nanoparticles (AlgNP/IRN), that afforded nanocomposite hydrogel with 42-fold increase in storage modulus comparing to peptide gel alone. Next, the nanocomposite hydrogel with excellent injectability served as a depot for controlled release of dual drugs, and guaranteed a fast release of CDDP prior to a tunable release of IRN that is dependent on fraction ratios of AlgNP in the composite materials. Comparing to simple mixture of CDDP and IRN solution, CDDP/Pept-AlgNP/IRN hydrogel formulation demonstrated excelling synergism of CDDP and IRN in cell inhibition studies, with efficacious antitumor potency further proved in tumor regression studies in vivo. We believe that the strategy of utilizing co-assembly of multiple pairs of entities (i.e. drug-gelator, nanoparticle-gelator) in composite materials provides a generalized method to design mechanically stable supramolecular hydrogels, and further promises an exact temporal control of drug dosing by packing individual drugs in co-assembled structures/domains to satisfy clinical demands from combination therapy. STATEMENT OF SIGNIFICANCE: This study reports the design of nanocomposite hydrogels with two distinct co-assembling domains for structural reinforcement of hydrogel and differential release of two drugs (CDDP and IRN) in combination therapy. We first investigated the effects of co-assembling processes for the reinforcement of hydrogel. Then we utilized the hydrogel for differential release of CDDP and IRN to achieve better synergistic efficacy of drugs in inhibiting the growth of cancer cell A549 and better anticancer efficacies than single drug formulations or solution mixtures of dual drugs in an A549-xenografted mouse model. We believe that the strategy of packing individual drugs in distinct co-assembling structures promises a paradigm shift for regulating temporal control of drug dosing in combination therapy.
为了成功实施顺铂（CDDP）和伊立替康（IRN）联合治疗，药物给药时间的控制是不可或缺的，临床证据表明，先给予 CDDP 后给予 IRN 可提高应答率。在此，设计了一种基于肽的纳米复合水凝胶（CDDP/Pept-AlgNP/IRN），以实现 CDDP 和 IRN 的差异化释放，从而最大限度地发挥两种药物的协同作用。首先，利用双重交联策略增强水凝胶的结构，将 CDDP 与水凝胶剂（Pept）之间的配位相互作用以及 Pept 与海藻酸钠纳米粒子（AlgNP/IRN）之间的静电相互作用结合起来，使纳米复合水凝胶的储能模量比单独的肽凝胶增加了 42 倍。接下来，具有良好可注射性的纳米复合水凝胶作为双药物控释的储库，保证了 CDDP 的快速释放，随后是依赖于复合材料中 AlgNP 比例的可调释 IRN。与 CDDP 和 IRN 溶液的简单混合物相比，CDDP/Pept-AlgNP/IRN 水凝胶配方在细胞抑制研究中表现出 CDDP 和 IRN 的出色协同作用，体内肿瘤消退研究进一步证明了其有效的抗肿瘤功效。我们相信，利用复合材料中多对实体（即药物-凝胶剂、纳米粒子-凝胶剂）的共组装策略为设计机械稳定的超分子水凝胶提供了一种通用方法，并通过将单个药物包装到共组装结构/域中来进一步实现药物给药时间的精确控制，以满足联合治疗的临床需求。
本研究报告了具有两个不同共组装域的纳米复合水凝胶的设计，用于增强水凝胶的结构并在联合治疗中实现两种药物（CDDP 和 IRN）的差异化释放。我们首先研究了共组装过程对水凝胶增强的影响。然后，我们利用水凝胶实现了 CDDP 和 IRN 的差异化释放，以在抑制肺癌细胞 A549 生长方面获得更好的药物协同效果，并在 A549-xenografted 小鼠模型中比单一药物制剂或双药物溶液混合物具有更好的抗肿瘤功效。我们相信，将单个药物包装到不同的共组装结构中有望为调节联合治疗中药物给药时间的控制提供一种范式转变。
