Double-Crosslinked Nanocomposite Hydrogels for Temporal Control of Drug Dosing in Combination Therapy

Abstract

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) was designed for sequential 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), 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 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 for designing 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.