Serially pH-Modulated Hydrogels Based on Boronate Ester and Polydopamine Linkages for Local Cancer Therapy

초록

Elaborately and serially pH-modulated hydrogels possessing optimized viscoelastic natures for short gelation time and single syringe injection were designed for peritumoral injection of an anticancer agent. Boronate ester bonds between phenylboronic acid (PBA) (installed in HA-PBA (HP)) and dopamine (included in HA-dopamine (HD)) along with self-polymerization of dopamine (via interactions between HD conjugates) were introduced as the main cross-linking strategies of a hyaluronic acid (HA) hydrogel. Considering pK(a) values (8.0-9.5) of PBA and dopamine, the pH of each polymer dispersion was controlled elaborately for injection through a single syringe, and the final pH was tuned nearby the physiological pH (pH 7.8). The shear-thinning behavior, self-healing property, and single syringe injectability of a designed hydrogel cross-linked nearby physiological pH may provide its convenient application to peritumoral injection and prolonged retention in local cancer therapy. Erlotinib (ERT) was encapsulated in a microsphere (MS), and it was further embedded in an HP/HD-based hydrogel for sustained and locoregional delivery. A rheologically tuned hydrogel containing an ERT MS exhibited superior tumor-suppressive efficiencies compared to the other groups in A549 tumor-bearing mice. A designed injectable hydrogel through a single syringe system may be efficiently applied to local cancer therapy with lower toxicities to healthy organs.

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