Biocompatible and pH-sensitive PEG hydrogels with degradable phosphoester and phosphoamide linkers end-capped with amine for controlled drug delivery

A series of biocompatible poly(ethylene glycol) (PEG) hydrogels that are suitable for a variety of biomedical applications have been presented. The cross-linked, water-swellable and multi-amine-functionalized PEG hydrogels (CWMPHs) with degradable phosphoester and phosphoamide linkages in the backbone were successfully produced by the condensation crosslinking reactions between PEG-O-P(O)Cl₂ with different functionalities and 3-arm-PEG-NH ₂ pre-polymers, followed by the chain-terminating amination using propane-1,3-diamine in a one-pot process. The newly invented protocol for the fabrication of PEG hydrogels exhibits promising advantages over prior methods including a short reaction time, mass-production, easy separation, and high yield. The structures of the pre-polymers and CWMPHs were well characterized by FT-IR, ¹H NMR, and solid state ³¹P NMR analyses. The mechanical properties of the CWMPHs measured by a rheometer indicate that both storage modulus (G′) and loss modulus (G′′) increase as the functionality of PEG-O-P(O)Cl₂ increases. All the CWMPHs exhibit pH-sensitive water swellability and degradability at room temperature, so that they show a higher water swelling ratio and faster degradation under acidic conditions via an activated cleavage of P-O and P-N bonds. The non-hemolytic property and reasonable biocompatibility of the CWMPHs were proven by in vivo histological assays and in vitro cell viability tests using 293T and HCT-116 cells. We have also demonstrated promising positive results for the use of CWMPHs as a sustained drug delivery system, by mounting an anticancer drug-doxorubicin in vitro, with specifically enhanced release at a low pH 4.0.