Smart zwitterionic biodegradable hydrogel for sustained peptide delivery: Application to the neurotherapeutic peptide NX210c

Therapeutic peptides offer a promising balance between specificity, safety, and bioavailability. However, their clinical use is limited by poor in vivo stability and short half-life, requiring frequent administrations that can compromise patient compliance and therapeutic outcomes. NX210c, a synthetic cyclic dodecapeptide derived from the thrombospondin repeat motif of the sub-commissural organ-spondin shows neuroprotective effects, making it a promising candidate for the treatment of neurological disorders. However, its short half-life (~15 min) requires intravenous infusion highlighting the interest of an alternative delivery method to improve the quality of life for patients. This study, report the preclinical development of an injectable, biodegradable chitosan-based hydrogel functionalized with the macrocyclic ligand DOTAGA, designed for the sustained subcutaneous release of NX210c. The hydrogel forms in situ under physiological conditions, via electrostatic and hydrogen bonding interactions. The solvent-free formulation is simple and clinically compatible. Hydrogel candidate were screened in vitro for injectability, gelation, peptide loading, and release kinetics. In vivo validation on rodents confirmed subcutaneous injectability, gelation ability, biocompatibility and biodegradability within few weeks. Pharmacokinetics studies demonstrated distinct profiles: intravenous injection led to peptide clearance within 1 h; free NX210c administered subcutaneously slightly prolonged its presence in the bloodstream, with complete elimination observed within approximately 3 h. The use of hydrogel, enables AUCs dozens of times higher, with peptide levels sustained for over 10 to 15 days. These results highlight the hydrogel's potential as a patient-friendly, clinically translatable platform for therapeutic peptides requiring sustained release. Future studies will focus on the evaluation of its therapeutic efficiency.