A pH-Responsive Poly Beta-Amino Ester Nanoparticulate Thermo-Responsive PEG-PCL-PEG Hydrogel Dispersed System for the Delivery of Interferon Alpha to the Ocular Surface.

Background/Objectives: The management of ocular tumours is faced with the challenge of developing a suitable treatment strategy with consideration of the anatomical and physiological protective barriers of the eye. Interferon alpha has been employed to treat patients with ocular tumours for decades; however, its short half-life and poor tolerability necessitate frequent administration. This study focuses on the design of an injectable pH-responsive and protective nanoparticle system dispersed into a thermo-responsive hydrogel for site-specific sustained delivery of interferon alpha (IFN-α2b) in the treatment of ocular surface tumours. Methods: The synthesis of a poly(ethylene glycol)-poly(caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG) triblock copolymer (PECE) was undertaken. The IFN-α2b was encapsulated in poly(β-amino ester) (PBAE) nanoparticles (NP) with pH-responsive characteristics to proposedly release the IFNα-2b in response to the acidic nature of the tumour microenvironment. This was followed by characterisation via Fourier transform infrared spectroscopy (FT-IR), (1)H-nuclear magnetic resonance ((1)H-NMR) analysis, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) analysis, thermogravimetric analysis (TGA), and thermal-transition analysis of the PECE hydrogels. Results: Release studies demonstrated that the PBAE nanoparticulate PEG-PCL-PEG hydrogel was both pH-responsive, while providing controlled release of IFN-α2b, and thermo-responsive. Release analysis highlighted that IFN-α2b-loaded NP dispersed into the hydrogel (IFNH) further prolonged the release of IFN-α2b with a pH-responsive yet controlled release rate in an acidic environment simulating a tumour microenvironment. The developed system proved to be biocompatible with human retinal pigment epithelial cells and the released IFN-α demonstrated bioactivity in the presence of an A172 glioblastoma cell line. Conclusions: In conclusion, the PECE hydrogel has promising potential for application as an ocular drug delivery system for the treatment of ocular tumours and could potentially overcome and prevent the drawbacks associated with the commercially available IFN-α2b injection.