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Drug Delivery

Drug Delivery - Poster Session E

Poster W18 - Engineering an affinity-based platform for the stabilization and controlled delivery of fibroblast growth factor 2

Saturday, October 26, 2024
10:00 AM - 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  Visual impairment due to retinal disease has been reported to affect up to 1 in 5 individuals over the age of 40. Researchers have sought to reverse damage to the retina through the use of stem cell technologies, such as by activating quiescent, endogenous retinal stem cells (RSCs) located in the ciliary epithelium [1]. This can be achieved via the combined delivery of certain proteins, such as fibroblast growth factor 2 (FGF2) and insulin, which stimulate RSC proliferation[2]. However, the effect is transient due to clearance of the therapeutics within 24-48 hours post-injection. We hypothesize that we can design an affinity-based system for the sustained release of FGF2 and insulin or insulin-like growth factor-1 (IGF1).

Materials and

Methods:  Binding partners for FGF2 and insulin were first identified using deep learning and molecular modeling systems and synthesized using a solid-phase peptide synthesizer. Subsequently, the affinities of each peptide candidate to FGF2 and insulin were assessed through biolayer interferometry (BLI) to identify those with high specificity and medium-to-low affinity. These peptides were then functionalized onto hyaluronic acid (HA) through oxyamine-ketone chemistry, which was used to form hydrogels containing FGF2 or insulin. The release of these therapeutic proteins was tracked over a period of two weeks, with the goal of achieving a sustained delivery profile spanning 7-14 days.

Results, Conclusions, and Discussions: A binding partner for FGF2 was identified and synthesized through the aforementioned methods and then optimized to a 0.1 micromolar dissociation constant by introducing alanine mutations to weaken electrostatic binding interactions. The resulting peptide was found to interact with the heparin-binding domain of FGF2 and confer additional thermal stability to FGF2, with competition observed at higher heparin concentrations. Controlled release of FGF2 from peptide-functionalized hydrogels was observed at various ratios of excess peptide to protein, with release extending to over 7 days. In comparison, free FGF2 incubated under the same conditions was observed to degrade by over ninety percent within twenty-four hours, Altogether, these results underscore the potential of affinity-based hydrogels for the delivery of proteins, both in terms of preserving protein function and in terms of extending their therapeutic window.

Acknowledgements (Optional):  We are grateful to the Krembil Foundation (to MSS, DvdK), the Donnelly Centre Best PDF and NSERC PDF (to CH).