Versatile Tissue-Injectable Hydrogels with Extended Hydrolytic Release of Bioactive Protein Therapeutics

bioRxiv preprint, 2023 · DOI: https://doi.org/10.1101/2023.09.01.554391 · Published: September 2, 2023

Simple Explanation

The study engineered injectable, biocompatible hydrogels for local protein therapeutic delivery, allowing customization of drug release. The hydrogels use hydrolysable esters to control the release of protein payloads over time, ranging from days to months. The hydrogel system enabled successful recruitment of T-cells to a mouse melanoma model using hydrolytically released murine CXCL10, demonstrating biological activity.

Study Duration

4 Weeks in vitro, 7 days in vivo

Participants

C57BL/6 mice, B16.F10 melanoma cells

Evidence Level

Not specified

Key Findings

1
The release rate of payloads from the hydrogels can be customized by selecting azidoacids of varying lengths, thereby controlling ester hydrophobicity.
2
Sortase-mediated transpeptidation enables site-specific modification of proteins with PolyG-azidoesters for transient linkage to the hydrogel.
3
Hydrogel solutions can be injected into living tissue and polymerize in situ, demonstrating their suitability for delivery in sensitive areas like the brain.

Research Summary

The study developed a customizable hydrogel platform for local delivery of protein therapeutics, using bioorthogonal SPAAC click chemistry for tunable release rates and compatibility with various proteins. The platform employs hydrolytic linkers with user-defined release rates, enabling sustained protein release and minimizing the need for repeat surgeries. In vivo experiments demonstrated the hydrogel's ability to deliver bioactive murine CXCL10, effectively recruiting CD8+ T-cells to a melanoma tumor and attenuating tumor growth.

Practical Implications

Controlled Drug Release

The hydrogel platform allows for controlled and sustained release of protein therapeutics, reducing the need for frequent administrations.

Localized Delivery

Local delivery minimizes systemic toxicities associated with potent protein-based drugs, especially monoclonal antibodies and chemokines.

Versatile Application

The customizable release profiles and broad protein compatibility make the hydrogel suitable for various clinical circumstances.

Study Limitations

1
The PEG-tBCN hydrogels used in our studies were not designed to lose structural integrity
2
diffusion rate of protein payloads, as demonstrated with insulin, may extend release rates on the scale of hours.
3
Larger molecules may be more affected by diffusion

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