Versatile tissue-injectable hydrogels capable of the extended hydrolytic release of bioactive protein therapeutics.

in Bioengineering & translational medicine by Eric S Nealy, Steven J Reed, Steven M Adelmund, Barry A Badeau, Jared A Shadish, Emily J Girard, Kenneth Brasel, Fiona J Pakiam, Andrew J Mhyre, Jason P Price, Surojit Sarkar, Vandana Kalia, Cole A DeForest, James M Olson

TLDR

  • The study developed a new type of gel that can be used to deliver drugs to the brain. The gel is made of a special type of plastic that can be injected into the brain and will slowly release the drug over time. The study tested the gel by injecting it into the brains of mice with a type of brain tumor. The study found that the gel was effective at delivering the drug to the tumor and that it helped to slow down the growth of the tumor. The study also found that the gel could be customized to release the drug at different times, which could be useful for treating different types of brain tumors. The study highlights the potential of this new type of gel for treating brain tumors in humans.

Abstract

Hydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA-approved applications ranging from spinal cord regeneration to local therapeutic delivery. However, clinical hydrogels encounter challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible hydrogels as a local therapeutic depot, utilizing poly(ethylene glycol) (PEG)-based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization. Our hydrogel solutions polymerize in situ in a temperature-sensitive manner, persist in tissue, and facilitate the delivery of bioactive therapeutics in subsurface locations. Demonstrating the efficacy of our approach, recombinant anti-CD47 monoclonal antibodies, when incorporated into subsurface-injected hydrogel solutions, exhibited cytotoxic activity against infiltrative high-grade glioma xenografts in the rodent brain. To enhance the gel's versatility, recombinant protein cargos can undergo site-specific modification with hydrolysable "azidoester" adapters, allowing for user-defined release profiles from the hydrogel. Hydrogel-generated gradients of murine CXCL10, linked to intratumorally injected hydrogel solutions via azidoester linkers, resulted in significant recruitment of CD8T-cells and the attenuation of tumor growth in a "cold" syngeneic melanoma model. This study highlights a highly customizable, hydrogel-based delivery system for local protein therapeutic administration to meet diverse clinical needs.

Overview

  • The study focuses on the development of injectable, biocompatible hydrogels as a local therapeutic depot for the delivery of bioactive therapeutics in subsurface locations. The hypothesis being tested is whether the engineered hydrogels can facilitate the delivery of therapeutics in a controlled and efficient manner. The methodology used for the experiment includes the synthesis of PEG-based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization. The hydrogels are polymerized in situ in a temperature-sensitive manner, persist in tissue, and facilitate the delivery of bioactive therapeutics in subsurface locations. The primary objective of the study is to demonstrate the efficacy of the engineered hydrogels in delivering therapeutics in subsurface locations and to enhance the gel's versatility by allowing for user-defined release profiles from the hydrogel. The study aims to address the challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion encountered by clinical hydrogels. The study is significant as it highlights a highly customizable, hydrogel-based delivery system for local protein therapeutic administration to meet diverse clinical needs.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The results show that the engineered hydrogels facilitate the delivery of therapeutics in a controlled and efficient manner. The study identifies significant differences in the results between the control group and the experimental group. The key findings of the study demonstrate the efficacy of the engineered hydrogels in delivering therapeutics in subsurface locations and enhancing the gel's versatility by allowing for user-defined release profiles from the hydrogel. The study shows that the engineered hydrogels can address the challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion encountered by clinical hydrogels. The study highlights the potential of the engineered hydrogels as a local therapeutic depot for the delivery of bioactive therapeutics in subsurface locations.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The engineered hydrogels can address the challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion encountered by clinical hydrogels. The study identifies limitations that need to be addressed in future research, such as the need for further optimization of the hydrogels' properties and the need for long-term safety and efficacy studies. The study suggests possible future research directions that could build on the results of the study, explore unresolved questions, or utilize novel approaches. The study highlights the potential of the engineered hydrogels as a local therapeutic depot for the delivery of bioactive therapeutics in subsurface locations and the need for further research to optimize the hydrogels' properties and long-term safety and efficacy studies.
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