Synthetic networks with tunable responsiveness, biodegradation, and molecular recognition for precision medicine applications

Abstract

Formulations and devices for precision medicine applications must be tunable and multiresponsive to treat heterogeneous patient populations in a calibrated and individual manner. We engineered modular poly(acrylamide-co-methacrylic acid) copolymers, cross-linked into multiresponsive nanogels with either a nondegradable or degradable disulfide cross-linker, that were customized via orthogonal chemistries to target biomarkers of an individual patient’s disease or deliver multiple therapeutic modalities. Upon modification with functional small molecules, peptides, or proteins, these nanomaterials delivered methylene blue with environmental responsiveness, transduced visible light for photothermal therapy, acted as a functional enzyme, or promoted uptake by cells. In addition to quantifying the nanogels’ composition, physicochemical characteristics, and cytotoxicity, we used a QCM-D method for characterizing nanomaterial degradation and a high-throughput assay for cellular uptake. In conclusion, we generated a tunable nanogel composition for precision medicine applications and new quantitative protocols for assessing the bioactivity of similar platforms.

Hydrogels in the clinic

“…Due to this high water content, hydrogels exhibit favorable biocompatibility and as such have been developed for and used in a variety of medical applications 1‐3 . Since hydrogel properties can be tuned through a variety of chemical approaches, their rational design and engineering has enabled new modalities for delivery of small molecules, 4‐7 proteins, 8‐12 and cells 13,14 and as tissue engineering scaffolds for directing cell fate/lineage, 15,16 stem cell expansion, 17‐20 and tissue regeneration 21‐25 . Research efforts to develop hydrogels for biomedical applications represents one of the most studied areas at the interface of engineering and medicine 26 .…”

QCM‐D assay for quantifying the swelling, biodegradation, and protein adsorption of intelligent nanogels

“…Assuming that monomer incorporation was proportional to the monomer feed, the final nanogels contained 22.5 mol% methacrylic acid, 75 mol% acrylamide, and 2.5 mol% crosslinker. These formulations have been characterized extensively in previous reports …”

“…Poly(acrylamide‐ co ‐methacrylic acid) nanogels, crosslinked with methylenebisacrylamide or N,N′‐bis(acryloyl)cystamine were synthesized as described by Zhong et al . and Clegg et al ., respectively.…”

“…This suggested similar incorporation of the acrylamide and methacrylic acid monomers within the two formulations. The figure is reproduced from Clegg et al …”

“…We concluded that degradation was complete when the nanogels were indistinguishable from a linear copolymer of the same composition (10 mg/mL nanogels in 1× PBS, pH = 7.4, T = 37 °C). The figure is adapted from Clegg et al …”