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.
Subject(s)
Drug Carriers , Nanogels/chemistry , Nanoparticles/chemistry , Precision Medicine , Acrylic Resins/chemistry , Acrylic Resins/pharmacokinetics , Acrylic Resins/pharmacology , Animals , Cell Line, Tumor , Drug Carriers/chemical synthesis , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Drug Carriers/pharmacology , Humans , Methacrylates/chemistry , Methacrylates/pharmacokinetics , Methacrylates/pharmacology , Mice , RAW 264.7 CellsABSTRACT
Environmentally responsive biomaterials have played key roles in the design of biosensors and drug delivery vehicles. Their physical response to external stimuli, such as temperature or pH, can transduce a signal or trigger the release of a drug. In this work, we designed a robust, highly tunable, pH-responsive nanoscale hydrogel system. We present the design and characterization of poly(methacrylic acid-co-acrylamide) hydrogel nanoparticles, crosslinked with methylenebisacrylamide, through inverse emulsion polymerization. The effects of polymerization parameters (i.e., identities and concentrations of monomer and surfactant) and polymer composition (i.e., weight fraction of ionic and crosslinking monomers) on the nanoparticles' bulk and environmentally responsive properties were determined. We generated uniform, spherical nanoparticles which, through modulation of crosslinking, exhibit a volume swelling of 1.77-4.07, relative to the collapsed state in an acidic environment. We believe our system has potential as a base platform for the targeted, injectable delivery of hydrophilic therapeutics. With equal importance, however, we hope that our systematic analysis of the individual impacts of polymerization and purification conditions on nanoparticle composition, morphology, and performance can be used to expedite the development of alternate hydrophilic nanomaterials for a range of biomedical applications. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1677-1686, 2018.
