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Smart, multi-stimuli-responsive nanogels that possess dynamic covalent bonds (DCBs) exhibit reversibility under equilibrium conditions allowing for controlled disassembly and release of cargo. These nanomaterials have innumerable applications in areas including drug delivery, sensors, soft actuators, smart surfaces, and environmental remediation. In this work, we implement one-pot, photo-controlled atom transfer radical polymerization-induced self-assembly (PhotoATR-PISA), mediated by UV light (λ = 365 nm) and parts per million (ppm) levels (ca. <20 ppm) of a copper(II) bromide catalyst, to fabricate dual crosslinked, polymeric nanogels with tunable orthogonal reversible covalent (TORC-NGs) core-crosslinks (CCLs). These TORC-NGs were crosslinked efficiently via coumarin photodimerization which occured simultaneously during polymerization using coumarin-functionalized methacrylate crosslinkers (CouMA). At the same time, crosslinking of nanocarriers with N,N-cystamine bismethacrylamide (CBMA) introduced orthogonal, redox-responsive, disulfide CCLs. Furthermore, incorporation of poly(glycidyl methacrylate) (PGMA) core-forming segments provided a simple handle for switchable solubility through acid-catalyzed ring-opening hydrolysis of pendant epoxide groups. In this way, the kinetics of release were tailored by the pH of the surrounding media. Thus, these TORC-NG systems showed coupled pH-, redox- and photo-responsive controlled release and disassembly behavior with full release of cargo only observed in the right sequence of stimuli and only when all three are utilized. The multi-stimuli-responsive nature of these TORC-NGs was successfully utilized herein for the controlled encapsulation and on-demand AND-gate release of hydrophobic Nile Red fluorescent reporters used as drug simulants. Various TORC-NG morphologies were synthesized in this report including nanosphere, worm-like and tubesome NGs showing variable release characteristics.
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This content will become publicly available on November 1, 2025
A Novel Poly(ε-Caprolactone)-Based Photo-Crosslinkable Liquid Copolymer as a Versatile Drug Delivery Platform
Background/Objectives: Hydrophobic semi-solid or liquid biodegradable polymers have shown unique advantages as injectable matrices for sustained release of a wide range of drugs. Here we report the design, synthesis, and characterization of a new low-melt liquid copolymer based on poly(ε-caprolactone) (PCL) and establish its utility as a versatile delivery platform. Methods: The copolymer, mPA20, consisting of short PCL blocks connected via acid-labile acetal linkages, was synthesized using a one-pot reaction and its properties were comprehensively characterized. Results: mPA20 is an amorphous, injectable liquid at physiological temperature and can undergo pH-sensitive hydrolytic degradation. mPA20 bearing methacrylate end groups can be photo-crosslinked into solid matrices with tunable mechanical properties. A hydrophobic fluorophore, Nile Red (NR), was solubilized in mPA20 without any solvent. Sustained release of NR into aqueous medium was achieved using mPA20, either as an injectable liquid depot or a photo-crosslinked solid matrix. Further, mPA20 self-emulsified in water to form nanodroplets, which were subsequently photo-crosslinked into nanogels. Both the nanodroplets and nanogels mediated efficient intracellular delivery of NR with no cytotoxicity. Conclusions: mPA20, a new photo-crosslinkable, hydrophobic liquid copolymer with pH-sensitive degradability, is highly adaptable as either an injectable or implantable depot or nanoscale carrier for the controlled release and intracellular delivery of poorly soluble drugs.
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- Award ID(s):
- 2011401
- PAR ID:
- 10590034
- Publisher / Repository:
- Pharmaceutics
- Date Published:
- Journal Name:
- Pharmaceutics
- Volume:
- 16
- Issue:
- 11
- ISSN:
- 1999-4923
- Page Range / eLocation ID:
- 1380
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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