“Clickable” Nanogels via Thermally Driven Self-Assembly of Polymers: Facile Access to Targeted Imaging Platforms using Thiol–Maleimide Conjugation

Abstract

Multifunctionalizable nanogels are fabricated using thermally driven self-assembly and cross-linking of reactive thermoresponsive copolymers. Nanogels thus fabricated can be easily conjugated with various appropriately functionalized small molecules and/or ligands to tailor them for various applications in delivery and imaging. In this study, a poly(ethylene glycol)-methacrylate-based maleimide-bearing copolymer was cross-linked with a dithiol-based cross-linker to synthesize nanogels. Because of lower critical solution temperature (LCST) around 55 °C in aqueous media, these copolymers assemble into nanosized aggregates when heated to this temperature, and they are cross-linked using the thiol−maleimide conjugation. Nanogels thus fabricated contain both thiol and maleimide groups in the same cross-linked nanogels. Postgelation functionalization of the residual maleimide and thiol groups is demonstrated through conjugation of a thiol-bearing hydrophobic dye (BODIPY-SH) and N-(fluoresceinyl) maleimide, respectively. In addition, to demonstrate the utility of multifunctionality of these nanogels, a thiol-bearing cyclic-peptide-based targeting group, cRGDfC, and N-(fluoresceinyl)-maleimide-based fluorescent tag was conjugated to nanogels in aqueous media. Upon treatment with breast cancer cell lines, MDA-MB-231, it was deduced from cellular internalization studies using fluorescence microscopy and flow cytometry that the peptide carrying constructs were preferentially internalized. Overall, a facile synthesis of multifunctionalizable nanogels that can be tailored using effective conjugation chemistry under mild conditions can serve as promising candidates for various applications.

Reactive Precursor Particles as Synthetic Platform for the Generation of Functional Nanoparticles, Nanogels, and Microgels

“…Complete Functionalization Using Thiol–Maleimide Michael Addition : Due to the high orthogonality owned by the “click” chemistry reactions, it is possible to employ the same precursor nanoparticle for several purposes. Sanyal and co‐workers reported a “clickable” nanogel on the basis of a poly(ethylene glycol)‐methacrylate‐based maleimide‐bearing copolymer . The nanogels were prepared by thermally induced self‐assembly of the copolymers and subsequent crosslinking, using a dithiol crosslinker.…”

“…The nanogels were prepared by thermally induced self‐assembly of the copolymers and subsequent crosslinking, using a dithiol crosslinker. Residual maleimide groups on the polymer backbone were used to conjugate a thiol‐bearing peptide‐based targeting group, while residual thiol groups from crosslinking were used to introduce a maleimide‐bearing fluorescent dye . The Sanyal group went even further and added another reactive group to the precursor nanoparticle.…”

Recent Developments in the Area of Click‐Crosslinked Nanocarriers for Drug Delivery

“…For instance, Sanyal et al. fabricated multifunctionalizable nanogels via self‐assembly of the maleimide‐containing polymer and crosslinking via thiol–maleimide click reaction . The maleimide‐containing hydrophilic polymer was synthesized via atom transfer radical polymerization (ATRP) of furan‐protected maleimide‐containing methacrylate monomer and PEG‐based methacrylate monomer followed by removal of the furan protecting group via retro Diels–Alder reaction ( Figure a).…”

“…d) Fluorescence images and flow cytometry analysis of MDA‐MB‐231 cells cultured using control, nanogels with only N ‐(fluoresceinyl) maleimide, and nanogels with cRGDfC as well as N ‐(fluoresceinyl) maleimide. Reproduced with permission . Copyright 2017, American Chemical Society.…”

Facile approach to prepare pH and redox-responsive nanogels via Diels-Alder click reaction

“…Their outstanding properties include a high drug loading capacity, prolonged circulation period in the blood stream, and enhanced permeability, allowing efficient delivery of drug molecules to tumor site [7,8]. Two approaches are commonly used for preparation of polymeric nanogels including physical and chemical crosslinking of preformed polymers [9][10][11]. Physical self-assembly in nanogel formation occurs via non-covalent attractive forces such as hydrophilic-hydrophilic, hydrophobic-hydrophobic, and ionic interactions, whereas chemical crosslinking can prevent dissolution of the hydrophilic polymer chains in aqueous media by covalent bonds [12].…”