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Peptide conjugation enhances the cellular co-localization, but not endosomal escape, of modular poly(acrylamide-co-methacrylic acid) nanogels.

ABSTRACT: Nanoparticles must recognize, adhere to, and/or traverse multiple barriers in sequence to achieve cytosolic drug delivery. New nanoparticles often exhibit a unique ability to cross a single barrier (i.e. the vasculature, cell membrane, or endosomal compartment), but fail to deliver an adequate dose to intracellular sites of action because they cannot traverse other biological barriers for which they were not optimized. Here, we developed poly(acrylamide-co-methacrylic acid) nanogels that were modified in a modular manner with bioactive peptides. This nanogel does not recognize target cells or disrupt endosomal vesicles in its unmodified state, but can incorporate peptides with molecular recognition or environmentally responsive properties. Nanogels were modified with up to 15 wt% peptide without significantly altering their size, surface charge, or stability in aqueous buffer. Nanogels modified with a colon cancer-targeting oligopeptide exhibited up to a 324% enhancement in co-localization with SW-48 colon cancer cells in vitro, while influencing nanogel uptake by fibroblasts and macrophages to a lesser extent. Nanogels modified with an endosome disrupting peptide failed to retain its native endosomolytic activity, when coupled either individually or in combination with the targeting peptide. Our results offer a proof-of-concept for modifying synthetic nanogels with a combination of peptides that address barriers to cytosolic delivery individually and in tandem. Our data further motivate the need to identify endosome disrupting moieties which retain their activity within poly(acidic) networks.

SUBMITTER: Clegg JR

PROVIDER: S-EPMC7904656 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Thermoresponsive poly((N,N-dimethyl acrylamide)-co-(N-isopropyl acrylamide)) (P(DMA-co-NIPAM)) copolymers were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The monomer reactivity ratios were determined by the Kelen-Tüdős method to be rNIPAM = 0.83 and rDMA = 1.10. The thermoresponsive properties of these copo-lymers with varying molecular weights were characterized by visual turbidimetry and dynamic light scattering (DLS). The copolymers showed a lower critical solution temperature (LCST) in water with a dependence on the molar fraction of DMA in the copolymer. Chaotropic and kosmotropic salt anions of the Hofmeister series, known to affect the LCST of thermoresponsive polymers, were used as additives in the aqueous copolymer solutions and their influence on the LCST was demonstrated. Further on, in order to investigate the thermoresponsive behavior of P(DMA-co-NIPAM) in a confined state, P(DMA-co-NIPAM)-b-PS diblock copolymers were prepared via polymerization induced self-assembly (PISA) through surfactant-free RAFT mediated emulsion polymerization of styrene using P(DMA-co-NIPAM) as the macromolecular chain transfer agent (mCTA) of the polymerization. As confirmed by cryogenic transmission electron microscopy (cryoTEM), this approach yielded stabilized spherical micelles in aqueous dispersions where the PS block formed the hydrophobic core and the P(DMA-co-NIPAM) block formed the hydrophilic corona of the spherical micelle. The temperature-dependent behavior of the LCST-type diblock copolymers was further studied by examining the collapse of the P(DMA-co-NIPAM) minor block of the P(DMA-co-NIPAM)-b-PS diblock copolymers as a function of temperature in aqueous solution. The nanospheres were found to be thermosensitive by changing their hydrodynamic radii almost linearly as a function of temperature between 25 °C and 45 °C. The addition of kosmotropic salt anions, as a potentially useful tuning feature of micellar assemblies, was found to increase the hydrodynamic radius of the micelles and resulted in a faster collapse of the micelle corona upon heating.

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Peptide conjugation enhances the cellular co-localization, but not endosomal escape, of modular poly(acrylamide-co-methacrylic acid) nanogels.

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