The rational design of a synthetic polymer nanoparticle that neutralizes a toxic peptide in vivo

Abstract

Synthetic polymer nanoparticles (NPs) that bind venomous molecules and neutralize their function in vivo are of significant interest as "plastic antidotes." Recently, procedures to synthesize polymer NPs with affinity for target peptides have been reported. However, the performance of synthetic materials in vivo is a far greater challenge. Particle size, surface charge, and hydrophobicity affect not only the binding affinity and capacity to the target toxin but also the toxicity of NPs and the creation of a "corona" of proteins around NPs that can alter and or suppress the intended performance. Here, we report the design rationale of a plastic antidote for in vivo applications. Optimizing the choice and ratio of functional monomers incorporated in the NP maximized the binding affinity and capacity toward a target peptide. Biocompatibility tests of the NPs in vitro and in vivo revealed the importance of tuning surface charge and hydrophobicity to minimize NP toxicity and prevent aggregation induced by nonspecific interactions with plasma proteins. The toxin neutralization capacity of NPs in vivo showed a strong correlation with binding affinity and capacity in vitro. Furthermore, in vivo imaging experiments established the NPs accelerate clearance of the toxic peptide and eventually accumulate in macrophages in the liver. These results provide a platform to design plastic antidotes and reveal the potential and possible limitations of using synthetic polymer nanoparticles as plastic antidotes.

Engineering red‐blood‐cell‐membrane–coated nanoparticles for broad biomedical applications

“…The inhibition of PFTs is beneficial in the fight against various bacterial infections and venomous attacks by animals, such as sea anemones, scorpions, and snakes. 27 To neutralize PFTs, numerous detoxification platforms, including antisera, 28 monoclonal antibodies, 29 small-molecule inhibitors, 30 and molecularly imprinted polymers, 31 have been developed. However, these platforms act by targeting the specific molecular structures of toxins and require customized treatments for different diseases.…”

Preparation of nanogel-immobilized porous gel beads for affinity separation of proteins: fusion of nano and micro gel materials

“…Figure 3e and f indicate that the surface morphology of the pore structures after adsorption of the NPs were less angulated than the surface morphology before adsorption, although none of the pores were filled by the NPs. The apparent surface roughness of the NPs-immobilized pore surface seemed to be comparable to that of the mono-layered dried NPs films (o10 nm), 10,19,20 suggesting that the surface of GBs were coated with NPs. From those results, it was established that NP-adsorbed macroporous GBs could be prepared simply by incubating negatively charged NPs and positively charged GBs in water.…”

“…The procedure reported by Shea and colleagues 19 was modified to prepare compound 1. A solution of dansyl chloride (0.94 g, 3.47 mmol) in dry tetrahydrofuran (THF) (75 ml) was added dropwise to a cooled (0°C) solution of ethylenediamine (2.32 ml, 34.7 mmol) in dry THF (150 ml).…”

“…[5][6][7][8] Shea and colleagues reported that multifunctional nanogel particles (NPs) polymerized with a combination of functional monomers capture target peptides, 9-12 proteins [13][14][15] and specific domains of proteins 16 via a combination of multipoint electrostatic, hydrophobic, aromatic 17 and/or hydrogen binding 18 interactions. Target affinity can be enhanced by optimizing the feed ratio of functional monomers, 19 by molecular imprinting polymerization 20,21 and/or by affinity purification procedures. 22 It has also been reported that porous membranes polymerized with functional monomers containing carbohydrates can be used as affinity separation media for lectins.…”

Core-Shell Microgels as Nanoreactors

“…On the other hand, layers of charged polymers, e.g., polyelectrolyte brushes [92][93][94][95][96] or charged microgel networks [97][98][99][100][101][102][103][104][105][106], generally cause strong adherence of proteins to the colloidal particles. The identification of the various forces resulting in attraction/repulsion of the proteins to/from the particles remains an important task for the future.…”