Hemocompatible Poly(NIPAm-MBA-AMPS) Colloidal Nanoparticles as Carriers of Anti-inflammatory Cell Penetrating Peptides

Abstract

Anionic copolymer systems containing sulfated monomers have great potential for delivery of cationic therapeutics, but N-isopropylacrylamide (NIPAm) 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS) copolymer nanoparticles have seen limited characterization to date with regard to physical properties relevant to loading and release of therapeutics. Characterization of polymeric nanoparticles incorporating AMPS showed an increased size and decreased thermodynamic swelling ratios of AMPS containing particles as compared to NIPAm nanoparticles lacking AMPS. Particles with increasing AMPS addition showed an increased propensity for uniformity, intraparticle colloidal stability, and drug loading capacity. Peptide encapsulated in particles was shielded from peptide degradation in serum. Particles were shown not impede blood coagulation or to cause hemolysis. This study has demonstrated that AMPS incorporation into traditional NIPAm nanoparticles presents a tunable parameter for changing particle LCST, size, swelling ratio, ζ potential, and cationic peptide loading potential. This one-pot synthesis results in a thermosensitive anionic nanoparticle system that is a potentially useful platform to deliver cationic cell penetrating peptides.

Prevention of Collagen-Induced Platelet Binding and Activation by Thermosensitive Nanoparticles

“…Previous work shows that unmodified sulfated poly(NIPAm) nanoparticles exhibit zeta potentials of approximately −15 mV, indicating that they are colloidally stable in an aqueous environment (43). The addition of a second negatively charged co-monomer to our particles reduced their zeta potential to approximately −35 mV.…”

“…Previous work on similar sulfated poly(NIPAm-MBA-AMPS) nanoparticles showed a 20% decrease in particle diameter at temperatures above the VPTT. These particles were able to serve as a controlled release platform for therapeutic peptides, with release being observed for up to 1 week in vitro (43,44). Our unmodified particles demonstrated similar size change of 14.3%, with the smaller size change being attributed to the addition of the hydrophilic AAc to the polymer chain.…”

“…The charge of our particles, as determined by zeta potential and electrophoretic mobility, can be used to facilitate electrostatic loading of oppositely charged therapeutics, thereby increasing their loading efficiency beyond those obtained with simple passive loading (43,44). Previous work shows that unmodified sulfated poly(NIPAm) nanoparticles exhibit zeta potentials of approximately −15 mV, indicating that they are colloidally stable in an aqueous environment (43).…”

“…The zeta potentials and electrophoretic mobility of the particles were investigated to gain insight into the particles surface charge and expected colloidal stability (43,49). Additionally, the change in charge after peptide conjugation provided insight into whether peptides were successfully attached, as the positively charged SILY peptide neutralizes some of the surface charge when covalently bound to the surface of the oppositely charged particle with an increase in the overall potential (less negative) and lower mobility following the addition of the SILY peptide (Fig.…”

“…Additionally, poly(NIPAm) is readily copolymerized with acrylic acid (AAc), which adds easily modified carboxylic acid functional groups to the backbone of the particle, allowing for the addition of targeting ligands while simultaneously increasing the colloidal stability of the nanoparticle (38)(39)(40)(41)(42). In addition to carboxylic acid, the charged sulfated comonomer 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS) has been added to poly(NIPAm) nanoparticles, resulting in colloidally stable, hemocompatible sulfated poly(NIPAm-AMPS) nanoparticles (29,43,44).…”