Synthesis, Characterization and Structure-Property Relationships of Polymer-Stabilized Nanoparticles Containing Imaging and Therapeutic Agents
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The controllable design of magnetic nanocarriers is essential for advanced in vivo applications such as magnetic resonance image-guided therapeutic delivery and alternating magnetic field-induced remote release of drugs. This work describes the fabrication of polymer-stabilized nanoparticles encapsulating imaging and therapeutic agents and delineates relationships among materials parameters and response. The effect of aggregation of magnetic iron oxide nanoparticles in aqueous suspension was characterized using a well-defined core-corona complex comprised of a superparamagnetic magnetite nanoparticle stabilized by terminally-anchored poly(N-isopropylacrylamide) (PNIPAM) corona. The modified Vagberg density distribution model was employed to verify that the complexes were individually dispersed prior to aggregation and was found to accurately predict the intensity-weighted hydrodynamic diameter in water. Aggregation of the complexes was systematically induced by heating the suspension above the lower critical solution temperature (LCST) of the polymer, and substantial increase in the NMR transverse relaxation rates was noted. Controlled clusters of primary iron oxide nanoparticles stabilized by the biodegradable block copolymer, poly(ethylene oxide-b-D,L-lactide) were fabricated by a scalable, rapid precipitation technique using a multi-inlet vortex mixer. Quantitative control over iron oxide loading, up to 40 wt%, was achieved. Correlations between particle parameters and transverse relaxivities were studied within the framework of the analytical models of transverse relaxivity. The experimental relaxivities typically agreed to within 15% with the values predicted using the analytical models and cluster size distributions derived from cryo-transmission electron microscopy. Hydrophilic-core particles assembled using the poly(ethylene oxide-b-acrylate) copolymer and at similar primary nanoparticle sizes and loadings had considerably higher transverse (r2) and longitudinal (r1) relaxivities, with r2s approaching the theoretical limit for ~ 8 nm magnetite. Block copolymer nanoparticles comprised of poly(D,L-lactide) and poly(butylene oxide) cores were utilized to encapsulate the poorly water-soluble antiretroviral drug, ritonavir, at therapeutically-useful loadings. Controlled size distributions were achieved by incorporation of homopolymer additives, poly(L-lactide) or poly(butylene oxide) during the nanoparticle preparation process. Nanoparticles either co-encapsulating a highly hydrophobic polyester poly(oxy-2,2,4,4-tetramethyl-1,3-cyclobutanediyloxy-1,4-cyclohexanedicarbonyl) within the core or possessing crosslinkable groups around the core were also successfully fabricated for potential sustained release of ritonavir from block copolymer carriers.
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