Development of Polymeric Nanocarriers for Dual Magnetic Resonance Imaging and Drug Delivery
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Two types of (polymer-imaging agent-drug) complexes were prepared and characterized. These included block and graft copolymer complexes with magnetite nanoparticles and manganese ions. Magnetite block ionomer complexes (MBICs) were formed through binding of a portion of the anionic segment of poly(ethylene oxide)-b-poly(acrylic acid) (PEO-b-PAA) block copolymers with the magnetite nanoparticle surfaces. The remainder of the carboxylic acids were utilized to bind with high concentrations of the cationic antibiotic gentamicin (31 wt%). A near zero-order release of gentamicin (pH 7.4 in PBS) that reached ~35 wt% of the initial gentamicin within 10 hours was observed, and this was followed by slower release of another 7 % by 18 hours. These nanoparticles were efficiently taken up by macrophages and appeared to enhance intracellular antimicrobial activities of gentamicin. To increase the complex sizes and NMR T2 relaxivities, amine functional MBICs (MBICs-NH2) were first assembled by adsorbing the polyacrylate block of an aminofunctional poly(ethylene oxide)-b-poly(acrylic acid)) (H2N-PEO-b-PAA) copolymer onto magnetite nanoparticles. Amines at the tips of the H2N-PEO corona were then linked through reaction with a PEO diacrylate oligomer to yield MBIClusters where the metal oxides in the precursor nanoparticles were distinctly separated by the hydrophilic polymer. These MBIClusters with hydrophilic intra-cluster space had transverse relaxivities (r2's) that increased from 190 to 604 s-1 mM Fe-1 measured at 1.4 T and 37°C as their average sizes increased. The clusters were loaded with up to ~38 wt% of the multi-cationic drug gentamicin. MRI scans focused on the livers of mice demonstrated that these MBIClusters are very sensitive contrast agents. These results indicate that these complexes could be potential theranostic agents for dual imaging and drug delivery. Manganese graft ionomer complexes (MaGICs) comprised of Mn ions and a novel polyaminobisphosphonate-g-PEO copolymer were developed for use as T1 weighted MRI positive contrast agents. The graft copolymers were prepared by free radical copolymerization of ammonium bisphosphonate methacrylate monomers with PEO-acrylate macromonomers. The complexes exhibited good colloidal stability without release of free manganese and did not show any in vitro toxicity against mouse hepatocytes. The T1 relaxivities of the MaGICs were 2-10 times higher than that of a commercial manganese based contrast agent MnDPDP. These MaGICs with encapsulated anticancer drugs including doxorubicin, cisplatin and carboplatin have encapsulation efficiencies of 80-100 %. Drug release was sustained and depended on environmental pH, drug structure and drug concentration in the MaGICs. Moreover, these drug-loaded complexes exhibited high anticancer efficacy against MCF-7 breast cancer cells. The prominent MRI relaxivities and high anticancer efficacy suggest that these MaGICs have potential as effective dual imaging and chemotherapeutic agents.
- Doctoral Dissertations