(221d) Fabrication of ‘Theranostic' Magnetite and Antiretroviral Nanoparticles

In the past decade, multifunctional magnetite nanocarriers that integrate therapeutic agents into a single system have attracted considerable interest in theranostics integrating drug delivery and drug biodistribution. Using magnetic resonance imaging (MRI) to guide nanomaterial development can improve therapeutic endpoints. To this end nanoformulations of antiretroviral therapy (nanoART) previously developed for treatment of human immunodeficiency virus (HIV) infection were modified for theranostic testing. Herein, we describe the fabrication of polymer nanocarriers co-encapsulating the HIV protease inhibitor, ritonavir (RTV) within magnetite (Fe₃O₄) nanoparticles. Discrete ~ 8 nm nanoparticles (M_s = 65 A.m²/kg) were synthesized by reducing iron (III) acetylacetonate in benzyl alcohol and their surfaces were subsequently modified to be hydrophobic by coating with oleic acid. A poly(ethylene glycol)-b-poly(D,L-lactide) block copolymer [mPEG(5 kDa)-b-PDLLA(10 kDa)] was synthesized by ring-opening polymerization of D,L-lactide in the presence of mPEG using stannous octoate as the catalyst. Drug-copolymer, magnetite-copolymer and drug-magnetite-copolymer ‘theranostic’ nanoparticles were fabricated by rapid nanoprecipitation in a multi-inlet vortex mixer.

The hydrophobic polyester core of the copolymer nanoparticles sequestered RTV and/or oleic acid-coated magnetite whereas the PEG chains extended into aqueous solutions to provide steric stability. Nanoparticles with hydrodynamic diameters in the range of 100-150 nm and polydispersity indices less than 0.2 were obtained, as measured by dynamic light scattering. For the drug-copolymer nanoparticles, the addition of a PLLA homopolymer in the nanoprecipitation step yielded monomodal size distributions. The drug and magnetite loadings determined by high-performance liquid chromatography (HPLC) and thermogravimetric analysis respectively indicated drug loading as high as 45 wt% and quantitative incorporation of magnetite. The transverse and longitudinal NMR relaxivities of the magnetite-loaded nanoparticles were ~ 200 s^-1.mM Fe^-1 and ~ 1 s^-1.mM Fe^-1 respectively. The transverse relaxivities enabled sensitive T₂-weighted MRI and the low longitudinal relaxivities are consistent with the hydrophobic nature of the cores of the nanoparticle clusters. The therapeutically-relevant drug loadings and high transverse relaxivities for magnetic resonance imaging render these nanoparticles valuable for development of HIV theranostics.