Magnetic resonance imaging of folic acid-coated magnetite nanoparticles reflects tissue biodistribution of long-acting antiretroviral therapy

Abstract

Regimen adherence, systemic toxicities, and limited drug penetrance to viral reservoirs are obstacles limiting the effectiveness of antiretroviral therapy (ART). Our laboratory’s development of the monocyte-macrophage-targeted long-acting nanoformulated ART (nanoART) carriage provides a novel opportunity to simplify drug-dosing regimens. Progress has nonetheless been slowed by cumbersome, but required, pharmacokinetic (PK), pharmacodynamics, and biodistribution testing. To this end, we developed a small magnetite ART (SMART) nanoparticle platform to assess antiretroviral drug tissue biodistribution and PK using magnetic resonance imaging (MRI) scans. Herein, we have taken this technique a significant step further by determining nanoART PK with folic acid (FA) decorated magnetite (ultrasmall superparamagnetic iron oxide [USPIO]) particles and by using SMART particles. FA nanoparticles enhanced the entry and particle retention to the reticuloendothelial system over nondecorated polymers after systemic administration into mice. These data were seen by MRI testing and validated by comparison with SMART particles and direct evaluation of tissue drug levels after nanoART. The development of alendronate (ALN)-coated magnetite thus serves as a rapid initial screen for the ability of targeting ligands to enhance nanoparticle-antiretroviral drug biodistribution, underscoring the value of decorated magnetite particles as a theranostic tool for improved drug delivery.

Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging

“…The concentration dependent relaxivity in PBS of Si-CFEu and FA-Si-CFEu nanoparticles was found to be r 2 =433.42 mM –1 s –1 , and r 2 =419.52 mM –1 s –1 , respectively (Fig. 7B), which are more than one log greater r 2 compared to our previous USPIO nanoparticles (r 2 = 31.15 s –1 mM –1 Fe) [21]. Relaxivity measures of FA/Si-CFEu in MDM was linear with increased cellular iron concentrations (Fig.…”

“…The folate receptor (FR) present on the macrophage surface [33, 34] was engaged by placing folic acid (FA) on the particle surface. This enabled the synthesized particles to seek out the FR and potentially enhance drug delivery in cell culture as was previously demonstrated [6, 9, 20, 21, 35, 36]. These next generation FA decorated probes combine accurate histologic (fluorescent) and magnetic properties to facilitate the utility of multimodal nanoprobes.…”

“…USPIO with size ~ 67.3 nm were fabricated in our laboratory using functional alendronate-coated iron oxide particles [21]. These were employed for comparative studies with the newly synthesized FA/Si-CFEu nanoparticles.…”

“…Indeed, targeting drug nanoparticle delivery systems to macrophages encourages transport to sites of viral growth and inflammation as such sites harbor residual virus that cannot be eliminated by current ARV therapy. Elimination of resultant latent infections will require optimal delivery of therapeutic payloads designed to excise HIV from sites of host chromosomal integration [6, 11, 12, 20, 21]. As a first step towards achieving such goals we synthesized nanoparticles with combinations of ultra-small superparamagnetic iron oxide particles (USPIO) and ARV to speed assessment of drug tissue biodistribution [9, 21].…”

Long-acting slow effective release antiretroviral therapy

“…In recent years, magnetic resonance imaging (MRI) has been extended to the development of contrast agents to enable in vivo tracking of drug carrying nanoparticles. Our laboratory first developed small magnetite antiretroviral therapy (SMART) [18]. SMART is defined by the use of alendronate polyethylene glycol superparamagnetic iron oxide nanoparticles (ALN-PEG SPIO) and used for screening of targeted nanoformulations.…”