Oligonucleotide-conjugated nanoparticles for targeted drug delivery via scavenger receptors class A: An in vitro assessment for proof-of-concept.

Spherical nucleic acid gold nanoparticles represent a unique nanotechnology in which the spherical arrangement of oligonucleotides enables the nanoparticles to be efficiently internalized into cells expressing scavenger receptors class A (SR-A). Herein, we seek to replace the gold core with a biodegradable polymeric construct and explore their potential applications in targeted drug delivery. Oligonucleotide-conjugated poly(ethylene glycol)-block-poly(ε-caprolactone) was synthesized and characterized by 1H NMR and gel electrophoresis. This polymer was applied to fabricate micellar nanoparticles (OLN-NPs) by an anti-solvent method. These nanoparticles have a mean particle size about 58.1nm with a narrow size distribution (PDI <0.2) and they were also non-cytotoxic. Relative to non-targeted NPs, OLN-NPs exhibited substantially better uptake (3.94×) in a mouse endothelial cell line (C166), attributing to lipid-raft-mediated endocytosis via SR-A. To explore the potential applications of OLN-NPs as drug carriers, paclitaxel, a poorly soluble anti-angiogenic compound, was selected as the model. OLN-NPs increased the solubility of paclitaxel by at least 300×. The boosted drug solubility in conjunction with improved cellular uptake translated into enhanced in vitro efficacy in the inhibition of angiogenesis. In conclusions, OLN-NPs show considerable promise in targeted drug delivery and their potential applications should be further investigated.

Micellar delivery of dasatinib for the inhibition of pathologic cellular processes of the retinal pigment epithelium.

The objective of this study was to fabricate dasatinib-loaded nanoparticles and evaluate their efficacy in inhibiting cellular processes of the retinal pigment epithelium (RPE) related to proliferative vitreoretinopathy (PVR), for which there are no approved pharmacological approaches. We successfully encapsulated dasatinib, a poorly soluble multi-targeted tyrosine kinase inhibitor which has great potential for the treatment of PVR, into nanoparticles prepared from micellation of PEG-b-PCL. The size of the nanomicelles was approximately 55nm with a narrow distribution. They increased the solubility of dasatinib by 475× and provided a sustained drug release. ARPE-19, an immortal RPE cell line, was used to assess the in vitro efficacy of micellar dasatinib because the RPE is believed to play a key role in the pathogenesis of PVR. Three cell-based assays, namely, proliferation, adhesion and migration, which represent three important PVR-related cellular changes of the RPE, were conducted and the cytotoxicity of micelles was also evaluated. Both blank and dasatinib-loaded micelles were non-cytotoxic towards ARPE-19 cells. Micellar dasatinib significantly inhibited cell proliferation, adhesion and migration compared to the free drug; this might be attributable to enhanced solubility. PEG-b-PCL micelles were taken up into the ARPE-19 cells by an energy-dependent clatharin and caveolae-mediated endocytosis. Our results indicated that cellular uptake and the anti-proliferation effect of drugloaded micelles were linearly correlated. Drug loading appears to be a critical parameter for cellular uptake which in turn impacts the in vitro bioactivities of polymeric micelles. Our results clearly demonstrated that dasatinib-encapsulated micelles offer considerable promise in the management of PVR.