In the present study, two methods were used to evaluate the in vitro release of leuprolide acetate (LA) from poly(lactide-co-glycolide) (PLGA) microspheres: Franz diffusion cells, typically referred to as "vertical diffusion cells" (VDC), and rotating bottle apparatus (RBA), both modified with a dialysis membrane. This hydrosoluble peptide was chosen as a model drug to study different possibilities of in vitro testing and analyze the variables that affect drug release, respecting sink and physiological conditions. Microspheres were prepared with a conventional double emulsion-solvent evaporation method using PLGA (50:50) with a relatively low molecular weight. Comprehensive stability tests for LA were performed in the conditions used for in vitro release assays. In phosphate-buffered saline (PBS), LA showed no significant degradation, but in an acidic medium, it degraded dramatically. The release profile of the delivery system was governed mainly by diffusion as explained by the low molecular weight of the polymer and the high water solubility of the peptide. The in vitro release profiles were triphasic in vertical diffusion cells and biphasic in the rotating bottle apparatus. The release kinetics was enhanced in RBA with respect to VDC, probably because the constant movement of a suspension of loose microspheres in a large volume and the large membrane area facilitated drug migration. The smoother, triphasic profiles obtained with VDC can be explained by the partial confinement of microspheres, which is similar to the described in vivo behavior of an injectable delivery system.
Imaging agents with affinity for bone can enable early detection of changes to bone mineral density, which is a hallmark of many bone-associated pathologies such as Paget’s disease and osteoporosis. Here, we report the development of a polymer nanoparticle (NP)-based multimodal imaging probe that enables visualization of bone mineral phase in near-infrared (NIR) optical tomography and detection in T2-weighted magnetic resonance imaging (MRI). Ultrasmall superparamagnetic iron oxide was first encapsulated in NPs derived by blending poly(dl-lactic-co-glycolic acid)–poly(ethylene glycol) (PLGA–PEG) with N-hydroxysuccinimide functionalized-PLGA (NHS–PLGA). Postmodification of NHS surface functionality on the NPs with alendronic acid (Aln), a bone-targeting ligand, yielded stable ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) containing NPs that exhibit good serum stability and favorable cytocompatibility. These post-Aln-modified NPs exhibit 8- to 10-fold higher affinity for synthetic and biogenic hydroxyapatite in comparison to NPs where Aln was introduced before NP formation and shorten the T2 relaxation times in both agarose phantoms and fresh spongy bone, thus enabling the interrogation of bone mineral phase in T2-MRI. Finally, by introducing an NIR-dye-modified PLGA during the NP formation step, NP probes that enable the visualization of bone mineral phase in both NIR optical tomography and MRI have been realized. The system presented herein meets many of the criteria for clinical translation and therefore opens new opportunities for bone imaging and targeted therapeutics.
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