ABSTRACT
The most common treatment for osteoarthritis is daily oral administration of a nonsteroidal anti-inflammatory drug such as diclofenac. This daily dosage regime is often associated with severe side effects. In this study, we explored the potential of utilizing a high molecular weight cross-linked polyurethane polymer covalently linked to diclofenac (C-DCF-PU) for intra-articular administration. We aim to exploit the advantages of local drug delivery by developing an implant with improved efficacy and reduced side effects. The polymer was synthesized from a diclofenac-functionalized monomer unit in a simple one-pot reaction, followed by cross-linking. In vitro drug release studies showed zero-order drug release for 4 days, followed by a gradual decline in drug release rate until diclofenac was depleted after 15 days. The cross-linked polymer was triturated to yield an injectable microgel formulation for administration. Whole animal fluorescence imaging of the rhodamine-labeled C-DCF-RH-PU showed good retention of the polymer in the knee joints of healthy rats, with approximately 30% of the injected dose still present 2 weeks post intra-articular administration. In a reactivation arthritis animal model, the C-DCF-RH-PU formulation reduced pain and significantly reduced inflammation after a short lag phase, showing that this drug delivery system warrants further development for long-term treatment of osteoarthritis with the benefit of reduced side effects.
ABSTRACT
A facile synthesis method of polymer diclofenac conjugates (PDCs) based on biocompatible polyurethane chemistry that provides a high drug loading and offers a high degree of control over diclofenac (DCF) release kinetics is described. DCF incorporating monomer was reacted with ethyl-l-lysine diisocyanate (ELDI) and different amounts of polyethylene glycol (PEG) in a one-step synthesis to yield polymers with pendent diclofenac distributed along the backbone. By adjusting the co-monomers feed ratio, the drug loading could be tailored accordingly to give DCF loading of up to 38 w/w%. The release rate could also be controlled easily by changing the amount of PEG in the backbone. Above 10 w/w% of PEG, the in vitro DCF release studies in physiological conditions showed an apparent zero-order profile without an initial burst effect for up to 120 days. The PDCs described may be suitable for long-term intra-articular (IA) delivery for the treatment of osteoarthritis (OA).
ABSTRACT
In this work, the use of a nanoreactor is demonstrated to rapidly prepare monodisperse polymer nanoparticles in water-based dispersion consisting of 4-arm star polymer via the R-group RAFT approach. It is shown that by heating a nanoparticle assembler above its lower critical solution temperature (LCST), stabilized nanoparticles are formed that act as a template for the 4-arm star RAFT-mediated polymerization of styrene. Monodisperse nanoparticles of size (between 40 and 90 nm) containing monodisperse polymer of desired molecular weight (30-95 k) are obtained with little star-star coupling due to compartmentalization. The nanoreactor technique allows independent control over the size and molecular weight with a 4-arm star topology.
Subject(s)
Nanoparticles , Water/chemistry , TemperatureABSTRACT
l-Proline moieties bound to a thermoresponsive polymer nanoreactor efficiently directed the asymmetric aldol reaction in water with excellent yields and enantioselectivity (ee). The reactions were efficient at higher temperatures in direct contrast to the low yields and ee values found when the reaction was carried out in a DMF/water mixture due to the location of the l-proline moieties within the hydrophobic pocket inside the core of the nanoreactors. This ideal environment formed for catalysis allows control over the water content as well as enhancing interactions between the carboxylic acid of l-proline and the aldehyde substrate. The nanoreactors were disassembled to fully water-soluble polymers by lowering the temperature to below the lower critical solution temperature (LCST) of the polymer, resulting in precipitation of the product in near pure form. The product was isolated by centrifugation and the polymer/water solution reused in additional catalytic cycles by heating the polymer above its LCST and thus reforming the nanoreactors. Although a small decrease in yield after five cycles was observed, the selectivity (anti/syn ratio and ee) remained high.
ABSTRACT
Poly(ethylene glycol) (PEG) conjugates of Dicer-substrate small interfering RNA (DsiRNA) have been prepared to investigate a new siRNA release strategy. 3'-sense or 5'-antisense thiol-modified, blunt-ended DsiRNAs, inhibiting enhanced green fluorescent protein (eGFP) expression, were covalently conjugated to PEG with varying molecular weights (2, 10, and 20 kg/mol) through a stable thioether bond using a Michael addition reaction. The DsiRNA conjugates with 2 kg/mol PEG (both 3'-sense or 5'-antisense strand conjugated) and the 10 kg/mol PEG conjugated to the 3'-sense strand of DsiRNA were efficiently cleaved by recombinant human Dicer to 21-mer siRNA, as determined by gel electrophoresis. Importantly, 2 and 10 kg/mol PEG conjugated to the 3'-sense strand of DsiRNA showed potent gene silencing activity in human neuroblastoma (SH-EP) cells, stably expressing eGFP, at both the mRNA and protein levels. Moreover, the 10 kg/mol PEG conjugates of the 3'-sense strand of DsiRNA were less immunogenic when compared with the unmodified DsiRNA, determined via an immune stimulation assay on human peripheral blood mononuclear cells.
