Application of controlled release technology to the peritoneum would allow for sustained drug levels. However, some polymeric systems either create adhesions, or rapidly exit the peritoneum; neither result is desirable. Here we have produced particles based on sphyngomyelin, a phospholipid that occurs naturally in the peritoneum, along with hyaluronic acid and the polymethacrylate Eudragit E100 (to modulate drug release). Particles with a low proportion of E100 (5% (w/w); "high SPM") release albumin rapidly over 2 days, then more slowly; increasing the E100 to 20% (w/w; high "E100") slowed drug release markedly. When injected in the murine peritoneum, high SPM particles were disseminated as free particles, without forming collections. There was a mild inflammatory response but no formation of adhesions. High E100 particles formed collections in all animals, with an intense inflammatory response. Even so, there were very few adhesions. These results suggest that microparticulate formulations can be produced that have acceptable drug-releasing properties and are suitable for use in the peritoneum from the standpoint of biocompatibility.
[Show abstract][Hide abstract] ABSTRACT: Major traumatic spinal cord injury (SCI) results in permanent paralysis below the site of injury. The effectiveness of systemically delivered pharmacological therapies against SCI can be limited by the blood-spinal cord barrier and side effects. Local drug delivery to the injured spinal cord can be achieved using a minimally invasive biopolymer matrix of hyaluronan and methylcellulose injected into the intrathecal space, bypassing the blood-spinal cord barrier and overcoming limitations of existing strategies. Composite hydrogels of drug-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles dispersed in this biopolymer matrix meet the in vitro design criteria for prolonged local release. Using a blank (without drug) composite designed for 28-day sustained release, we presently explore the mechanism of particle-mediated hydrogel stabilization in vitro and aspects of biocompatibility and safety in vivo. The composite hydrogel is well tolerated in the intrathecal space of spinal cord injured rats, showing no increase in inflammation, scarring, or cavity volume relative to controls, and no significant effect on locomotor function up to 28 days. Furthermore, there was no effect on locomotor function in healthy animals which received the composite hydrogel, although a qualitative increase in ED-1 staining was apparent. These data support the further development of composite hydrogels of hyaluronan and methylcellulose containing PLGA nanoparticles for sustained local delivery to the injured spinal cord, an application for which there are no approved alternatives.
[Show abstract][Hide abstract] ABSTRACT: Hyaluronic acid (HA) is one of nature's most versatile and fascinating macromolecules. Being an essential component of the natural extracellular matrix (ECM), HA plays an important role in a variety of biological processes. Inherently biocompatible, biodegradable and non-immunogenic, HA is an attractive starting material for the construction of hydrogels with desired morphology, stiffness and bioactivity. While the interconnected network extends to the macroscopic level in HA bulk gels, HA hydrogel particles (HGPs, microgels or nanogels) confine the network to microscopic dimensions. Taking advantage of various scaffold fabrication techniques, HA hydrogels with complex architecture, unique anisotropy, tunable viscoelasticity and desired biologic outcomes have been synthesized and characterized. Physical entrapment and covalent integration of hydrogel particles in a secondary HA network give rise to hybrid networks that are hierarchically structured and mechanically robust, capable of mediating cellular activities through the spatial and temporal presentation of biological cues. This review highlights recent efforts in converting a naturally occurring polysaccharide to drug releasing hydrogel particles, and finally, complex and instructive macroscopic networks. HA-based hydrogels are promising materials for tissue repair and regeneration.
[Show abstract][Hide abstract] ABSTRACT: Drug-delivery carriers must endure harsh pH conditions in the gastrointestinal tract and still maintain a high drug load-ing (DL) for oral therapeutic drugs to be effectively delivered to the colon area. In this research, a pH-sensitive drug-delivery system with an enhanced DL was developed by the coating of 5-fluorouracil (5-FU)-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) with Eudragit S100 with an oil-in-oil solvent evaporation technique. The enhanced DL and encapsulation efficiency were achieved by the optimization of the fabrication parameters and by the use of particles of a proper size. A DL of 5.8% was obtained by a moderate initial drug feeding, a high volume ratio of the outer water phase to the organic phase, and by the adjustment of the pH value of the outer aqueous phase to the isoelectric point of 5-FU. An in vitro drug-dissolution test showed that the coating of the Eudragit S100 microspheres could effectively prevent drugs from being released in an environment with a pH lower than 7. The PLGA NPs showed an initial burst release followed by a slow and sustained release over an extended period of over 120 h at pH value of 7.4. Therefore, the prepared systems have great potential for practical applications in the treatment of colorectal cancer. V C 2012 Wiley Periodicals, Inc.
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