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Biodegradable polyesters containing ibuprofen and naproxen as pendant groups.

ABSTRACT: Controlled release of nonsteroidal anti-inflammatory drugs such as ibuprofen and naproxen could be beneficial for the treatment of inflammatory diseases while reducing the side effects resulting from their continuous use. Novel biodegradable polyesters solely comprised of biocompatible components (e.g., tartaric acid, 1,8-octanediol, and ibuprofen or naproxen as pendant groups) have been synthesized using tin(II) 2-ethylhexanoate as catalyst at 130 °C and subsequently characterized to determine their structures and physicochemical properties. The polymers release the free drug (ibuprofen or naproxen) in vitro in a controlled manner without burst release, unlike the release rates achieved when the drugs are encapsulated in other polymers. These new biomaterials are not cytotoxic toward mouse fibroblasts up to 0.10 mg/mL. The drugs retain their chemical structure following hydrolytic degradation of the polymer, suggesting that bioactivity is preserved.

SUBMITTER: Rosario-Melendez R

PROVIDER: S-EPMC3812688 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Biodegradable polyesters containing ibuprofen and naproxen as pendant groups.

Rosario-Meléndez Roselin R Yu Weiling W Uhrich Kathryn E KE

Biomacromolecules 20130906 10

Controlled release of nonsteroidal anti-inflammatory drugs such as ibuprofen and naproxen could be beneficial for the treatment of inflammatory diseases while reducing the side effects resulting from their continuous use. Novel biodegradable polyesters solely comprised of biocompatible components (e.g., tartaric acid, 1,8-octanediol, and ibuprofen or naproxen as pendant groups) have been synthesized using tin(II) 2-ethylhexanoate as catalyst at 130 °C and subsequently characterized to determine ...[more]

PMID: 23957612

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Project description:Non-steroidal anti-inflammatory drugs (NSAIDs) are used for relieving pain and inflammation accompanying numerous disease states. The primary therapeutic mechanism of these widely used drugs is the inhibition of cyclooxygenase 1 and 2 (COX1, 2) enzymes that catalyze the conversion of arachidonic acid into prostaglandins. At higher doses, NSAIDs are used for prevention of certain types of cancer and as experimental treatments for Alzheimer's disease. In the immune system, various NSAIDs have been reported to influence neutrophil function and lymphocyte proliferation, and affect ion channels and cellular calcium homeostasis. Transient receptor potential melastatin 7 (TRPM7) cation channels are highly expressed in T lymphocytes and are inhibited by Mg2+, acidic pH, and polyamines. Here, we report a novel effect of naproxen, ibuprofen, salicylate, and acetylsalicylate on TRPM7. At concentrations of 3-30mM, they reversibly inhibited TRPM7 channel currents. By measuring intracellular pH with the ratiometric indicator BCECF, we found that at 300μM to 30mM, these NSAIDs reversibly acidified the cytoplasm in a concentration-dependent manner, and propose that TRPM7 channel inhibition is a consequence of cytosolic acidification, rather than direct. NSAID inhibition of TRPM7 channels was slow, voltage-independent, and displayed use-dependence, increasing in potency upon repeated drug applications. The extent of channel inhibition by salicylate strongly depended on cellular PI(4,5)P2 levels, as revealed when this phospholipid was depleted with voltage-sensitive lipid phosphatase (VSP). Salicylate inhibited heterologously expressed wildtype TRPM7 channels but not the S1107R variant, which is insensitive to cytosolic pH, Mg2+, and PI(4,5)P2 depletion. NSAID-induced acidification was also observed in Schneider 2 cells from Drosophila, an organism that lacks orthologous COX genes, suggesting that this effect is unrelated to COX enzyme activity. A 24-h exposure to 300μM-10mM naproxen resulted in a concentration-dependent reduction in cell viability. In addition to TRPM7, the described NSAID effect would be expected to apply to other ion channels and transporters sensitive to intracellular pH.

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Biodegradable polyesters containing ibuprofen and naproxen as pendant groups.

Publications

Biodegradable polyesters containing ibuprofen and naproxen as pendant groups.

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