Release-Modulated Antioxidant Activity of a Composite Curcumin-Chitosan Polymer

Abstract

Curcumin is known to have immense therapeutic potential but is hindered by poor solubility and rapid degradation in solution. To overcome these shortcomings, curcumin has been conjugated to chitosan through a pendant glutaric anhydride linker using amide bond coupling chemistry. The hybrid polymer has been characterized by UV-visible, fluorescence, and infrared spectroscopies as well as zeta potential measurements and SEM imaging. The conjugation reactivity was confirmed through gel permeation chromatography and quantification of unconjugated curcumin. An analogous reaction of curcumin with glucosamine, a small molecule analogue for chitosan, was performed and the purified product characterized by mass spectrometry, UV-visible, fluorescence, and infrared spectroscopies. Conjugation of curcumin to chitosan has greatly improved curcumin aqueous solubility and stability, with no significant curcumin degradation detected after one month in solution. The absorbance and fluorescence properties of curcumin are minimally perturbed (λmax shifts of 2 and 5 nm, respectively) by the conjugation reaction. This conjugation strategy required use of one out of two curcumin phenols (one of the main antioxidant functional groups) for covalent linkage to chitosan, thus temporarily attenuating its antioxidant capacity. Hydrolysis-based release of curcumin from the polymer, however, is accompanied by full restoration of curcumin's antioxidant potential. Antioxidant assays show that curcumin radical scavenging potential is reduced by 40% after conjugation, but that full antioxidant potential is restored upon hydrolytic release from chitosan. Release studies show that curcumin is released over 19 days from the polymer and maintains a concentration of 0.23 ± 0.12 μM curcumin/mg polymer/mL solution based on 1% curcumin loading on the polymer. Release studies in the presence of carbonic anhydrase, an enzyme with known phenolic esterase activity, show no significant difference from nonenzymatic release studies, implying that simple ester hydrolysis is the dominant release mechanism. Conjugation of curcumin to chitosan through a phenol ester modification provides improved stability and solubility to curcumin, with ester hydrolysis restoring the full antioxidant potential of curcumin.

Radiation-induced curcumin release from curcumin–chitosan polymer films

“…This curcumin release at 0 Gy supports previously published results for the release of curcumin from chitosan-curcumin polymer, which concluded that it took 19 days to reach 100% curcumin release via ester-hydrolysis. 27 However, this ester-hydrolysis release prole is not an ideal curcumin release mechanism for situations such as radiation exposure that require rapid drug response aer the harmful stimuli. 27,42 For comparison, the 6 Gy release of 98% curcumin occurred in 30 minutes.…”

“…27 However, this ester-hydrolysis release prole is not an ideal curcumin release mechanism for situations such as radiation exposure that require rapid drug response aer the harmful stimuli. 27,42 For comparison, the 6 Gy release of 98% curcumin occurred in 30 minutes. The radiation sensitivity for releasing curcumin from the chitosan-curcumin polymer makes this a unique system for radiation exposure situations.…”

“…1) was formulated using a previously published protocol. 27 Briey, glutaric anhydride modied curcumin was conjugated to chitosan 90/200 via EDC/ NHS (1 : 1) chemistry in 1 wt/v% acetic acid solution. 27…”

“…The ATR FT-IR transmission bands of chitosan-curcumin polymer/lm at 3290 cm À1 (m), 1763 cm À1 (w), 1540 cm À1 (m) and 1025 cm À1 (s) were attributed to hydroxyl (-OH), curcumin, chitosan amine (-NH 2 ) group and glycosidic (C-O-C) groups respectively. 27,41,43 Per literature, the amine (-NH 2 ) group is not altered aer g-radiation exposure, and so the ATR FT-IR analysis of radiation-induced cleavage was referenced to this band. 29,44,45 The data showed radiationinduced scission of glycosidic bonds leading to the formation of hydroxyl groups.…”

“…Covalent linkage of curcumin to chitosan to produce chitosan-curcumin (CC) polymer has previously shown (1) improved curcumin stability over $1 month in solutions at above-freezing and ambient temperatures, (2) improved solubility in aqueous media, (3) improved curcumin bioavailability, (4) controlled release of conjugated-curcumin over 19 days relative to the encapsulated-curcumin (doped), which had been reported to release completely from the spraydried particles over a 2 h period, and (5) retention of nearly $100% recovery of curcumin's antioxidant potential upon cleavage from the polymer backbone via ester hydrolysis. 27,28 Biomacromolecules have been found to degrade into fragments under radiation stress. 8,29 Hydrolysis driven glycosidic bond (C-O-C) cleavage is well-known among carbohydrates and nucleic acids, rendering them an excellent drug-payload carrier in biological environments.…”