Poly(pro-curcumin) Materials Exhibit Dual Release Rates and Prolonged Antioxidant Activity as Thin Films and Self-Assembled Particles

Abstract

Curcumin is a natural polyphenol that exhibits remarkable antioxidant and anti-inflammatory activities; however, its clinical application is limited in part by its physiological instability. Here, we report the synthesis of curcumin-derived polyesters that release curcumin upon hydrolytic degradation to improve curcumin stability and solubility in physiological conditions. Curcumin was incorporated in the polymer backbone by a one-pot condensation polymerization in the presence of sebacoyl chloride and polyethylene glycol (PEG, M n = 1 kDa). The thermal and mechanical properties, surface wettability, self-assembly behavior, and drug-release kinetics all depend sensitively on the mole percentage of curcumin incorporated in these statistical copolymers. Curcumin release was triggered by the hydrolysis of phenolic esters on the polymer backbone, which was confirmed using a PEGylated curcumin model compound, which represented a putative repeating unit within the polymer. The release rate of curcumin was controlled by the hydrophilicity of the polymers. Burst release (2 days) and extended release (>8 weeks) can be achieved from the same polymer depending on curcumin content in the copolymer. The materials can quench free radicals for at least 8 weeks and protect primary neurons from oxidative stress in vitro. Further, these copolymer materials could be processed into both thin films and self-assembled particles, depending on the solvent-based casting conditions. Finally, we envision that these materials may have potential for neural tissue engineering application, where antioxidant release can mitigate oxidative stress and the inflammatory response following neural injury.

Development of a Slow-Degrading Polymerized Curcumin Coating for Intracortical Microelectrodes

“…Through hydrolytic degradation followed by decarboxylation, we expect that cleavage of the urethane linkages will result in the release of curcumin, as well as the known auto-oxidation byproducts of curcumin. − In addition, byproducts include PEG and the diaminotoluene derived from the TDI linker unit. At the same time, it has been shown that the curcumin within intact (not degraded) repeating units can still exert antioxidant activity, such that degradation is not a strict prerequisite for activity of the coated films.…”

“…Different polymer architectures may also be assessed, such as dendrimers, to see if curcumin loading efficiency could be increased . Furthermore, future studies may consider using alternative linkers and copolymers to further improve biocompatibility; for example, a recent study in our lab used a sebacoyl linker in place of toluene diisocyanate . In addition to the incorporation of curcumin, future studies may also incorporate other small molecule anti-inflammatory agents to better target the macrophage and microglia response; for example, research has shown that Itgam, Cd14, and Irak4 play a major role in the innate immune response to electrode implantation and are potential targets for electrode coatings.…”

“…54−56 In addition, byproducts include PEG and the diaminotoluene derived from the TDI linker unit. At the same time, it has been shown that the curcumin within intact (not degraded) repeating units can still exert antioxidant activity, 57 such that degradation is not a strict prerequisite for activity of the coated films.…”

Melt Polycondensation Strategy for Amide-Functionalized l-Aspartic Acid Amphiphilic Polyester Nano-assemblies and Enzyme-Responsive Drug Delivery in Cancer Cells

“…Biodegradable polymers are emerging as important components in tissue engineering, bone repair, nano-vehicles for therapeutics drugs and genes in cancer treatment, and so forth. − Among various chemical linkages that are readily susceptible to biodegradation under physiological conditions, aliphatic polyesters are very special due to their unique ability to degrade by lysosomal enzyme stimuli at the intracellular compartments. − Aliphatic polyesters are typically synthesized either by ring opening polymerization (ROP) of cyclic monomers , or direct polycondensation of dicarboxylic acids and diols. , The ROP strategy has been used industrially for the production of polycaprolactone (PCL), − poly­( l -lactic acid) and poly­( d , l -lactic- co -glycolic acid), and their di- and tri-block copolymers. , In the last decade, significant efforts have been taken to enhance the hydrolytic and environmental stability of the PLLA . Attempts have also been made to overcome the slow enzymatic biodegradation of PCL chains by functionalization of various side chains for drug delivery in cancer − and antimicrobial agents. , On the contrary, the polycondensation approach for aliphatic polyesters has had limited success in commercial exploration due to poor mechanical properties, low molecular weights, limited enzymatic or microbial biodegradation, and so forth .…”

Next-Generation Hydrogels as Biomaterials for Biomedical Applications: Exploring the Role of Curcumin

“…Later on, several scientists developed methods for high yield synthesis of curcumin which are in use today . Curcumin is the most widely used plant-based drug with various pharmacological benefits, including anti-inflammatory, antioxidant, anti-viral, anti-bacterial, anti-fungal, anti-parasite, and anti-cancer. − Numerous preclinical studies have proven curcumin to be effective in several cancers because of curcumin’s capability to induce G2/M cell cycle arrest, trigger apoptosis, induce autophagy, disturb molecular signaling, inhibit invasion and metastasis, and increase the efficiency of existing chemotherapeutics. , The inflammatory response of curcumin is often steered by the radical production of pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α). , Consequently, the downregulation of pro-inflammatory cytokines may effectively reduce the incidence of inflammation . Curcumin is also involved in other signaling pathways like it induces degranulation in human neutrophils by increasing the cell surface expression of clusters of differentiation 35 (CD35), CD66b, and CD63 .…”