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Burn wound healing is a complex multifactorial process that relies on coordinated signaling molecules to succeed. Curcumin is believed to be a potent antioxidant and anti-inflammatory agent; therefore, it can prevent the prolonged presence of oxygen free radicals which is a significant factor causing inhabitation of optimum healing process. This study describes an extension of study about the biofunctional nanocomposite hydrogel platform that was prepared by using curcumin and an amphiphilic chitosan-g-pluronic copolymer specialized in burn wound healing application. This formular (nCur-CP, nanocomposite hydrogel) was a free-flowing sol at ambient temperature and instantly converted into a nonflowing gel at body temperature. In addition, the storage study determined the great stability level of nCur-CP in long time using UV-Vis and DLS. Morphology and distribution of nCur in its nanocomposite hydrogels were observed by SEM and TEM, respectively. In vitro studies suggested that nCur-CP exhibited well fibroblast proliferation and ability in antimicrobacteria. Furthermore, second- and third-degree burn wound models were employed to evaluate the in vivo wound healing activity of the nCur-CP. In the second-degree wound model, the nanocomposite hydrogel group showed a higher regenerated collagen density and thicker epidermis layer formation. In third degree, the nCur-CP group also exhibited enhancement of wound closure. Besides, in both models, the nanocomposite material-treated groups showed higher collagen content, better granulation, and higher wound maturity. Histopathologic examination also implied that the nanocomposite hydrogel based on nanocurcumin and chitosan could enhance burn wound repair. In conclusion, the biocompatible and injectable nanocomposite scaffold might have great potential to apply for wound healing.

Abstract:In this study, in order to enhance the aqueous solubility and to overcome the limitation of curcumin (Cur) in free form, as well as to develop a carrier for transdermal delivery of hydrophobic pharmaceutical agents such as Cur, a sonicated synthetic process of nanocurcumin (nCur) in thermally responsive Chitosang-Pluronic (CP) copolymer is disclosed herein. The use of CP copolymer solution as a dispersant medium is a very attractive method to avoid the use of toxic organic solvent and non-biocompatible surfactant. The obtained Cur nanoparticles had a fairly narrow distribution of 8-23 nm. nCur-dispersed CP solution showed good stability with no change in color characteristic and no phase separation after 1 month of storage. Rheological characterization of CP hydrogels had indicated sol-gel transition at the same temperature (35°C). Interestingly, the rate of Cur release for this system can be conveniently modulated as transdermal drug delivery.

Herein, a new process to manufacture multicore micelles nanoparticles reinforced with co-assembly via hydrophobic interaction and electrostatic interaction under the help of ultrasonication was developed. The precise co-assembly between negative/hydrophobic drug and positive charged amphiphilic copolymer based pluronic platform allows the formation of complex micelles structures as the multicore motif with predefined functions. In this study, curcumin was selected as a drug model while positively charged copolymer was based on a pluronic-conjugated gelatin with different hydrophobicity length of Pluronic F87 and Pluronic F127. Under impact of dual hydrophobic and electrostatic interactions, the nCur-encapsulated core–shell micelles formed ranging from 40 nm to 70 nm and 40–100 nm by transmission electron microscopy (TEM) and Dynamic Light Scattering (DLS), respectively. It is found that the structures emerged depended on the relative lengths of the hydrophobic blocks in pluronic. Regarding g2(τ) behavior from DLS measurement, the nanogels showed a high stability in spherical form. Surprisingly, the release profiles showed a sustainable behavior of Cur from this system for drug delivery approaches. In vitro study exhibited that nCur-encapsulated complex micelles increased inhibitory activity against cancer cells growth with IC50 is 4.02 ± 0.11 mg/L (10.92 ± 0.3 µM) which is higher than of free curcumin at 9.40 ± 0.17 mg/L (25.54 ± 0.18 µM). The results obtained can provide the new method to generate the hierarchical assembly of copolymers with incorporated loading with the same property.

Self-assembly of the amphiphilic copolymer into core−shell-like nanoparticles is the new tactic to tailor carriers toward rationalization in the field of drug-delivery systems. Herein, a facile route for examining how the entrapment of a hydrophobic and negative-charge drug affects the micellar structure of a positive-charged copolymer and its biological behavior was developed. In this study, Pluronic F127-grafted chitosan (CF127) was utilized as a positivecharged copolymer for in situ loading of nanocurcumin in a cosolvent condition. Ultrasonication was found to be an effective method to control the self-assembly of phosphocasein and its interaction with curcumin. The superstructure of the incorporated nanoparticles was fabricated in the medium under unimolecular micelles as vesicular structure (SV) at lower ultrasonic condition while large complex micelles (multimicelle aggregates, LCMs) at higher ultrasonic power density. According to transmission electron microscopy, variable UV−visible spectrophotometry, as well as fluorescence spectroscopy, nanocurcumin was not only incorporated into the hydrophobic micelle cores via hydrophobic interaction but also underwent electrostatic interaction with amine groups on chitosan backbone, resulting in micellar aggregation and finally turning in LCMs. Furthermore, regarding dynamic light scattering measurements, correlation coefficients of SV, as well as LCMs, were higher than 0.9, which means that all nanostructures were homogeneous in size under precise control by ultrasonication. Cell-culture studies showed that both unique morphologies endowed fibroblast cell development. Interestingly, the more complex structure as LCM exhibited as a potential candidate in cancer therapy. These corollaries suggest that the morphology of micelles based on cationic amphiphilic block copolymer can be modulated by adding negative-charged/hydrophobic molecules under varying condition of ultrasonication that reinforces their prospective applications as nanocarriers for drug-delivery systems.

To utilize the potent pharmaceutical properties of curcumin (Cur) and gelatin-based materials in tissue regeneration, we fabricated a thermosensitive nanocomposite hydrogel based on pluronic-grafted gelatin (PG) and nanocurcumin (nCur) to enhance burn healing. In this method, the amphiphilic PG played a role as a surfactant to prepare and protect nanosized Cur particles, which could overcome the poor dissolution of the phytochemical. The synthesized PG was identified by 1 H nuclear magnetic resonance. Depending on the amount of Cur, size distribution of the dispersed nCur ranged from 1.5 ± 0.5 to 16 ± 3.2 nm as observed using transmission electron microscopy and dynamic light scattering. The nCur-dispersed PG solution formed nCur-PG nanocomposite hydrogel on warming up to 35 • C. Release profile indicated sustainable release of Cur from the injectable platform. Fibroblast cells were well proliferated on the nanocomposite hydrogel. The nCur-PG enhanced the healing process of second-degree burn wound. These results showed potential applications of the biomaterial in tissue regeneration.

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