Immunosuppressive Cyclotides: A Promising Approach for Treating Autoimmune Diseases.

The immune system maintains constant surveillance to prevent the infiltration of both endogenous and exogenous threats into host organisms. The process is regulated by effector immune cells that combat external pathogens and regulatory immune cells that inhibit excessive internal body inflammation, ultimately establishing a state of homeostasis within the body. Disruption to this process could lead to autoimmunity, which is often associated with the malfunction of both T cells and B cells with T cells playing a more major role. A number of therapeutic mediators for autoimmune diseases are available, from conventional disease-modifying drugs to biologic agents and small molecule inhibitors. Recently, ribosomally synthesized peptides, specifically cyclotides from plants are currently attracting more attention as potential autoimmune disease therapeutics due to their decreased toxicity compared to small molecules inhibitors as well as their remarkable stability against a number of factors. This review provides a concise overview of various cyclotides exhibiting immunomodulatory properties and their potential as therapeutic interventions for autoimmune diseases.

Thermally-responsive and reduced glutathione-sensitive folate-targeted nanocarrier based on alginate and pluronic F127 for on-demand release of methotrexate.

A specific rheumatoid arthritis (RA)-microenvironment-triggered nanocarrier for RA treatment of a first-line antirheumatic drug (Methotrexate, MTX) has been proposed. Reduced glutathione (GSH) responsivity, cystamine, was first introduced on the alginate backbone, which was then used as the bridge to connect pluronic F127 (temperature-responsive factor) and folic acid (targeting factor for active immune cells), resulting in dual-responsive triggered targeting carrier, PCAC-FA. In vitro study demonstrated that PCAC-FA was preferentially taken up by activated macrophage cells rather than normal ones, suggesting the targeting of PCAC-FA to inflamed tissue. The loading capacity of the designed carrier was 21.23 ± 0.91 %. MTX from the PCAC-FA carrier was significantly accelerated release in the presentation of glutathione or in cold shock condition, proposing the efficacy-controlled release. MTX@PCAC-FA showed excellent hemocompatibility, confirming a suitable application with parenteral administration. Notably, the acute and subacute toxicity in the mice model showed that the toxicity of MTX had significantly reduced after encapsulating in the PCAC-FA carrier. These nanoplatforms not only provide an alternative safe strategy for the clinical treatment of rheumatoid arthritis with MTX but also deliver MTX selectively and provide on-demand drug release via external and internal signals, thus emerging as a promising therapeutic option for precise RA therapy.

Injectable thermogel incorporating reactive oxygen species scavenger and nitric oxide donor to accelerate the healing process of diabetic wounds.

The healing of diabetic wounds is challenging due to redox imbalances. Herein, the thermogelling system AR-ACP hydrogel, with encapsulated biosafe nitric oxide (NO) donor L-arginine and resveratrol as an ROS scavenger, is established for sustainable wound therapy in the diabetic state. The innovated AR-ACP hydrogel dressings shows the sol-gel transition at 34 °C, allowing the hydrogel to fully cover wounds. The combination of L-arginine and resveratrol showed a prominent effect on anti-oxidative activity. The elimination of superoxide anions from the activated immune cells/oxidative cells by resveratrol maintained the NO-proangiogenic factors generated from L-arginine. Furthermore, the AR-ACP hydrogel endowed outstanding features such as haemocompatibility, non-skin irradiation as well as antibacterial activity. In the in vivo diabetic mice model, complete epidermal regeneration comparable to undamaged skin was observed with AR-ACP hydrogel. The synergy between L-arginine and resveratrol in the ACP hydrogel facilitated neovascularisation in the early stage, resulting in the higher balance in cellularity growth and collagen deposition in the dermal layer compared to control groups. Taken together, our findings demonstrate that the use of a customised ACP-based hydrogel, with the additional L-arginine and resveratrol, resulted in significant skin regeneration in the diabetic state.

Potential from synergistic effect of quercetin and paclitaxel co-encapsulated in the targeted folic-gelatin-pluronic P123 nanogels for chemotherapy.

Dual-drug delivery systems for anticancer therapy have recently attracted substantial attention due to their potency to overcome limitations of conventional anti-cancer drugs, tackle drug resistance problems, as well as improve the therapeutic efficacy. In this study, we introduced a novel nanogel based on folic acid-gelatin-pluronic P123 (FA-GP-P123) conjugate to simultaneously deliver quercetin (QU) and paclitaxel (PTX) to the targeted tumor. The results indicated that the drug loading capacity of FA-GP-P123 nanogels was significantly higher than that of P123 micelles. The kinetic release profiles of QU and PTX from the nanocarriers were governed by Fickian diffusion and swelling behavior, respectively. Notably, FA-GP-P123/QU/PTX dual-drug delivery system induced higher toxicity to MCF-7 and Hela cancer cells than either QU or PTX individual delivery system, and the non-targeted dug delivery system (GP-P123/QU/PTX), indicating the synergistic combination of dual drugs and FA positive targeting effect. Furthermore, FA-GP-P123 could effectively deliver QU and PTX to tumors in vivo after administration into MCF-7 tumor-bearing mice, which resulted in 94.20 ± 5.90 % of tumor volume reduced at day 14. Moreover, the side effects of the dual-drug delivery system were significantly reduced. Overall, we suggest FA-GP-P123 as potential nanocarrier for dual-drug delivery for targeted chemotherapy.

Nano-Lipids Based on Ginger Oil and Lecithin as a Potential Drug Delivery System.

Lipid nanoparticles based on lecithin are an interesting part of drug delivery systems. However, the stability of lecithin nano-lipids is problematic due to the degradation of lecithin, causing a decrease in pH. In this study, the modification of the conventional nano-lipid-based soybean lecithin was demonstrated. Ginger-oil-derived Zingiber officinale was used along with lecithin, cholesterol and span 80 to fabricate nano-lipids (GL nano-lipids) using a thin-film method. TEM and a confocal microscope were used to elucidate GL nano-lipids' liposome-like morphology. The average size of the resultant nano-lipid was 249.1 nm with monodistribution (PDI = 0.021). The ζ potential of GL nano-lipids was negative, similarly to as-prepared nano-lipid-based lecithin. GL nano-lipid were highly stable over 60 days of storage at room temperature in terms of size and ζ potential. A shift in pH value from alkaline to acid was detected in lecithin nano-lipids, while with the incorporation of ginger oil, the pH value of nano-lipid dispersion was around 7.0. Furthermore, due to the richness of shogaol-6 and other active compounds in ginger oil, the GL nano-lipid was endowed with intrinsic antibacterial activity. In addition, the sulforhodamine B (SRB) assay and live/dead imaging revealed the excellent biocompatibility of GL nano-lipids. Notably, GL nano-lipids were capable of carrying hydrophobic compounds such as curcumin and performed a pH-dependent release profile. A subsequent characterization showed their suitable potential for drug delivery systems.

Multifunctional injectable pluronic-cystamine-alginate-based hydrogel as a novel cellular delivery system towards tissue regeneration.

This paper presents a new thermal sensitive hydrogel system based on cystamine-functionalised sodium alginate-g-pluronic F127 (ACP). The introduction of cystamine to the alginate backbone not only creates a covalent bond with pluronic F127 but also provides intrinsic anti-bacterial activity for the resultant hydrogel. The amount of water uptake inside the hydrogel remained ~200% for 6 days and the degradation was completed in 12 days in physiological media. The ACP copolymer solution could form a hydrogel at body temperature (~37 °C) and could return to the solution phase if the temperature decreased below 25o °C. Fibroblast encapsulated in situ in the ACP hydrogel maintained their viability (≥90% based on the live/dead assay) for 7 days, demonstrating the good biocompatibility of the ACP hydrogel for long-term cell cultivation. In addition, three-dimensional (3D) culture showed that fibroblast attached to the hydrogels and successfully mimicked the porous structure of the ACP hydrogel after 5 days of culture. Fibroblast cells could migrate from the cell-ACP clusters and form a confluent cell layer on the surface of the culture dish. Altogether, the obtained results indicate that the thermal-responsive ACP hydrogel synthesised in this study may serve as a cellular delivery platform for diverse tissue engineering applications.

Cytocompatible dendrimer G3.0-hematin nanoparticle with high stability and solubility for mimicking horseradish peroxidase activity in in-situ forming hydrogel.

Hematin has been used as an alternative enzyme catalyst to horseradish peroxidase (HRP) due to its iron-containing activity center. Although hematin and it derivatives have been widely used for polymerization of phenol/analine compounds, it has some drawbacks such as the limited solubility and reaction only at high pH condition. Herein, we report a nanosized biomimetic catalyst, hematin-decorated polyamidoamine dendrimer (G3.0-He) that can effectively catalyze the in situ hydrogelation of phenol-conjugated polymers under neutral pH condition. We demonstrate that G3.0-He particles are smaller than 100 nm and have excellent enzyme-mimetic functions. Interestingly, the nanosized catalyst is not inactivated at high H2O2 concentration. Compared to pure hematin, G3.0-He has significantly higher dispersion in acidic and neutral media, and preserves the percentage of survival of fibroblasts over 90%. Notably, G3.0-He possesses an exquisite HRP-mimicking activity in gelation of gelatin derivative with phenolic hydroxyl (tyamine) moieties under mild physiological conditions. The in vitro study demonstrated that Gel-Tyr hydrogel by G3.0-He catalyzed reaction had excellent cytocompatibility and an excellent scaffold for adhesion to fibroblast cells. Therefore, the designed minimalistic G3.0-He catalyst could serve as an effective catalytic alternative for HRP enzyme in the preparation of biomedical hydrogels.

A dual synergistic of curcumin and gelatin on thermal-responsive hydrogel based on Chitosan-P123 in wound healing application.

This study aimed to fabricate the potential therapeutic scaffold to efficiently and safely fastening skin wound healing. A biocompatible grafting polymer-based thermal sensitive hybrid hydrogel (Chitosan-P123, CP) containing gelatin and curcumin was designed to be suitable stiffness for tissue regeneration. A detailed in the rheological study found that the encapsulated agents induced the change in the stiffness of the hydrogel from the hard to the soft. Especial, the thermally induced phase transition of CP hydrogel was governed by the participant of gelatin rather than curcumin. For example, at 25 wt% gelatin, CP hydrogel exhibited a unique gel-sol-gel transition following the function of temperature. Moreover, in vitro investigation revealed that the hybrid hydrogel provides the capacity of especially induced curcumin release with a sustainable rate as well as the excellent biocompatibility scaffold. Altogether with in vivo study, the hybrid hydrogel highlighted the advance of the dual synergistic of curcumin and gelatin in development of smart scaffold system, which promoted the efficacy in the regeneration of the structure and the barrier's function of damaged skin such as wound or skin cancer.

Dual Interactions of Amphiphilic Gelatin Copolymer and Nanocurcumin Improving the Delivery Efficiency of the Nanogels.

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.

Injectable Nanocurcumin-Formulated Chitosan-g-Pluronic Hydrogel Exhibiting a Great Potential for Burn Treatment.

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.