Enzyme-Triggered Polyelectrolyte Complex for Responsive Delivery of α-Helical Polypeptides to Optimize Antibacterial Therapy.

Responsive nanomaterials hold significant promise in the treatment of bacterial infections by recognizing internal or external stimuli to achieve stimuli-responsive behavior. In this study, we present an enzyme-responsive polyelectrolyte complex micelles (PTPMN) with α-helical cationic polypeptide as a coacervate-core for the treatment of Escherichia coli (E. coli) infection. The complex was constructed through electrostatic interaction between cationic poly(glutamic acid) derivatives and phosphorylation-modified poly(ethylene glycol)-b-poly(tyrosine) (PEG-b-PPTyr) by directly dissolving them in aqueous solution. The cationic polypeptide adopted α-helical structure and demonstrated excellent broad-spectrum antibacterial activity against both Gram-negative and Gram-positive bacteria, with a minimum inhibitory concentration (MIC) as low as 12.5 µg mL-1 against E. coli. By complexing with anionic PEG-b-PPTyr, the obtained complex formed ß-sheet structures and exhibited good biocompatibility and low hemolysis. When incubated in a bacterial environment, the complex cleaved its phosphate groups triggered by phosphatases secreted by bacteria, exposing the highly α-helical conformation and restoring its effective bactericidal ability. In vivo experiments confirmed accelerated healing in E. coli-infected wounds.

Layer-by-layer assembly of quercetin-loaded zein/γPGA/low-molecular-weight chitosan/fucoidan nanosystem for targeting inflamed blood vessels.

Chitosan acts as a versatile carrier in polymeric nanoparticle (NP) for diverse drug administration routes. Delivery of antioxidants, such as quercetin (Qu) showcases potent antioxidant and anti-inflammatory properties for reduction of various cardiovascular diseases, but low water solubility limits uptake. To address this, we developed a novel layer-by-layer zein/gamma-polyglutamic acid (γPGA)/low-molecular-weight chitosan (LC)/fucoidan NP for encapsulating Qu and targeting inflamed vessel endothelial cells. We used zein (Z) and γPGA (r) to encapsulate Qu (Qu-Zr NP) exhibited notably higher encapsulation efficiency compared to zein alone. Qu-Zr NP coated with LC (Qu-ZrLC2 NP) shows a lower particle size (193.2 ± 2.9 nm), and a higher zeta potential value (35.2 ± 0.4 mV) by zeta potential and transmission electron microscopy analysis. After coating Qu-ZrLC2 NP with fucoidan, Qu-ZrLC2Fa NP presented particle size (225.16 ± 0.92 nm), zeta potential (-25.66 ± 0.51 mV) and maintained antioxidant activity. Further analysis revealed that Qu-ZrLC2Fa NP were targeted and taken up by HUVEC cells and EA.hy926 endothelial cells. Notably, we observed Qu-ZrLC2Fa NP targeting zebrafish vessels and isoproterenol-induced inflamed vessels of rat. Our layer-by-layer formulated zein/γPGA/LC/fucoidan NP show promise as a targeted delivery system for water-insoluble drugs. Qu-ZrLC2Fa NP exhibit potential as an anti-inflammatory therapeutic for blood vessels.

Examining the wound healing potential of curcumin-infused electrospun nanofibers from polyglutamic acid and gum arabic.

Advancements in medicine have led to continuous enhancements and innovations in wound dressing materials, making them pivotal in medical care. We used natural biological macromolecules, γ-polyglutamic acid and gum arabic as primary raw materials to create nanofibers laden with curcumin by blending electrostatic spinning technology in the current investigation. These nanofibers were meticulously characterized using fluorescence microscopy, scanning electron microscopy, Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD). Our comprehensive analyses confirmed the successful encapsulation of curcumin within the nanofiber carrier and it has uniform diameter, good water absorption and mechanical properties. Subsequently, we evaluated the antimicrobial effects of these curcumin-loaded nanofibers against Staphylococcus aureus through an oscillating flask method. We created a mouse model with acute full-thickness skin defects to further investigate the wound healing potential. We conducted various biochemical assays to elucidate the mechanism of action. The results revealed that curcumin nanofibers profoundly impacted wound healing. They bolstered the expression of TGF-ß1 and VEGF and reduced the expression of inflammatory factors, leading to an accelerated re-epithelialization process, enhanced wound contraction, and increased regeneration of new blood vessels and hair follicles. Furthermore, these nanofibers positively influenced the proportion of three different collagen types. This comprehensive study underscores the remarkable potential of curcumin-loaded nanofibers to facilitate wound healing and lays a robust experimental foundation for developing innovative, natural product-based wound dressings.

Fabrication of yeast ß-glucan/sodium alginate/γ-polyglutamic acid composite particles for hemostasis and wound healing.

Particles with a porous structure can lead to quick hemostasis and provide a good matrix for cell proliferation during wound healing. Recently, many particle-based wound healing materials have been clinically applied. However, these products show good hemostatic ability but with poor wound healing ability. To solve this problem, this study fabricated APGG composite particles using yeast ß-glucan (obtained from Saccharomyces cerevisiae), sodium alginate, and γ-polyglutamic acid as the starting materials. The structure of yeast ß-glucan was modified with many carboxymethyl groups to obtain carboxymethylated ß-glucan, which could coordinate with Ca2+ ions to form a crosslinked structure. A morphology study indicated that the APGG particles showed an irregular spheroidal structure with a low density (<0.1 g cm-3) and high porosity (>40%). An in vitro study revealed that the particles exhibited a low BCI value, low hemolysis ratio, and good cytocompatibility against L929 cells. The APGG particles could quickly stop bleeding in a mouse liver injury model and exhibited better hemostatic ability than the commercially available product Celox. Furthermore, the APGG particles could accelerate the healing of non-infected wounds, and the expression levels of CD31, α-SMA, and VEGF related to angiogenesis were significantly enhanced.

Cucumber (Cucumis sativus L.) with heterologous poly-γ-glutamic acid has skin moisturizing, whitening and anti-wrinkle effects.

Three genes involved in poly-γ-glutamic acid(γ-PGA)synthesis cloned from Bacillus licheniformis were transformed into cucumber for the first time. Compared with control, its water content increased by 6-14 % and water loss rate decreased by 11-12 %. In zebrafish and human skin experiments, the moisturizing effect of transgenic cucumber was significantly higher than that of CK, γ-PGA and hyaluronic acid group. Transgenic cucumber reduced facial wrinkles and roughness by 19.58 % and 24.97 %, reduced skin melanin content by 5.27 %, increased skin topological angle and L-value by 5.89 % and 2.49 %, and increased the R2 and Q1 values of facial elasticity by 7.67 % and 5.64 %, respectively. The expressions of aqp3, Tyr, silv and OCA2 were down-regulated, eln1, eln2, col1a1a and col1a1b were up-regulated in zebrafish after treated with transgenic cucumber. This study provides an important reference for the endogenous synthesis of important skin care functional molecules in plants.

Antimicrobial activity of gamma-poly (glutamic acid), a preservative coating for cherries.

We investigated the minimum inhibitory concentration (MIC), antibacterial activity, and preservation ability of four molar masses of γ-polyglutamic acid (PGA) against Escherichia coli, Bacillus subtilis, and yeast. The antibacterial mechanism was determined based on the cell structure, membrane permeability, and microscopic morphology of the microorganisms. We then measured the weight loss, decay rate, total acid, catalase activity, peroxidase activity, and malondialdehyde content toward the possible use of PGA as a preservative coating for cherries. When the molar mass was greater than 700 kDa, the MIC for Escherichia coli and Bacillus subtilis was less than 2.5 mg/mL. The mechanism of action of the four molar masses of PGA was different with respect to the three microbial species, but a higher molar mass of PGA corresponded to stronger inhibition against the microbes. PGA of 2000 kDa molar mass damaged the microbial cellular structure, resulting in excretion of alkaline phosphatase, but PGA of 1.5 kDa molar mass affected the membrane permeability and the amount of soluble sugar. Scanning electron microscopy indicated the inhibitory effect of PGA. The antibacterial mechanism of PGA was related to the molar mass of PGA and the microbial membrane structure. Compared with the control, a PGA coating effectively inhibit the spoilage rate, delay the ripening, and prolong the shelf life of cherries.

pH Responsive Poly(Amino Acid) Nanoparticles as Potent Carrier Adjuvants for Enhancing Cellular Immunity.

Adjuvants are widely used in vaccine to improve the protection or treatment efficacy. However, so far they inevitably produce side effects and are hard to induce cellular immunity in practical application. Herein, two kinds of amphiphilic poly(glutamic acid) nanoparticles (α-PGA-F and γ-PGA-F NPs) as nanocarrier adjuvants are fabricated to induce an effective cellular immune response. Amphiphilic PGA are synthesized by grafting phenylalanine ethyl ester to form biodegradable self-assembly nanoadjuvants in a water solution. The model antigen, chicken ovalbumin (OVA), can be loaded into PGA-F NPs (OVA@PGA-F NPs) with the high loading ratio >12%. Moreover, compared with γ-PGA-F NPs, the acidic environment can induce the α-helical secondary structure of α-PGA NPs, promoting membrane fusion and more fast antigen lysosomal escape. Hence, the antigen presenting cells treated with OVA@α-PGA-F NPs show higher secretion of inflammatory cytokines, and higher expression of major biological histocompatibility complex class I and CD80 than those of OVA@γ-PGA-F NPs. Overall, this work indicates that pH responsive α-PGA-F NPs as a carrier adjuvant can effectively improve the ability of cellular immune responses, leading to it being a potent candidate for vaccine applications.

A KPV-binding double-network hydrogel restores gut mucosal barrier in an inflamed colon.

Ulcerative colitis (UC) usually occurs in the superficial mucosa of the colorectum. Here, a double-network hydrogel (PMSP) was constructed from maleimided γ-polyglutamic acid and thiolated γ-polyglutamic acid through crosslinking of thiol-maleimide and self-oxidized thiols. PMSP with a negative charge specifically adhered to the inflamed mucosa with positively charged proteins rather than to the healthy mucosa. PMSP exhibited good mechanical strength with storage modulus (G') of 17.6 Pa and a linear viscoelastic region (LVR) of 107.2% strain. Moreover, PMSP showed a stronger bio-adhesive force toward the inflamed tissue-mimicking substrate than toward its healthy counterpart. In vivo imaging confirmed that PMSP specifically adhered to the inflamed colonic mucosa of rats with TNBS-induced UC. KPV (Lys-Pro-Val) as a model drug was easily captured by PMSP through electrostatic interactions, thus retaining its bioactivity for a longer time under high temperature conditions. Moreover, the alleviating effect of KPV on rats with TNBS-induced colitis was significantly improved by PMSP after intracolonic administration. The epithelial barrier of the colon also effectively recovered following PMSP-KPV treatment. PMSP-KPV also modulated the gut flora, markedly augmenting the abundance of beneficial microorganisms in gut homeostasis. The mechanism by which PMSP-KPV induces a therapeutic effect may be associated with the inhibition of oxidative stress. Conclusively, the PMSP hydrogel seems to be a promising rectal delivery system for the therapy of UC. STATEMENT OF SIGNIFICANCE: Ulcerative colitis (UC) is a chronic and relapsing disease of the gastrointestinal tract. A key therapeutic approach to treat UC is to repair the mucosal barriers. Here, a double-network hydrogel (PMSP) was constructed from maleimided and thiolated γ-polyglutamic acid through crosslinking of thiol-maleimide and self-oxidized thiols. The negatively charged PMSP specifically adhered to the inflamed colon rather than its healthy counterpart and was retained for a longer time. KPV as a model drug was easily captured by PMSP, which provided better stability to KPV when exposed to high temperature of 50 °C. The epithelial mucosal barrier of the colon was effectively recovered by the rectal administration of PMSP-KPV to rats with TNBS-induced UC. Moreover, PMSP-KPV modulated the gut flora of colitic rats, markedly augmenting the abundance of beneficial microorganisms. Conclusively, PMSP seems to be a promising rectal delivery system for UC therapy.

Poly-γ-glutamic acid enhanced the drought resistance of maize by improving photosynthesis and affecting the rhizosphere microbial community.

BACKGROUND: Compared with other abiotic stresses, drought stress causes serious crop yield reductions. Poly-γ-glutamic acid (γ-PGA), as an environmentally friendly biomacromolecule, plays an important role in plant growth and regulation. RESULTS: In this project, the effect of exogenous application of γ-PGA on drought tolerance of maize (Zea mays. L) and its mechanism were studied. Drought dramatically inhibited the growth and development of maize, but the exogenous application of γ-PGA significantly increased the dry weight of maize, the contents of ABA, soluble sugar, proline, and chlorophyll, and the photosynthetic rate under severe drought stress. RNA-seq data showed that γ-PGA may enhance drought resistance in maize by affecting the expression of ABA biosynthesis, signal transduction, and photosynthesis-related genes and other stress-responsive genes, which was also confirmed by RT-PCR and promoter motif analysis. In addition, diversity and structure analysis of the rhizosphere soil bacterial community demonstrated that γ-PGA enriched plant growth promoting bacteria such as Actinobacteria, Chloroflexi, Firmicutes, Alphaproteobacteria and Deltaproteobacteria. Moreover, γ-PGA significantly improved root development, urease activity and the ABA contents of maize rhizospheric soil under drought stress. This study emphasized the possibility of using γ-PGA to improve crop drought resistance and the soil environment under drought conditions and revealed its preliminary mechanism. CONCLUSIONS: Exogenous application of poly-γ-glutamic acid could significantly enhance the drought resistance of maize by improving photosynthesis, and root development and affecting the rhizosphere microbial community.

Depletion of Mannose Receptor-Positive Tumor-associated Macrophages via a Peptide-targeted Star-shaped Polyglutamate Inhibits Breast Cancer Progression in Mice.

Although many studies have explored the depletion of tumor-associated macrophages (TAM) as a therapeutic strategy for solid tumors, currently available compounds suffer from poor efficacy and dose-limiting side effects. Here, we developed a novel TAM-depleting agent ("OximUNO") that specifically targets CD206+ TAMs and demonstrated efficacy in a triple-negative breast cancer (TNBC) mouse model. OximUNO comprises a star-shaped polyglutamate (St-PGA) decorated with the CD206-targeting peptide mUNO that carries the chemotherapeutic drug doxorubicin (DOX). In the TNBC model, a fluorescently labeled mUNO-decorated St-PGA homed to CD206+ TAMs within primary lesions and metastases. OximUNO exhibited no acute liver or kidney toxicity in vivo. Treatment with OximUNO reduced the progression of primary tumor lesions and pulmonary metastases, significantly diminished the number of CD206+ TAMs and increased the CD8/FOXP3 expression ratio (indicating immunomodulation). Our findings suggest the potential benefit of OximUNO as a TAM-depleting agent for TNBC treatment. Importantly, our studies also represent a novel design of a peptide-targeted St-PGA as a targeted therapeutic nanoconjugate. Significance: A peptide-targeted nanoformulation of DOX exclusively eliminates mannose receptor+ TAMs in breast cancer models, generating response without off-target effects (a drawback of many TAM-depleting agents under clinical study).

Design and optimization of 3D-bioprinted scaffold framework based on a new natural polymeric bioink.

OBJECTIVES: This aimed at the design and production of engineered 3D scaffold prototypes using a natural polymeric bioink made of chitosan and poly-γ-glutamic acid with a specific focus on 3D-bioprinting process and on 3D framework geometry. METHODS: Prototypes were produced using a 3D bioprinter exploiting layer-by-layer deposition technology. The 3D scaffold prototypes were fully characterized concerning pore size and size distribution, stability in different experimental conditions, swelling capability, and human dermal fibroblasts viability. KEY FINDINGS: Hexagonal framework combined with biopaper allowed stabilizing the 3-layers structure during process manufacturing and during incubation in cell culture conditions. The stability of 3-layers structure was well preserved for 48 h. Crosslinking percentages of 2-layers and 3-layers prototype were 88.2 and 68.39, respectively. The swelling study showed a controlled swelling capability for 2-layers and 3-layers prototype, ∼5%. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay results showed good biocompatibility of 3-layers prototype and their suitability for preserving 48 h cell viability in 3D cultures. Moreover, a significant increment of absorbance value was measured after 48 h, demonstrating cell growth. CONCLUSIONS: Bioink obtained combining chitosan and poly-γ-glutamic acid represents a good option for 3D bioprinting. A stable 3D structure was realized by layer-by-layer deposition technology; compared with other papers, the present study succeeded in using medical healthcare-grade polymers, no-toxic crosslinker, and solvents according to ICH Topic Q3C (R4).

Dynamic regulable sodium alginate/poly(γ-glutamic acid) hybrid hydrogels promoted chondrogenic differentiation of stem cells.

Traditional hydrogels often fail to match the dynamic interactions between mechanical and cellular behaviors exhibited by the natural cartilage extracellular matrix. In this research, we constructed a novel hybrid hydrogels system based on sodium alginate and polyglutamic acid. By controlling the grafting rate and concentration of polymer, the gelation time and mechanical strength can be adjusted between range of 8-28 s and 60-144 kPa. By adding microcrystalline cellulose into the system, so that the degradation time was prolonged (125%) and the swelling rate was reduced (470%). Additionally, the presence of hydrazone bonds gives the system some dynamic response characteristics, and the hydrogel exhibits excellent self healing and injectable ability. It was found that the system had positive cytocompatibility (80%), which accelerated regulatory gene expression in cartilage tissue. In conclusion, this injectable hydrogel with self-healing and customizable mechanical strength will have broad application prospects in future biomedical engineering.

Mechanoadaptive injectable hydrogel based on poly(γ-glutamic acid) and hyaluronic acid regulates fibroblast migration for wound healing.

Injectable hydrogels have shown therapeutic effects on wound repair, but most of them exhibit poor mechanical strength. The impacts of stiff injectable hydrogels on cell behavior and wound healing remain unclear. Herein, an injectable hydrogel was developed based on thiolated poly(γ-glutamic acid) (γ-PGA-SH) and glycidyl methacrylate-conjuated oxidized hyaluronic acid (OHA-GMA). Thiol-methacrylate Michael chemistry-mediated post-stabilization and increase of polymer concentration were found to improve the mechanical strength of γ-PGA-SH/OHA-GMA hydrogel. Moreover, in vitro studies confirmed its biodegradability, biocompatibility, and self-healing property. Using the mechanically-tunable hydrogel, it further showed that fibroblasts migrated faster on the surface of stiffer hydrogel, but infiltrated slowly inside it compared with softer hydrogel. In animal experiments, the injectable hydrogel could promote wound healing by increasing collagen deposition and vascularization. In summary, γ-PGA-SH/OHA-GMA hydrogel is able to regulate migration and infiltration of fibroblasts by altering stiffness and offers effective in situ forming scaffolds towards skin tissue regeneration.

Induction of mucosal immunity by pulmonary administration of a cell-targeting nanoparticle.

We previously found that a nanoparticle constructed with an antigen, benzalkonium chloride (BK) and γ-polyglutamic acid (γ-PGA) showed high Th1 and Th2-type immune induction after subcutaneous administration. For prophylaxis of respiratory infections, however, mucosal immunity should be induced. In this study, we investigated the effect of pulmonary administration of a nanoparticle comprising ovalbumin (OVA) as a model antigen, BK, and γ-PGA on induction of mucosal immunity in the lungs and serum. The complex was strongly taken up by RAW264.7 and DC2.4cells. After pulmonary administration, lung retention was longer for the OVA/BK/γ-PGA complex than for OVA alone. OVA-specific serum immunoglobulin (Ig)G was highly induced by the complex. High IgG and IgA levels were also induced in the bronchoalveolar lavage fluid, and in vivo toxicities were not observed. In conclusion, we effectively and safely induced mucosal immunity by pulmonary administration of an OVA/BK/γ-PGA complex.

Assessing monocyte phenotype in poly(γ-glutamic acid) hydrogels formed by orthogonal thiol-norbornene chemistry.

Hydrogels with tunable properties are highly desirable in tissue engineering applications as they can serve as artificial extracellular matrix to control cellular fate processes, including adhesion, migration, differentiation, and other phenotypic changes via matrix induced mechanotransduction. Poly(γ-glutamic acid) (PGA) is an natural anionic polypeptide that has excellent biocompatibility, biodegradability, and water solubility. Moreover, the abundant carboxylic acids on PGA can be readily modified to introduce additional functionality or facilitate chemical crosslinking. PGA and its derivatives have been widely used in tissue engineering applications. However, no prior work has explored orthogonal crosslinking of PGA hydrogels by thiol-norbornene (NB) chemistry. In this study, we report the synthesis and orthogonal crosslinking of PGA-norbornene (PGANB) hydrogels. PGANB was synthesized by standard carbodiimide chemistry and crosslinked into hydrogels via either photopolymerization or enzymatic reaction. Moduli of PGA hydrogels were readily tuned by controlling thiol-NB crosslinking conditions or stoichiometric ratio of functional groups. Orthogonally crosslinked PGA hydrogels were used to evaluate the influence of mechanical cues of hydrogel substrate on the phenotype of naïve human monocytes and M0 macrophages in 3D culture.

Bioinspired mineral-polymeric hybrid hyaluronic acid/poly (γ-glutamic acid) hydrogels as tunable scaffolds for stem cells differentiation.

Aiming at the difficulty of integrated repair of osteochondral tissue, we designed a hybrid hydrogel scaffold that mimicked the microenvironment of osteochondral niches. Besides, the nano-hydroxyapatite (nHAP) was specially introduced into the hydrogel for its natural ability to promote bone regeneration. The hydrogel also exhibited good toughness (7500 KJ/m3), strength (1000 kPa), viscoelasticity, and in vitro cell experiments showed that hydrogels had quite good cytocompatibility (near 100 % viability). The results of the three-dimensional (3D) cell culture also proved that the survival rate of the cells in the hybrid hydrogels doped with nHAP and dispersion were the highest. In vitro RT-qPCR experiments proved that after being cultured in hydrogel scaffolds doped with nHAP, bone mesenchymal stem cells (BMSCs) could express genes related to osteoblasts and chondrocytes. As a result, this hydrogel provides a general for developing alternative materials applicable for stem cells differentiation and even osteochondral tissue engineering.

Poly (γ-glutamic acid)/chitooligo-saccharide/papain hydrogel prevents hypertrophic scar during skin wound healing.

Hypertrophic scar, a common skin disorder typically caused by deep burns or scald were usually treated via surgical resection, laser irradiation, and drugs. However, all the approaches were always companied with complications and devastatingly subjected to relapse, which indicated the urgently need of an effective treatment method. In this project, a new hydrogel composed of Poly (γ-glutamic acid) (γ-PGA), Chitooligo-saccharide, and Papain was developed via crosslinker (EDC&NHS), and characterized with good porously three-dimensional network structure, good water absorption, and mechanical properties. Besides, G/C/P hydrogel facilitated cell adhesion and inhibited excessive proliferation of fibroblasts, which indicated the potential of in vivo application. After applied onto skin wound healing in vivo on a rabbit ear skin wound model, G/C/P hydrogel inhibited excessive collagen deposition and the generation of hyperplastic scars effectively during wound healing. The hydrogel described here provide a new platform for regeneration field and hold great promise for solving serious skin disorder.

Bacillus subtilis extracellular polymeric substances conditioning layers inhibit Escherichia coli adhesion to silicon surfaces: A potential candidate for interfacial antifouling additives.

Biofouling on material surfaces is a ubiquitous problem in a variety of fields. In aqueous environments, the process of biofouling initiates with the formation of a layer of macromolecules called the conditioning layer on the solid-liquid interface, followed by the adhesion and colonization of planktonic bacteria and the subsequent biofilm development and maturation. In this study, the extracellular polymeric substances (EPS) secreted by Bacillus subtilis were collected and used to prepare conditioning layers on inert surfaces. The morphologies and antifouling performances of the EPS conditioning layers were investigated. It was found that the initial adhesion of Escherichia coli was inhibited on the surfaces precoated with EPS conditioning layers. To further explore the underlying antifouling mechanisms of the EPS conditioning layers, the respective roles of two constituents of B. subtilis EPS (γ-polyglutamic acid and surfactin) were investigated. This study has provided the possibility of developing a novel interfacial antifouling additive with the advantages of easy preparation, nontoxicity, and environmental friendliness.

The enzymatic poly(gallic acid) reduces pro-inflammatory cytokines in vitro, a potential application in inflammatory diseases.

Cytokines like IL-6, TNF-α, and IL-1ß are important mediators of inflammation in many inflammatory diseases, as well as in cellular processes like cell proliferation and cell adhesion. Finding new molecules that decrease cell proliferation, adhesion (inflammatory infiltrate), and pro-inflammatory cytokine release could help in the treatment of many inflammatory diseases. The naturally derived poly(gallic acid) (PGAL), produced enzymatically from gallic acid in aqueous medium, is a non-toxic, thermostable multiradical polyanion that is antioxidant and has potential biomedical uses. Experimental evidence has demonstrated that PGAL reduces pro-inflammatory cytokines, which are the target of some inflammatory diseases. PGAL decreased IL-6, TNF-α, and IL-1ß production in human monocytes exposed to PMA without affecting cell viability. Additionally, PGAL reduced cell proliferation by affecting the transition from the S phase to the G2 phase of the cell cycle. Cell adhesion experiments showed that PMA-induced cell adhesion was diminished with the presence of PGAL, particularly at a concentration of 200 µg/mL. These properties of PGAL show a potential use for treating inflammatory diseases, such as psoriasis or arthritis.

Poly(L-Glutamic Acid)-Drug Conjugates for Chemo- and Photodynamic Combination Therapy.

Despite the polymeric vascular disrupting agent (poly(L -glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4) nanoparticles can efficiently inhibit cancer growth, their further application is still a challenge owing to the tumor recurrence and metastasis after treatment. In this study, two poly(L -glutamic acid)-drug conjugates for chemo-and photodynamic combination therapy are fabricated. PLG-g-mPEG-CA4 nanoparticles are prepared by combretastatin A4 (CA4) and poly(L -glutamic acid)-graft-methoxy poly(ethylene glycol) (PLG-g-mPEG) using the Yamaguchi esterification reaction. PLG-g-mPEG-TPP (TPP: 5, 10, 15, 20-tetraphenylporphyrin) nanoparticles are constructed using PLG-g-mPEG and amine porphyrin through condensation reaction between carboxyl group of PLG-g-mPEG and amino group of porphyrin. The results showed that PLG-g-mPEG-CA4 nanoparticles have good antitumor ability. PLG-g-mPEG-TPP nanoparticles can produce singlet oxygen under the laser irradiation. Moreover, the combined therapy of PLG-g-mPEG-CA4 and PLG-g-mPEG-TPP nanoparticles has higher antitumor effect than the single chemotherapy or the single photodynamic therapy in vitro. The combination of CA4 nondrug and photodynamic therapy provides a new insight for enhancing the tumor therapeutic effect with vascular disrupting agents and other therapy.