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Recently, hydrogel adhesive patches have been explored for treating myocardial infarction. However, achieving secure adhesion onto the wet beating heart and local regulation of pathological microenvironment remains challenging. Herein, a dough-kneading-inspired design of hydrogel adhesive cardiac patch is reported, aiming to improve the strength of prevalent powder-formed patch and retain wet adhesion. In mimicking the polysaccharide and protein components of natural flour, methacrylated polyglutamic acid (PGAMA) is electrostatically interacted with hydroxypropyl chitosan (HPCS) to form PGAMA/HPCS coacervate hydrogel. The PGAMA/HPCS hydrogel is freeze-dried and ground into powders, which are further rehydrated with two aqueous solutions of functional drug, 3-acrylamido phenylboronic acid (APBA)/rutin (Rt) complexes for protecting the myocardium from advanced glycation end product (AGEs) injury by reactive oxygen species (ROS) -responsive Rt release, and hypoxanthine-loaded methacrylated hyaluronic acid (HAMA) nanogels for enhancing macrophage targeting ability to regulate glycometabolism for combating inflammation. The rehydrated powders bearing APBA/Rt complexes and HAMA-hypoxanthine nanogels are repeatedly kneaded into a dough-like gel, which is further subjected to thermal-initiated crosslinking to form a stabilized and sticky patch. This biofunctional patch is applied onto the rats' infarcted myocardium, and the outcomes at 28 days post-surgery indicate efficient restoration of cardiac functions and attenuation of cardiac fibrosis., (© 2024 Wiley‐VCH GmbH.)

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., (© 2023 Wiley-VCH GmbH.)

A nanoformulation composed of curdlan, a linear polysaccharide of 1,3-β-linked d-glucose units, hydrogen bonded to poly(γ -glutamic acid) (PGA), was developed to stimulate macrophage. Curdlan/PGA nanoparticles (C-NP) are formulated by physically blending curdlan (0.2 mg mL -1 in 0.4 m NaOH) with PGA (0.8 mg mL -1 ). Forster resonance energy transfer (FRET) analysis demonstrates a heterospecies interpolymer complex formed between curdlan and PGA. The 1 H-NMR spectra display significant peak broadening as well as downfield chemical shifts of the hydroxyl proton resonances of curdlan, indicating potential intermolecular hydrogen bonding interactions. In addition, the cross peaks in 1 H- 1 H 2D-NOESY suggest intermolecular associations between the OH-2/OH-4 hydroxyl groups of curdlan and the carboxylic-/amide-groups of PGA via hydrogen bonding. Intracellular uptake of C-NP occurs over time in human monocyte-derived macrophage (MDM). Furthermore, C-NP nanoparticles dose-dependently increase gene expression for TNF-α, IL-6, and IL-8 at 24 h in MDM. C-NP nanoparticles also stimulate the release of IL-lβ, MCP-1, TNF-α, IL-8, IL-12p70, IL-17, IL-18, and IL-23 from MDM. Overall, this is the first demonstration of a simplistic nanoformulation formed by hydrogen bonding between curdlan and PGA that modulates cytokine gene expression and release of cytokines from MDM., (© 2020 Wiley-VCH GmbH.)

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., (© 2020 Wiley-VCH GmbH.)

Biodegradable multi-l-arginyl-poly-l-aspartate (MAPA), more commonly cyanophycin, prepared with recombinant Escherichia coli contains a polyaspartate backbone with lysine and arginine as side chains. Two assemblies of polyelectrolyte multilayers (PEMs) are fabricated at three different concentration ratios of insoluble MAPA (iMAPA) with hyaluronic acid (iMAPA/HA) and with γ-polyglutamic acid (iMAPA/γ-PGA), respectively, utilizing a layer-by-layer approach. Both films with iMAPA and its counterpart, HA or γ-PGA, as the terminal layer are prepared to assess the effect on film roughness, cell growth, and cell migration. iMAPA incorporation is higher for a higher concentration of the anionic polymer due to better charge interaction. The iMAPA/HA films when compared to iMAPA/γ-PGA multilayers show least roughness. The growth rates of L929 fibroblast cells on the PEMs are similar to those on glass substrate, with no supplementary effect of the terminal layer. However, the migration rates of L929 cells increase for all PEMs. γ-PGA incorporated films impart 50% enhancement to the cell migration after 12 h of culture as compared to the untreated glass, and the smooth films containing HA display a maximum 82% improvement. The results present the use of iMAPA to construct a new layer-by-layer system of polyelectrolyte biopolymers with a potential application in wound dressing., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this study, an adjustable pH-responsive drug delivery system using mesoporous silica nanoparticles (MSNs) as the host materials and the modified polypeptides as the nanovalves is reported. Since the polypeptide can self-assemble via electrostatic interaction at pH 7.4 and be disassembled by pH changes, the modified poly(l-lysine) and poly(l-glutamate) are utilized for pore blocking and opening in the study. Poly(l-lysine)-MSN (PLL-MSN) and poly(l-glutamate)-MSN (PLG-MSN) are synthesized via the ring opening polymerization of N-carboxyanhydrides onto the surface of mesoporous silica nanoparticles. The successful modification of the polypeptide on MSN is proved by Zeta potential change, X-ray photoelectron spectroscopy (XPS), solid state NMR, and MALDI-TOF MS. In vitro simulated dye release studies show that PLL-MSN and PLG-MSN can successfully load the dye molecules. The release study shows that the controlled release can be constructed at different pH by adjusting the ratio of PLL-MSN to PLG-MSN. Cellular uptake study indicates that the drug is detected in both cytoplasm and nucleus, especially in the nucleus. In vitro cytotoxicity assay indicates that DOX loaded mixture nanoparticles (ratio of PLL-MSN to PLG-MSN is 1:1) can be triggered for drug release in HeLa cells, resulting in 88% of cell killing., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ebola DNA vaccine is incorporated into PLGA-PLL/γPGA nanoparticles and administered to skin using a microneedle (MN) patch. The nanoparticle delivery system increases vaccine thermostability and immunogenicity compared to free vaccine. Vaccination by MN patch produces stronger immune responses than intramuscular administration., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cisplatin (cis-diaminodichloroplatinum, CDDP) loaded methoxy poly (ethylene glycol)-block-poly (glutamic acid-co-phenyl alanine) [mPEG-b-P (Glu10 -co-Phe10 ) (PGlu10 ) and mPEG-b-P (Glu20 -co-Phe10 ) (PGlu20 )] nanoparticles with two different formulations (CDDP/PGlu10 and CDDP/PGlu20 ) are successfully developed in uniformly sizes. In 190 h, the CDDP/PGlu10 shows 30% release at physiological pH and 39% at lysosomal pH. Similarly, the CDDP/PGlu20 shows 60% release at physiological pH and 90% release at lysosomal pH. The sustained and controlled release of both formulations evidences the in vitro longevity of the nanoparticles. The cell proliferation inhibition of nanoparticles against human breast cancer cell line ZR-75-30 is dose and time dependent. Both CDDP/PGlu10 and CDDP/PGlu20 show excellent hemo compatibility as evaluated by hemolysis experiments. The in vivo fate of CDDP and CDDP loaded nanoparticles are evaluated by pharmacokinetics studies. Free CDDP underwgoes instant platinum concentration decrease after intravenous administration with 1.0 wt% left in 24 h while the CDDP loaded nanoparticles show prolonged blood circulation time with 5 wt% (CDDP/PGlu20 ) to 14 wt% (CDDP/PGlu10 ) left in 24 h. This prolonged blood circulation of CDDP loaded nanoparticles makes them as promising nanocarriers for tumor targeting delivery., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Well-defined amphiphilic polymers of the ABA and ABC type are synthesized, where A is poly(L-lysine hydrochloride) (PLL), B is poly(γ-benzyl-(d7) L-glutamate) (PBLG(-d7)), and C is poly(ethylene oxide) (PEO). The two polymers exhibit similar PBLG(-d7) composition, while in the ABC, the volume fraction of PEO block is higher than that of PLL. Both polymers form polymersomes in water. The polymersomes are loaded with doxorubicin or paclitaxel. It is found that in the ABC, due to asymmetry of the two hydrophilic blocks, PEO is always on the outer periphery and the dimensions of the vesicles are smaller. The release of the vesicles is temperature- and pH-dependent. In vivo toxicity tests of the empty vesicles show that they are not toxic. In vitro activity of the loaded vesicles against human pancreatic cancer cell lines reveals comparable activity to Myocet for the ABA loaded with doxorubicin, while lower activity is observed for the ABC., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In spite of their attractive features, widespread biomedical applications of CS nanoparticles are yet to be realized due to their poor stability in physiological conditions, such as in buffer system at pH 7.4. Buffer-stable chitosan-based hybrid NPs (HNPs) are reported and characterized. Buffer stability is achieved by introducing polyglutamic acid to chitosan. The effect of PGA to CS molar ratio and crosslinking on HNP integrity, buffer stability, and biodegradability are studied. Preliminary in vitro studies are carried out to evaluate targeted uptake efficiency of folate conjugated HNPs. Successful demonstration of buffer stability and cancer cell targeting by HNPs achieves important milestones for chitosan-based nanoparticle technology., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Porous scaffolds based on water-soluble PLGA and CS were prepared. The pores were verified to be alveolate, uniform and continuous. The effects of freezing temperature, freeze-drying time, solid content and molecular weight of reactants on the pore structure of the scaffolds were studied. The scaffold morphology could be adjusted by changing the freezing temperature and solid content of reacting polymer. Their degradation rate can be adjusted by changing the proportion of PLGA and CS. The porosity of scaffolds was higher than 90% and the high swelling ratio showed that these scaffolds had excellent hydrophilic performance. The in vitro culture of chondrocytes indicates that the obtained PLGA/CS porous scaffolds are very promising biomaterials for tissue engineering applications., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Novel water-insoluble, and reduction-responsive nonwoven scaffolds were fabricated from gamma-PGA and tested in cell culture. An electrospinning method was developed to produce scaffolds of fibers with diameters of 0.05-0.5 microm. Crosslinking of the fibers with cystamine in the presence of EDC resulted in water-insoluble gamma-PGA nonwovens with disulfide crosslinkages. These crosslinked fibers were easily decomposed under physiological conditions using L-cysteine, a biocompatible reductant. In vitro experiments with mouse L929 fibroblasts showed good adhesion onto gamma-PGA-SS fiber matrices and excellent cell proliferation. These gamma-PGA-SS nonwovens can be used as novel biocompatible and biodegradable scaffolds with reduction-responsiveness for biomedical or tissue engineering applications.

The complexation between cupric ions (Cu(II)) and poly(gamma-glutamic acid) (gamma-PGA) in aqueous solutions (pH 3-11) has been studied by UV-visible absorption and electron spin resonance (ESR) techniques. Formation of the Cu(II)-gamma-PGA complex is confirmed by the observation of the blue shift of the absorption band in the visible region, anisotropic line shapes in the ESR spectrum at room temperature, and a computer simulation of the visible absorption spectrum of the complex. The structure of the Cu(II)-gamma-PGA complex, depending on the pH, has been determined. The in vitro insulin-mimetic activity of the Cu(II)-gamma-PGA complex is examined by determining both inhibition of free fatty acid release and glucose uptake in isolated rat adipocytes treated with epinephrine, in which the concentration of the Cu(II)-gamma-PGA complex for 50% inhibition of free fatty acid release is very similar to that of CuSO4. However, it is significantly lower than that of a previously reported insulin-mimetic bis(3-hydroxypicolinato)copper(II), [Cu(3hpic)2], complex.