Synthesis of Poly-γ-Glutamic Acid and Its Application in Biomedical Materials

Abstract

Poly-γ-glutamic acid (γ-PGA) is a natural polymer composed of glutamic acid monomer and it has garnered substantial attention in both the fields of material science and biomedicine. Its remarkable cell compatibility, degradability, and other advantageous characteristics have made it a vital component in the medical field. In this comprehensive review, we delve into the production methods, primary application forms, and medical applications of γ-PGA, drawing from numerous prior studies. Among the four production methods for PGA, microbial fermentation currently stands as the most widely employed. This method has seen various optimization strategies, which we summarize here. From drug delivery systems to tissue engineering and wound healing, γ-PGA's versatility and unique properties have facilitated its successful integration into diverse medical applications, underlining its potential to enhance healthcare outcomes. The objective of this review is to establish a foundational knowledge base for further research in this field.

Keywords: drug delivery; poly-γ-glutamic acid; preparation methods of γ-PGA; tissue engineering; wound healing.

Figure 3

Regulation of γ-PGA synthesis via Fe²⁺/genetic engineering. The yellow box represents the regulation of Fe²⁺on synthesis, and the red arrows indicate a promoting effect on the processes [20]. The black box indicates regulation through genetic engineering, with the green box indicating the insertion position of the strong promoter and the green crosses indicating the deletion of this metabolic pathway by knocking out relevant genes [31].

Figure 4

(A) The porous structure of hydrogels formed by different PH regulators, different γ-PGA contents, and different drying methods [35]. (B) Effect of DOEs on CS/γ-PGA hydrogel [36]. (C) Preparation principle of HA/γ-PGA [41]. (D) HA/γ-PGA hydrogel based on dynamic covalent chemistry, stable covalent chemistry, and IPN strategy [43].

Figure 5

(A) Schematic diagram of GEL/PGA hydrogel preparation [48]. (B) Schematic diagram of collagen/PGA hydrogel crosslinking [51]. (C) A method to stabilize the SA/γ-PGA hydrogel network by adding MCC, and research has found that it can promote the development of stem cells into chondrocytes [54].

Figure 7

(A) The γ-PGA-CA-Pt(IV) was converted to Pt(II) in acidic environment, and the killing rate of Pt(IV) was enhanced after pre-incubation with GSH [65]. (B) CPTP/CDDP release CPT diagram [63]. (C) Schematic diagram of enhancing anti-tumor effect of PLG-CDDP nano-agent [66]. (D) Schematic illustration of cisplatin (CDDP)-loaded and TFR-targeted drug delivery systems constructed via the self-assembly method [64].

Figure 8

(A) Schematic diagram of assembling nanoparticles capable of producing CAR in situ [69]. (B) Various antibody–polymer–drug conjugates (APDCs) were synthesized through the use of polymer linkers, resulting in a “Lego-like” assembly approach [67]. (C) Schematic diagram of a zwitterionic cloak of multiple layers of short alternating glutamic and lysine (EK) peptides [68].

Figure 9

(A) The complexation reaction forms targeted polymer–protein particles, and mouse inhaled the drug (*** p < 0.001, **** p < 0.0001) [70]. (B) The production process and design schematic diagram of the new brushless torque method are presented [74]. (C) Shape comparison of the CS/PGA/SA hydrogel [73].

Figure 10

(A) Hydrogel formation mechanism and in vivo cartilage engineering diagram [76]. (B) Schematic diagram of single–double-crosslinked HA/γ-PGA hydrogel [79]. (C) Schematic diagram of fabrication of injectable bisphosphonated nanocomposite hydrogel inspired by mussels [85].

Figure 11

(A) Synthesis of γ-PGA-ε-PL hydrogel and treatment of infection model [88]. (B) This schematic shows the composition and source of adhesion properties of OKPP hydrogels [89]. (C) The preparation method of double-mesh CGLH and the schematic description of its biomedical application [91]. (D) Diagram of Ceria-modified vesicle loaded with antibiotics to heal diabetic wounds [92]. (E) Schematic diagram of MN-MOF-GO-Ag mechanism [95]. (F) Preparation of PDA-BNN6 nanosheets and hydrogels and application of hydrogels in wound healing of bacterial infection [90]. (G) Hemostatic agent coagulation process diagram [94].

Figure 12

(A) Preparation of CS/Hep/γ-PGA composite hydrogels [97]. (B) Design, synthesis, and biological function diagram of γ-PGA-SH/OHA-GMA hydrogel [98]. (C) Synthesis of CG, HD, and PA and formation and construction mechanism of injectable self-healing CG-HD-Pa hydrogel [100].

Figure 1

Molecular structure of poly-γ-glutamic acid.

Figure 2

(A) The synthesis steps of traditional peptide synthesis method and dimer condensation polymerization method [9]. (B) The process of enzymatic conversion. GTP is glutamine transpeptidase [11]. (C) The process of extraction method. (D) The mechanism of microbial synthesis of γ-PGA.

Figure 6

(A) The synthesis pathway for single-drug and combined-PGA-drug conjugates. (B) Representative 1H-NMR spectra recorded in D₂O at 500 MHz. (C) A representative SEC chromatogram showing parental PGA and PGA-DOX, PGA-(G-AGM)LL, and PGA-(G-AGM)LL-DOX conjugates with UV detection at 260 nm [57].