Poly(lactide-co-glycolide)-b-poly(ethylene glycol)-maleimide (PLGA-PEG-Mal): it is a performance amphiphilic block copolymer with end groups of polyethylene glycol (PEG) maleimide. The material is biocompatible and biodegradable making it the best material for biomedical devices. Moreover, maleimide group can react with thiol groups in particular states to make strong thioether bonds. This makes PLGA-PEG-Mal ideal for applications like drug delivery and protein engineering. These polymers combine PLGA's biodegradability and biocompatibility, PEG's hydrophilicity and stealthiness, with the maleimide group offering a bioconjugation site to attach desired ligands or drugs. This polymeric architecture is aimed at optimizing drug delivery systems for efficacy, specificity and safety.
Figure 1. Nanoparticle delivery system composed of PLGA-PEG-Mal. (Jiang T, et al.; 2018)
The active ingredient PLGA, the base of PLGA-b-PEG-Mal is a polymer of lactic acid and glycolic acid which are both natural metabolites, readily metabolised by the human body. This natural biodegradability is why PLGA is the ideal drug delivery material as it degrades into non-toxic byproducts that can easily be disposed of from the body. Furthermore, the degradation of PLGA can be adjusted by modifying the lactic acid/glycol acid ratio, offering a flexible base for the controlled release of pharmaceuticals. Combine that with PEG, a polymer that helps minimize protein adsorption and increases the duration of blood circulation, and the PLGA-b-PEG copolymer is nanoparticles that could get around the immune system and prolong the half-life of the encapsulated drug. Maleimide functionality for PLGA-b-PEG is another addition to this delivery system. Maleimide is very reactive against thiol groups (normally present in peptides, proteins and other biomolecules). This reactivity can be used to stable conjugate targeting ligands, like antibodies or peptides, to the surface of the nanoparticle. They can choose these ligands to target receptors expressed over-regularly on the surface of infected cells (like cancer cells), thereby delivering targeted therapeutics. Applied to the target of disease by concentrating the agent, such directed therapy reduces the off-target effects and enhances the drug's therapeutic index. PLGA is also studied extensively and utilized in drug delivery for the reasons of biocompatibility and biodegradability. This copolymer is produced by ring-opening polymerization of lactide and glycolic acid, and the rate of its decomposition can be exactly adjusted by changing the concentration of these two monomers. PLGA breaks down to lactic acid and glycolic acid, both of which the body naturally breaks down. This degradation can range from a few weeks to a few months depending on the particular formulation, and this is what makes PLGA such a versatile substance with respect to time-dependent treatment regimes. PLGA biocompatibility is another important reason that PLGA is suitable for drug delivery. PLGA does not provoke inflammatory reactions, which are important for patient safety and comfort. Further, PLGA nanoparticles can be programmed to hold various therapeutic molecules such as small molecule drugs, proteins, and nucleic acids. The capsules are not pre-degraded, but controlled release, enhancing the stability and bioavailability of the drug. This pharmacokinetic versatility of PLGA can be further complemented by PEG-PLGA-b-PEG copolymers.
PEG (Polyethylene glycol) is a hydrophilic polymer in drugs delivered in drug delivery systems to help improve drug pharmacokinetics. PEG gives some important properties to the copolymer nanoparticles in combination with PLGA. One of the biggest benefits of PEGylation is the "stealth" action that disables nanoparticle detection and clearance by RES. This is done because PEG a hydrophilic corona around the nanoparticles so that it can't be opsonized by serum proteins and then picked up by phagocytes. So, PLGA-b-PEG nanoparticles have longer blood circulation times and could be better deposited at target locations through enhanced permeability and retention (EPR). In addition to reducing the time of circulation, PEGylation also makes drug delivery vehicles more solubilized and stable. PEG's hydrophilic nature enables nanoparticles to be distributed in aqueous media and is therefore important for intravenous drug delivery. Furthermore, PEG on the nanoparticle surface prevents particle aggregate and dispenses the drug delivery system uniformly. This is especially critical to keep the treatment effects consistent and avoid side effects. Add maleimide groups to PLGA-b-PEG copolymers and you've got an important feature for selective delivery of drugs. Maleimide groups bind selectively to thiol groups to bind targeting ligands and lead the nanoparticles to cells or tissues. This targeting capability is especially useful in cancer treatment, where selectively delivering chemotherapy to tumor cells can make all the difference for patient treatment and reduce systemic side effects. For instance, antibodies or antibody fragments recognizing tumor antigens could be bound to maleimide-functionalised nanoparticles. Once administered, these nanoparticles can go after cancer cells to deliver targeted, capsulated drugs directly to the tumor site. Such selective therapy not only improves the efficacy of the drug but prevents collateral injury to normal tissue, a problem with conventional chemotherapy.
Alternate Names:
PLGA-PEG-Maleimide
Maleimide-Functionalized PLGA-PEG
PLGA-PEG-MAL
PLGA-PEG-Mal Diblock Copolymer
Poly(lactic-co-glycolic acid)-Polyethylene Glycol-Maleimide
Maleimide-Terminated PLGA-PEG
PLGA-PEG with Maleimide End Group
PLGA-PEG-Maleimide Copolymer
PLGA-PEG-MAL Conjugate
PLGA-PEG-Mal Functionalized Polymer
References:
1. Jiang T, et al.; Development of Targeted Nanoscale Drug Delivery System for Osteoarthritic Cartilage Tissue. J Nanosci Nanotechnol. 2018, 18(4):2310-2317.
Antimicrobial peptide-grafted PLGA-PEG nanoparticles to fight bacterial wound infections
Biomater Sci.
Authors: Ramôa AM, Campos F, Moreira L, Teixeira C, Leiro V, Gomes P, das Neves J, Martins MCL, Monteiro C.
Abstract
Wound infection treatment with antimicrobial peptides (AMPs) is still not a reality, due to the loss of activity in vivo. Unlike the conventional strategy of encapsulating AMPs on nanoparticles (NPs) leaving activity dependent on the release profile, this work explores AMP grafting to poly(D,L-lactide-co-glycolide)-polyethylene glycol NPs (PLGA-PEG NPs), whereby AMP exposition, infection targeting and immediate action are promoted. NPs are functionalized with MSI-78(4-20), an equipotent and more selective derivative of MSI-78, grafted through a thiol-maleimide (Mal) Michael addition. NPs with different ratios of PLGA-PEG/PLGA-PEG-Mal are produced and characterized, with 40%PLGA-PEG-Mal presenting the best colloidal properties and higher amounts of AMP grafted as shown by surface charge (+8.6 ± 1.8 mV) and AMP quantification (326 μg mL-1, corresponding to 16.3 μg of AMP per mg of polymer). NPs maintain the activity of the free AMP with a minimal inhibitory concentration (MIC) of 8-16 μg mL-1 against Pseudomonas aeruginosa, and 16-32 μg mL-1 against Staphylococcus aureus. Moreover, AMP grafting accelerates killing kinetics, from 1-2 h to 15 min for P. aeruginosa and from 6-8 h to 0.5-1 h for S. aureus. NP activity in a simulated wound fluid is maintained for S. aureus and decreases slightly for P. aeruginosa. Furthermore, NPs do not demonstrate signs of cytotoxicity at MIC concentrations. Overall, this promising formulation helps unleash the full potential of AMPs for the management of wound infections.
Datasheet
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