Poly(lactic-co-glycolic acid) (PLGA) nanoparticles for drug delivery
Poly(lactic-co-glycolic acid) (PLGA) is one of the most commonly used biodegradable synthetic polymer to generate biocompatible nanoparticles since it is a US FDA* and EMA**-approved platform to the delivery of drugs in humans. The biodegradability that are based on the hydrolysis of this polymer (see Figure 1)to generate the monomers, lactic and glycolic acid, which are metabolized by the body via the Krebs cycle, can be controlled by tuning the ratio of lactic and glycolic acid in the co-polymer chain and the molecular weight of the polymer. Because of this property, the release of the encapsulated drug can be modulated by only altering the polymer composition.
Figure 1. Biodegradability of PLGA based on the hydrolysis of the copolymer.
PLGA nanoparticles can be successfully used to encapsulate differenthydrophobic therapeutic molecules, like cancer drugs that are easily incorporated in the hydrophobic matrix of the particles generated by nanoprecipitation or single emulsion methods, or hydrophilic molecules, such asproteins, peptides, enzymes or genetic material that need to be entrapped in hydrophilic pockets that can be created by means of double emulsion or two step nanoprecipitation methods.
Due to opsonization process, the proteins that are present in the serum are adsorbed to the hydrophobic surface of the particles that are subsequently attached to macrophages, producing their phagocytosis. Moreover, these hydrophobic particles are recognized as foreign by the reticulo-endothelial system (RES) that removes them from the blood circulation, carrying them to the liver or the spleen. To overcome this challenge in drug delivery, the surface of particles can be modified by attaching molecules that provides hydrophilicity to its surface, like the non-ionic polymer poly(ethylene glycol) (PEG), or targeting moieties (peptides or antibodies) that bind with different cell surface receptors to increase the selectivity and specificity of the cellular binding process, avoiding the elimination of the particles by the clearance organs.
PLGA nanoparticles can be internalized in cells through clathrin mediated endocytosis and fluid phase pinocytosis. This type of particles, after internalization, can escape from endosome to the cytosol by means of the interaction of these particles with the vesicular membranes. A factor that is very important regarding the interaction and uptake of nanoparticles on cells is the surface charge on the nanoparticles. Positive charge on the surface of the particles increases the extent of internalization because of the electrostatic interaction between the positive charge of particles and the negative charge in the cell membranes. In addition, depending on the surface charge, particles are able to show different localization inside the cells, that is, positively charge particles are able to escape from lysosomes, showing a perinuclear localization, while negatively and neutrally charge particles are localized after internalization within lysosomes. PLGA nanoparticles have a negative charge that can be modified to neutral or positive by functionalization with different polymers like chitosan or polyethylenimine.
*US FDA à United States Food and Drug Administration.
**EMA à European Medicine Agency.