Concepts and practices used to develop functional PLGA-based nanoparticulate systems

Abstract

The functionality of bare polylactide-co-glycolide (PLGA) nanoparticles is limited to drug depot or drug solubilization in their hard cores. They have inherent weaknesses as a drug-delivery system. For instance, when administered intravenously, the nanoparticles undergo rapid clearance from systemic circulation before reaching the site of action. Furthermore, plain PLGA nanoparticles cannot distinguish between different cell types. Recent research shows that surface functionalization of nanoparticles and development of new nanoparticulate dosage forms help overcome these delivery challenges and improve in vivo performance. Immense research efforts have propelled the development of diverse functional PLGA-based nanoparticulate delivery systems. Representative examples include PEGylated micelles/nanoparticles (PEG, polyethylene glycol), polyplexes, polymersomes, core-shell-type lipid-PLGA hybrids, cell-PLGA hybrids, receptor-specific ligand-PLGA conjugates, and theranostics. Each PLGA-based nanoparticulate dosage form has specific features that distinguish it from other nanoparticulate systems. This review focuses on fundamental concepts and practices that are used in the development of various functional nanoparticulate dosage forms. We describe how the attributes of these functional nanoparticulate forms might contribute to achievement of desired therapeutic effects that are not attainable using conventional therapies. Functional PLGA-based nanoparticulate systems are expected to deliver chemotherapeutic, diagnostic, and imaging agents in a highly selective and effective manner.

Keywords: functionality; nanoparticles; nanoparticulate dosage forms; polylactide-co-glycolide.

Figure 1

Representative PLGA-based nanoparticulate dosage forms. (A) PEGylated micelle (eg, PEG-PLGA block copolymeric micelle), (B) polyplex (eg, DNA-PEI-PLGA), (C) PEGylated PLGA nanoparticle, (D) core-shell type nanoparticle (eg, PEGylated lipid-PLGA hybrid nanoparticle), (E) cell membrane-PLGA hybrid nanoparticle (eg, PLGA nanoparticles encased by red blood cell), (F) polymersome (eg, PEG-PLGA block copolymeric vesicle), and (G) magnetic PLGA particle either conjugated with gadolinium-chelate or laden with magnetite (eg, theranostics). Note: All of these nanoparticulate carriers can be further derivatized by cell-recognizable ligands. Abbreviations: PLGA, polylactide-co-glycolide; PEG, polyethylene glycol; DNA, deoxyribonucleic acid; PEI, polyethyleneimine.

Figure 2

Schematic representation of typical nanoencapsulation techniques used to prepare PLGA-based micelles: (A) the solid dispersion method and (B) the emulsion-based solvent evaporation/extraction method. Abbreviations: PLGA, polylactide-co-glycolide; PEG, polyethylene glycol; o/w, oil-in-water.

Figure 3

Derivatization of the surface of PLGA-based nanoparticulate carriers with cell-recognizable ligands: (A) physical association driven by the specific avidin-biotin binding affinity; (B–D) amide coupling reactions using carbodiimide reagents; (E) maleimide-thiol reaction; (F) thiol-thiol reaction; and (G) aldehyde-amine reaction. In most conjugation reactions, the surface of PLGA is first derivatized by PEGs with different end groups to produce amine-, aldehyde-, maleimide-, succinimidyl ester-, or sulfhydryl-functional PEG-PLGA conjugates. Abbreviations: PLGA, polylactide-co-glycolide; PEG, polyethylene glycol.