Journal of Controlled Release2012ReviewDrug Delivery

PLGA-based nanoparticles: An overview of biomedical applications

Fabienne Danhier, Eduardo Ansorena, Joana M. Silva, Regis Coco, Aude Le Breton, Véronique Préat29 September 2026DOI 10.1016/j.jconrel.2012.01.043

Summary

PLGA is one of the most successfully developed biodegradable polymers, with FDA and EMA approval for parenteral drug delivery, but a comprehensive overview linking its formulation methods, physicochemical pitfalls, targeting strategies, and applications across multiple diseases was needed. This review presents why PLGA has been chosen for nanoparticle-based drug delivery and how its properties can be exploited to target specific organs, tissues. Encapsulation efficiency and drug loading: EE varies widely from 6% (dexamethasone) to 90% (paclitaxel); mean EE around 60–70% for drugs such as estradiol or xanthones. However, drug loading is generally poor—around 1%.

Keywords

Nanoparticles PLGA Polymeric Drug delivery Chitosan Nucleic acids Biodistribution

Purpose: PLGA is one of the most successfully developed biodegradable polymers, with FDA and EMA approval for parenteral drug delivery, but a comprehensive overview linking its formulation methods, physicochemical pitfalls, targeting strategies, and applications across multiple diseases was needed. This review presents why PLGA has been chosen for nanoparticle-based drug delivery and how its properties can be exploited to target specific organs, tissues, or cells.

Hypothesis: As a review, there is no formal hypothesis. The central thesis is:

> If PLGA nanoparticles are appropriately formulated and surface-modified, then they can protect drugs from degradation, provide sustained release, and achieve passive or active targeting to specific tissues/cells—making them versatile platforms for vaccination, cancer, inflammation, cerebral, regenerative, cardiovascular, infectious, and other diseases.

Aims: Present why PLGA has been selected to design nanoparticles as drug delivery systems. - Review PLGA nanoparticle formulation methods, physicochemical properties, pitfalls, and encapsulation of hydrophobic drugs, proteins, and nucleic acids. - Describe PLGA-based nanoparticle applications in vaccination, cancer, inflammatory diseases, cerebral diseases, regenerative medicine, cardiovascular diseases, infections, and other pathologies. - Focus on specific characteristics exploited by PLGA-based nanoparticles to target a specific organ, tissue, or cell.

Delivery system:

Feature: Polymer; Description: Poly(lactic-co-glycolic acid) (PLGA); various LA:GA ratios and molecular weights

Feature: Particle types; Description: Nanospheres and nanocapsules; typically 50–250 nm

Feature: Formulation methods; Description: Emulsification-solvent evaporation (O/W), double emulsion (W/O/W), nanoprecipitation, spray drying

Feature: Surface modifications; Description: PEGylation, chitosan coating, poloxamer/poloxamine, targeting ligands

Feature: Targeting ligands; Description: Folate, RGD, LyP-1, AS1411 aptamer, PSMA ligand, transferrin, lactoferrin, mannan, antibodies (e.g., anti-HER2 Fab′), g7 peptide, Pep TGN

Feature: Payloads; Description: Hydrophobic small drugs (paclitaxel, doxorubicin, 9-nitrocamptothecin, cisplatin), proteins (endostar, rh-GCSF, SOD, VEGF, BMP-2/7, insulin), nucleic acids (plasmid DNA, siRNA, shRNA), vaccines/antigens, imaging agents (SPIOs, 99mTc)

Feature: Disease applications; Description: Cancer, vaccination/immunotherapy, inflammatory bowel disease, rheumatoid arthritis, lung inflammation, ophthalmic inflammation, cerebral/Parkinson’s, regenerative medicine, cardiovascular, infections, osteoporosis, diabetes

Approach: This is a narrative review synthesizing primary literature. It covers:

In vitro studies: cell lines (e.g., MCF-7, HEC-1A, LNCaP, A549, HepG2, BxPC3, HCT116, MCF-7/ADR), primary human fetal neurons, M-cell models.
In vivo models: mice, rats, rabbits, guinea pigs, pigs; tumor models (TLT, DMBA-induced breast tumors, PC3, SKOV3, B16 melanoma), colitis models (TNBS, DSS), arthritis models, Parkinson’s models (6-OHDA), spinal cord injury, ischemia-reperfusion, hind-limb ischemia, diabetes.
Disease contexts: cancer chemotherapy, gene therapy, cancer imaging/theranostics, vaccination, inflammatory diseases, cerebral diseases, regenerative medicine, cardiovascular diseases, infections, osteoporosis, diabetes.
Group structure / controls: As summarized from cited studies; comparisons typically include free drug vs. nanoparticle, targeted vs. non-targeted, and untreated/saline controls.

Key methods: Techniques from cited primary studies include:

Physicochemical characterization: dynamic light scattering (DLS) for size/polydispersity, zeta potential for surface charge, SEM/TEM/AFM for morphology.
Encapsulation/drug loading: ultracentrifugation to separate free drug; UV/ HPLC quantification.
Cellular uptake/internalization: flow cytometry, confocal microscopy.
Targeting validation: receptor binding assays, competitive inhibition, in vivo biodistribution.
Therapeutic efficacy: cytotoxicity assays (IC50), tumor growth inhibition, survival analysis, clinical activity scores, blood glucose reduction.
Imaging/biodistribution: MRI (SPIOs), gamma scintigraphy (99mTc), fluorescence microscopy.
Immune response: antibody titers, ELISPOT, T cell proliferation, cytokine ELISA.
Gene silencing/expression: mRNA knockdown (e.g., BCL-w >60%), reporter gene transfection.

Key results: Encapsulation efficiency and drug loading: EE varies widely from 6% (dexamethasone) to 90% (paclitaxel); mean EE around 60–70% for drugs such as estradiol or xanthones. However, drug loading is generally poor—around 1% (1 mg active per 100 mg polymer). Nucleic acid loading remains 0.1–1 mg per 100 mg nanoparticles. - Cationic additives improve nucleic acid encapsulation: PEI increased EE from 43% to 80%; chitosan increased EE from 28% to 44%. - Active targeting enhances uptake/effect: Folate-decorated DOX-PLGA NPs showed 1.5× higher uptake by MCF-7 cells than non-targeted NPs. LyP-1-targeted NPs showed ~8× higher uptake in metastatic lymph nodes than non-targeted NPs. PSMA-targeted Pt(IV)-PLGA-PEG NPs were ~10× more effective than free cisplatin against PSMA-overexpressing LNCaP cells. RGD-targeted PTX NPs retarded TLT tumor growth and prolonged survival vs. non-targeted NPs. - Oral bioavailability improvements: PTX-loaded PLGA NPs showed 10× higher oral bioavailability than Taxol; tamoxifen-loaded NPs showed 11× higher oral bioavailability than free tamoxifen. - CNS delivery: Lactoferrin-conjugated PEG-PLGA NPs accumulated in brain (substantia nigra, cortex, striatum); urocortin-loaded Lf-NPs showed anti-Parkinsonian activity in 6-OHDA rats. Loperamide-loaded g7-NPs produced antinociception for 5 h; double-conjugated SA-g7 NPs extended antinociception to 24 h. - Ischemia-reperfusion: SOD-loaded PLGA NPs improved survival to 75% vs. 0% in untreated controls at 28 days and reduced infarct volume.

Interpretation: The authors conclude that PLGA-based nanoparticles offer major advantages: protection of drugs from degradation, sustained release, improved pharmacokinetics/pharmacodynamics, and passive/active targeting to tumors, inflamed tissues, or the brain. Because PLGA is FDA/EMA-approved, it is well positioned for clinical translation. However, they emphasize that low drug loading is probably the major hurdle limiting clinical use, alongside high production cost and scale-up difficulties.

Limitations: Stated by authors: - Poor drug loading (~1%) for many drugs; this is a major hurdle for clinical trials. - High burst release from most PLGA-based nanoparticles. - Nanoparticle aggregation and colloidal instability. - Nanotoxicology and biocompatibility are incompletely understood; in vitro results often do not translate to in vivo. - Animal models are not fully representative of clinical situations. - GMP production of PLGA with well-defined properties is expensive. - Scale-up is difficult: dialysis, ultracentrifugation, sonication, etc., are hard to reproduce industrially. - EPR effect is highly heterogeneous across tumor models and patients. - Active targeting can increase immunogenicity and protein adsorption. - Few actively targeted PLGA-based nanoparticles have been tested both in vitro and in vivo.

Implicit limitations: - Review relies on proof-of-concept preclinical studies; clinical data are limited. - No meta-analysis or quantitative comparison across studies. - Long-term stability and toxicity data are sparse. - Regulatory pathways for nanomedicines are not discussed in detail.

Biochemical Pharmacology*, Volume 173, 2020, Article 113648 DOI/