Polymers2011ReviewDrug Delivery

Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier

Hirenkumar K. Makadia And Steven J. Siegel29 September 2026DOI 10.3390/polym3013717

Summary

PLGA has become one of the most attractive biodegradable polymers for drug delivery and tissue engineering, but its degradation and drug-release behaviour depend on many interconnected variables—polymer composition, molecular weight, crystallinity, device geometry, fabrication method, and drug type. A consolidated review was needed to describe PLGA fabrication techniques and the factors that control degradation and release, so that devices can be. Composition controls degradation: PLGA 50:50 degrades fastest; degradation rate order is 50:50 > 65:35 > 75:25 > 85:15. Higher glycolic acid content generally accelerates degradation, but the 50:50 ratio is the fastest.

Keywords

PLGA Drug delivery Polymeric Nanoparticles Biodistribution Peptides DNA

Purpose: PLGA has become one of the most attractive biodegradable polymers for drug delivery and tissue engineering, but its degradation and drug-release behaviour depend on many interconnected variables—polymer composition, molecular weight, crystallinity, device geometry, fabrication method, and drug type. A consolidated review was needed to describe PLGA fabrication techniques and the factors that control degradation and release, so that devices can be tuned for specific therapeutic applications.

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

> If PLGA composition, molecular weight, crystallinity, device size/shape, and fabrication method are appropriately selected, then PLGA carriers can be engineered to provide tunable, sustained, and predictable drug release for small molecules, proteins, peptides, and nucleic acids—while remaining biocompatible and biodegradable.

Aims: Review PLGA primarily as a delivery vehicle for drugs, proteins, and other macromolecules in commercial use and research. - Describe the main fabrication techniques for PLGA microspheres, nanoparticles, and implants. - Explain the factors affecting PLGA degradation and drug release, including composition, crystallinity/Tg, molecular weight, drug type, size/shape, pH, enzymes, and drug load. - Present possible future directions for PLGA in drug delivery applications.

Delivery system:

Feature: Polymer; Description: Poly(lactic-co-glycolic acid) (PLGA), a copolymer of poly(lactic acid) (PLA) and poly(glycolic acid) (PGA)

Feature: Polymer forms; Description: PDLA, PLLA, PLGA (D,L-lactic-co-glycolic acid); PLGA/PEG diblock and triblock copolymers (PLGA-PEG, PLGA-PEG-PLGA, PEG-PLGA-PEG)

Feature: Device types; Description: Microspheres, microcapsules, nanocapsules, nanospheres, implants, thermoresponsive gels, multifunctional micro/nanoparticles

Feature: Payloads; Description: Small molecule drugs, steroids, peptides, proteins, vaccines, DNA, RNA, macromolecules

Feature: Surface modification; Description: PEGylation for stealth properties and extended circulation

Feature: Targeting; Description: Not a major focus; some discussion of targeted delivery from diblock nanoparticles

Feature: Key property; Description: FDA-approved, biocompatible, biodegradable, tunable erosion times, tunable mechanical properties

Approach: This is a narrative review synthesising prior literature on PLGA drug delivery systems.

No primary experimental model is used.
The review covers fabrication methods, degradation mechanisms, release kinetics, pharmacokinetics/biodistribution, toxicology, and mathematical modelling.
It draws on in vitro and in vivo studies from cited references.
Disease/therapeutic contexts are broad: controlled drug delivery, protein/peptide delivery, vaccine delivery, tissue engineering, and implantable devices.
Group structure/controls are not applicable because this is a review.

Key methods: Techniques and analyses discussed from cited primary studies include:

Fabrication methods: single emulsion solvent evaporation, double/multiple emulsion, phase separation/coacervation, spray drying, nanoprecipitation, salting out, solvent casting/compression moulding, extrusion, supercritical CO₂ foaming, microfluidic/coaxial capillary flow.
Physicochemical characterisation: molecular weight, polydispersity index, glass transition temperature (Tg), crystallinity, intrinsic viscosity, mechanical strength, swelling behaviour.
Degradation/release studies: hydrolysis of ester linkages, bulk vs. surface erosion, biphasic release profiles, in vitro/in vivo release correlations.
Modelling: diffusion equation with molecular-weight-dependent diffusivity; first-order molecular weight decay \(M_w(t)=M_w(0)\exp(-k_{deg}t)\); Weibull/Rosin–Rammler distribution for microparticle size.
Toxicology: local tissue reaction studies and nanoparticle-specific biodistribution/toxicology considerations.

Key results: Composition controls degradation: PLGA 50:50 degrades fastest; degradation rate order is 50:50 > 65:35 > 75:25 > 85:15. Higher glycolic acid content generally accelerates degradation, but the 50:50 ratio is the fastest. - Molecular weight controls degradation: higher molecular weight PLGA generally degrades more slowly because longer polymer chains require more time to break down. - Biphasic release profile: PLGA devices typically show an initial burst release, followed by a slower diffusion/erosion-controlled release phase. - Release rate and LA/GA ratio: drug release increases as the lactide-to-glycolide proportion decreases; the modelled profiles show 50:50 releasing fastest, then 65:35, 75:25, and 85:15. - Tg: PLGA copolymers generally have Tg above physiological temperature (37 °C), so they are glassy and rigid at body temperature. - Size/shape effect: higher surface-area-to-volume ratio increases degradation and drug release. - PEG copolymers: PLGA/PEG diblock and triblock copolymers can improve release kinetics and enable thermoresponsive gel formation, but PEG can reduce encapsulation efficiency due to steric interference. - Drug loading: higher drug content generally causes a larger initial burst release because of a lower polymer-to-drug ratio.

Interpretation: The authors conclude that PLGA is an excellent controlled-delivery carrier because it is biocompatible, biodegradable, FDA-approved, and tunable across nano-, micro-, and millimeter-scale devices. They recommend:

Short-term release (up to 1 month): amorphous polymer with high hydrophilicity.
Longer-term release (1–6 months): amorphous polymer with high molecular weight.
Very long-term release (>6 months): semi-crystalline polymer with a high degree of crystallinity.

They emphasise that degradation and release can be tuned by composition, molecular weight, crystallinity, device geometry, and fabrication method, making PLGA suitable for a wide range of drugs and delivery routes.

Limitations: Stated or evident from the review: - PLGA degradation and release are complex and often unpredictable because many variables interact. - Potential toxicity from dose dumping, inconsistent release, and drug–polymer interactions requires detailed evaluation. - Conflicting reports exist on the effect of crystallinity on degradation rate. - The role of enzymes in PLGA biodegradation is unclear; in vivo degradation cannot always be correlated with in vitro results. - Nanoparticles may have unique biodistribution and toxicological profiles compared with macroscopic PLGA devices. - Local tissue reactions at the site of application may occur, though generally mild. - PEG addition can reduce encapsulation efficiency, and the precise mechanism is unclear. - The review is not systematic and does not provide meta-analysis or quantitative comparison across all studies. - Clinical translation, GMP manufacturing, and long-term safety are not deeply addressed.

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