PLGA is used extensively for drug delivery due to its favorable physicochemical properties. However, conventional methods of synthesis produce particles with wide size distributions, creating issues with reproducibility and a limited ability to control drug release.
Using stimuli-responsive smart polymer building blocks allows for the development of PLGA-based devices that respond to a variety of conditions. Despite this, the acidic environment produced during degradation might cause toxicity and hinder osteoconductivity of scaffolds.
Biodegradation
Poly(lactic-co-glycolic acid) (PLGA) has gained great interest as a biodegradable polymer for medical applications such as drug delivery systems. In these systems, the pulsatile release of drugs is highly dependent on the physicochemical characteristics of the PLGA and its ability to undergo biodegradation.
Currently, the FDA approves several medical devices that are made of PLGA. These include implants and biodegradable microchips for targeted drug delivery that breaking down into lactic acid and glycolic acid. In addition, a variety of studies have been conducted to explore the role of PLGA in bone tissue engineering, with a particular focus on the use of PGA co-polymers as bioresorbable scaffolds.
The physicochemical characteristics of PLGA, such as its mechanical strength and swelling behavior, are largely determined by the molar ratio of the monomer components, as well as their degree of crystallinity. Moreover, the rate of hydration and subsequent hydrolysis is significantly affected by the shape of the device under study. In the case of PLGA, the molar ratio of the lactic and glycolic acid monomers is particularly important, as it influences the degradation kinetics, with LA-rich copolymers degrading faster than GA-rich ones.
In aqueous environments, PLGA degrades via hydrolysis of the ester linkages. The first step is hydration, in which water permeates into the amorphous regions of the polymer and disrupts van der Waals forces and hydrogen bonds, lowering its glass transition temperature (Tg). The amorphous region also becomes less crystalline. This decrease in crystalline structure further lowers Tg, and the resulting reduction in molecular weight raises PLGA’s hydrophilicity, which speeds up its degradation into water-soluble fragments.
After hydrolysis, carboxylic end groups autocatalyze the degradation process, which ultimately leads to massive cleavage of covalent backbone chains. Consequently, the polymer breaks down into smaller and smaller fragments until it loses its integrity and is fully degraded.
The degradation of PLGA is relatively slow, but it can be varied depending on the monomer ratio and other factors. In general, the higher the molar ratio of the lactic acid monomer, the faster it degrades. The choice of the PLGA monomer mixture is therefore critical for controlled drug release applications.
Chemical Reactions
The biocompatibility of PLGA has led to the development of many pharmaceutical formulations that utilize it as a drug carrier. These include gels, implants, and microspheres that can be used for the controlled delivery of drugs, peptides, and proteins. The stability of these devices depends on their ability to keep the encapsulated molecules at a stable pH. This can be achieved by adding a less water-soluble alkaline material to the device, or by using an acidic biodegradation product to generate a mildly acidic environment in which the encapsulated drug can remain stable.
The degradation of PLGA is driven by the hydrolytic breaking of ester bonds and autocatalytic decomposition. The rate at which this occurs is determined by a number of factors, including the ratio of LA to GA monomers, molecular weight, surface area and volume, and chemical interactions. The copolymer that is chosen for a particular application will be selected according to the degradation rate desired, as well as the stability and compatibility with the drug or peptide to be delivered.
Generally, the crystalline regions of a PLGA structure are more resistant to degradation than the amorphous region. The Tg of a PLGA structure is also directly correlated to the relative molecular weight and composition of the polymer. A crystalline PLGA has a higher Tg than an amorphous one, as it has more polar hydroxyl groups, making it more rigid.
When the PLGA is exposed to an acidic environment, it can undergo autocatalytic degradation and be broken down into LA and GA. These are then metabolized by the body into carbon dioxide and water. The degradation process may result in an acidic local microenvironment, which can cause inflammatory reactions in the area where the PLGA is located.
PLGA-based drug carriers are often used to deliver leuprorelin, also known as Lupron depot, which is a prostate cancer medication. This drug works by blocking the production of testosterone in the male body, which can help prevent the growth of cancerous prostate tissue. The PLGA-based implant is designed to release this medication over a period of up to six months.
Oxidation
PLGA is a biodegradable and biocompatible material with high stability. This makes it an ideal drug delivery system (DDS) for controlled-release of drugs, peptides and proteins. Whether used as micro/nanoparticles or millimeter-sized implants, PLGA has been shown to effectively deliver medicines in various organs.
Depending on the monomer ratio, molecular weight and Tg of the copolymer used in its synthesis, PLGA can be designed to degrade at different rates in the body. These parameters influence the physico-chemical properties of the polymer, including the surface area available for drug interaction.
Another important factor is the pH of the local environment. A strongly acidic pH accelerates degradation of PLGA, whereas an alkaline pH slows it down. This has been shown to have a direct impact on how long encapsulated pharmaceuticals stay stable and the extent of their therapeutic effects.
The lactic and glycolic acids produced by the degradation of PLGA are not toxic to the body. Lactic acid is excreted unchanged via the kidneys, while glycolic acid enters the tricarboxylic acid cycle and is eventually eliminated as carbon dioxide and water. This process of biodegradation and the subsequent production of non-toxic byproducts is the reason why PLGA is considered to be highly biocompatible.
In addition to being biodegradable, PLGA is also highly resistant to corrosion in the body. This resistance is a result of the presence of large numbers of polar groups, which provide a barrier to the penetration of water molecules.
This characteristic makes PLGA useful for many medical applications, including MRI contrast agents and imaging modalities such as fluorescence, ultrasound and photoacoustic tomography (PAT). In these cases, the stability of PLGA particles can be adjusted to match the physico-chemical characteristics of the underlying drug, allowing it to remain stable for longer periods of time.
In addition, the polar groups of PLGA make it possible to incorporate other materials into the particle structure. For example, a group of researchers has developed PLGA micro/nanoparticles that encapsulate manganese oxide for use in a dual-modality approach to imaging tendon stem cells in the body using MRI and PAT.
Bioaccumulation
PLGA is a biodegradable synthetic polymer that can be easily incorporated into a variety of drug delivery devices and surgical instruments. These biodegradable materials are made of a copolymer of poly(lactic acid) and poly(glycolic acid). The lactic and glycolic acids in these polymers are produced through fermentation from sugars, making them eco-friendly and less reactive to the body. Moreover, the polymer degrades into non-toxic and non-reactive degradation products that are removed through the body’s natural processes. These properties have made PLGA an excellent choice for a variety of medical and pharmaceutical applications.
The amorphous nature of PLGA makes it possible to create a variety of shapes and sizes, allowing for the encapsulation of large molecules. Moreover, it is also soluble in a variety of organic solvents such as dichloromethane, tetrahydrofuran and acetone. This allows PLGA to be fabricated into drug delivery devices on all scales, from nanospheres to millimeter-sized implants. Moreover, it can encapsulate drugs, peptides and proteins, and release them over long periods of time.
When PLGA is used in drug delivery applications, the rate of degradation plays a key role in determining the pharmacokinetics of the encapsulated medication. This is because the kinetics of the drug/biomolecule release can be dramatically influenced by the degradation rate of the polymer.
One of the most common methods of modifying the PLGA degradation process is to use a catalyst. This can increase the rate at which the molecule is cleaved and decrease the overall molecular weight of the resulting degradation products. However, the toxicity of these catalysts can be an issue in some cases.
It is also important to consider the pH of the resulting degradation products. The acidic environment produced by PLGA degradation can have an impact on how long the encapsulated medications stay stable in the body. This can impact the effectiveness of the treatment and may cause inflammation.
The amorphous structure of PLGA also allows it to be readily phagocytosed by macrophages. This can help to improve the stability and bioavailability of PLGA-based drug carriers. In addition, it can also enhance the targeting of PLGA-based MPs for inhaled drug delivery to the lungs. However, the phagocytic characteristics of PLGA-IO MPs still need to be fully explored and characterized.
