INTRODUCTION:
Poly(lactide-co-glycolide) (PLGA) is a copolymer, synthesized of lactic acid and glycolic acid. Lactic acid has two optical isomers: L-lactic acid and D-lactic acid as it contains an asymmetric carbon atom. When the lactide and glycolide moieties get polymerised to form the PLGA co-polymer it forms different conformation and tacticities in it. In the body lactic acid is formed as an intermediate product through the metabolism of carbohydrates. And also the Glycolic acid could be formed as through the metabolic processes of the body. So, when the PLGA copolymer is given in the body, the body metabolizes it slowly to Lactic acid and Glycolic acid. These end products are eliminated from the body via the Krebs cycle. Thus, making the PLGA copolymer to be a biodegradable and biocompatible polymer. The polymer is not harmful to the body. So, this polymer is approved by the U.S. FDA for its clinical use in humans. By altering the copolymer ratio we can also alter the biodegradation rates of the PLGA copolymer. Also, PLGA could be formed as nanoparticles, micro-particles, microspheres, polymeric micelle, scaffold structures which can act as a potential device for loading of hydrophilic drug molecules, charged drug molecules in the core of the PLGA matrix in the above mentioned devices for drug delivery. The PLGA surface properties could be modified for targeting the drug to a specific site of action. Because of all these properties of PLGA this polymer gains interest of the researchers to work on for drug delivery modifications.
SYNTHESIS OF PLGA:
The PLGA copolymer is synthesized by means of random ring opening and copolymerization of the monomers, the cyclic dimers of lactic acid and glycolic acid. The copolymerisation is initiated by use of catalysts like tin (II) 2-ethylhexanoate, tin (II) alkoxides and aluminum isopropoxide. Thus, yields a linear polyester amorphous, aliphatic product having ester linkages between the two copolymers.

Synthesis of Higher Molecular Weight or Lower Molecular Weight PLGA:
The degree of condensation and the PLGA copolymer chain length decides the higher molecular weight and lower molecular weight of PLGA copolymer. PLGA of low molecular weight (below 10 kDa) can be obtained by a ring-opening co-polymerization of lactic and glycolic acid. PLGA of higher molecular weights can be synthesized using the same process by using the above mentioned catalysts or using cyclic dimers as a starting material.

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AMORPHOUS NATURE OF PLGA:
The number and types of sequences are limited in the ring-opening polymerizations. Typically, randomly distributed atactic or syndiotactic PLGAs are obtained. Thus, are amorphous in nature. As the atactic/syndiotactic sequences have the random(not on one side of the chain) arrangement of the pendant group, (in the case of PLGA are the carbonyl and methyl groups) across the linear chain thus not causing any ordered arrangement or crystalline form. So, they are amorphous in nature.
ADVANTAGES OF PLGA:
Biocompatibility.

Tailored biodegradation rate (depending on the molecular weight and copolymer ratio)
Approval for clinical use in humans by the U.S. Food and Drug Administration (FDA)
Potential to modify surface properties to provide better interaction with biological materials and targeting the site of action.
Suitability for export to countries and cultures where implantation of animal-derived products is unpopular.
PROPERTIES OF PLGA:
The mechanical strength of the PLGA copolymer depends on the crystallinity of the polymer. Also, properties like swelling ability, capacity to undergo hydrolysis and the biodegradation rate depends on the crystallinity of the polymer. While, we consider the individual polymers Poly lactic acid (PLA) and poly glycolic acid (PGA), the PLA is highly crystalline in nature and the PGA is amorphous in nature. So, there is influence of the molar ratios used for the preparation of the PLGA copolymer on the crystallinity. It is thus said that higher the PLA content the PLGA copolymer is more towards crystalline form.
Considering, the rates of biodegradation as the polymer is more towards crystalline form i.e. content or the molar ratio of PLA is more than that of the PGA in the PLGA copolymer, causes it to be less soluble than that of the amorphous form and so the rate of hydrolysis is less in this case and subsequently the rate of biodegradation is low in the case of the PLGA copolymer having PLA content more. So, we can say that by altering the copolymer ratio we are able to modify the biodegradation of the PLGA copolymer.
PLGA copolymer containing a 50:50 ratio of the monomers PLA and PGA is an exception and show higher rate of hydrolysis and biodegradation than those made with either monomer ratio to be higher. It has a glass transition temperature (Tg) of 45°C to 55°C and an inherent viscosity of 0.5-0.8 mPa.

BIODEGRADATION OF PLGA:
The PLGA co-polymer undergoes degradation hydrolytic degradation or biodegradation through cleavage of its backbone ester linkages. Mechanism for PLGA biodegradation could be explained in three steps:
Random chain scission process: There is scission of the long polymer chains, with no appreciable weight loss and no soluble monomer products formation.

In the middle phase, a decrease in M.W. and soluble oligomeric and monomer products are formed.

Soluble monomer products formed- This phase is that of complete polymer solubilization.

After this the polymer by Krebs cycle is elimanted from the body.
The biodegradation of PLGA could be affected by different factors:
29883103048000Effect of Molar Ratio:
PLA is more hydrophobic in nature than that of the PGA. So, when the ratio of PLA is more in the PLGA polymer, the biodegradation is slower in this case. The exception is only in the case, where the PLA:PGA ratio is 50:50 the degradation rates are faster than where the polymer ratios of either of them are higher.
Effect of Molecular Weight:
Higher molecular weight PLGA polymers are formed where the length of the chains is also longer. So, it takes a larger time for the biodegradation of the PLGA polymer with higher molecular weight.
Effect of Drug loading:
The drug loading plays a significant role in the degradation of the polymer. Larger amount of drug loading results in more content (burst) release at the initial stages of the polymer degradation.
Surface area in contact:
The higher the surface area in contact with aqueous environment (available for hydrolysis), greater is the biodegradation of the PLGA polymer.
MODIFICATIONS ON PLGA:
The PLGA system is hydrophobic in nature, due to PLA content. To alter the drug release pattern of hydrophilic drugs we need to modify the properties of the PLGA and the surface of the PLGA. Also, to increase the shelf life of the formulations and to avoid any kind of immune response inside the body due to the hydrophobicity of PLGA, we modify the PLGA surface with hydrophilic groups like PEG, Chitosan, Dextran.
34880558953500PEG Modification:
The PEG could be linked with the PLGA polymer chemically. It can thus form the PLGA-PEG block systems i.e. the diblock, triblock and so on and it could be made hydrophilic. The hydrophobicity could be maintained if the PLGA-PEG-PLGA triblock is formed where there are two PLGA molecules associated with a single PEG molecule. When there is need of more hydrophilicity of the formulation the PEG-PLGA-PEG triblock could be used. Also, the ratio when altered may result in formation of different systems (micelle formation) when administered or when are in the formulation for solubility of the drug inside the micelle.
The PLGA-PEG systems also show the solution-gel transitions. Because, while in the formulation they are in aqueous environment and stored at lower temperatures. In this case the hydrogen bonding between the PEG and the water molecules dominate thus dissolving the system in water. When the formulation is administered in-vivo at the body temperature, the PLGA and PEG interactions dominate and thus hydrophobicity increases due to PLGA. The solution state of the formulation then turns gel due to the transformation. So, these systems could also act as depot type of formulation with sufficient hydrophilicity for drug release in the body.

Dextran modified:
For the formation of the interaction and bond between Dextran and PLGA, the modification in Dextran is essential. Dextran is converted to aminated form, which forms an amide linkage with the PLGA and they are linked.
Chitosan modified:
34372555905500The chitosan is a weak cationic type of polymer. When it is surface coated on the PLGA surface it forms interactions with PLGA. Thus, chitosan could be over the surface of the PLGA. So, in the PLGA core hydrophobic in nature, encapsulation of hydrophobic drugs is possible. And in the chitosan layer the hydrophilic and/or charged moieties could be encapsulated. So, a co-drug delivery at a particular target site could be possible with this kind of modification.
End-Groups Modification of PLGA:
32258004169900End capped PLGA with modification of the free carboxylic end of it is achieved by esterification at the carboxylic group and the free hydroxylic end by attaching alkyl chain i.e. ether end capping is performed to modify the drug release patterns. This causes alteration in the drug release patterns of the PLGA as due to end capping it is more hydrophobic in nature due to attachment of alkyl chains. So, prolonged drug release could be achieved due to this modification.
COMMERCIALLY AVAILABLE PLGA WITH DIFFERENT MOLECULAR WEIGHTS:
Polymer Name Molecular Weight Range Viscosity dl/g Tg °C Tm °C End Group
Poly(L-lactide) — 0.8-1.2 60-65 180-185 Ester terminated
Poly(D,L-lactide) 10,000-18,000 0.16-0.24 38-42 Amorphous Ester terminated
Poly(D,L-lactide) 10,000-18,000 0.16-0.24 44-48 Amorphous Free carboxylic acid
Poly(D,L-lactide) 18,000-28,000 0.25-0.35 46-50 Amorphous Ester terminated
Poly(D,L-lactide) 18,000-28,000 0.25-0.35 48-52 Amorphous Free carboxylic acid
Poly(D,L-lactide-co-glycolide) 50:50 7,000-17,000 0.16-0.24 42-46 Amorphous Alkyl ester
Poly(D,L-lactide-co-glycolide) 50:50 7,000-17,000 0.16-0.24 42-46 Amorphous Free carboxylic acid
Poly(D,L-lactide-co-glycolide) 50:50 24,000 -38,000 0.32-0.44 44-48 Amorphous Ester
Poly(D,L-lactide-co-glycolide) 50:50 24,000-38,000 0.32-0.44 44-48 Amorphous Free carboxylic acid
Poly(D,L-lactide-co-glycolide) 50:50 38,000 -54,000 0.45-0.60 46-50 Amorphous Ester
Poly(D,L-lactide-co-glycolide) 50:50 38,000-54,000 0.45-0.60 46-50 Amorphous Free carboxylic acid
Poly(D,L-lactide-co-glycolide) 50:50 54,000 -69,000 0.61-0.74 48-52 Amorphous Ester
Poly(D,L-lactide-co-glycolide) 65:35 24,000-38,000 0.32-0.44 46-50 Amorphous Free carboxylic acid
Poly(D,L-lactide-co-glycolide) 75:25 4,000-15,000 0.14-0.22 42-46 Amorphous Free carboxylic acid
Poly(D,L-lactide-co-glycolide) 75:25 76,000-116,000 0.71-1.0 49-55 Amorphous Ester terminated
Poly(D,L-lactide-co-glycolide) 85:15 190,000 -240,000 1.3-1.7 – Amorphous Alkyl ether
DIFFERENT PLGA SYSTEMS:
In the literature people have reported different systems of PLGA in different forms for drug delivery like PLGA micro-particles, PLGA microspheres, PLGA micelles, PLGA nanoparticles, PLGA stents, PLGA scaffolds, PLGA solid implants.
PLGA Microspheres:
PLGA microspheres are used for localised drug delivery at specific site of action, thereby reducing side effects and increasing the therapeutic response of the drug administered within this system. According to the molecular weight, the distribution of particle size of PLGA microspheres is from 0.1 to 150µm. So, these are micron size particles. The uptake of PLGA microspheres by the cells thus depends on phagocytosis mechanism as the size is larger. The PLGA is hydrophobic, but due to the carbonyl functional groups on the surface of the PLGA it shows a strong negative zeta potential of almost 70mV. The drug is dispersed within the core of the PLGA microsphere. The release of the drug depends on the degradation of the PLGA microspheres. The degradation could be by surface erosion of the microspheres and by bulk erosion. The chain breaks and microsphere loses its integrity eventually releasing the drug. When the PLGA microspheres are in the body, their uptake is by phagocytosis. These are then produced to the lysozyme pathway for degradation by different enzymes. If the PLGA microspheres are given alone, due to its hydrophobicity it is recognized as foreign by the body and immunological responses like release of cytokines could be observed. When we want the PLGA microspheres to circulate in the blood for longer time, we generally coat them with hydrophilic substances to avoid the body recognize them as foreign due to its hydrophobicity. Generally, PEG modified PLGA are used to improve the shelf life of the formulation and t-half in the body.
The PLGA microspheres mostly in literature are prepared by keeping the copolymer ratio to be 50:50 of the monomers PLA and PGA. So, here the molecular weight plays a significant role in the process of biodegradation of the PLGA copolymer.
PLGA Nanoparticles:
The PLGA nanoparticles are solid Nano sized spherical structures of approximately 200nm. The nanoparticles could be used for targeting action at a specific site. When surface coated with hydrophilic moieties, can circulate in the blood for longer period. They can thus be used for prolonged action for 1 to 6 months based on the copolymer ratio and the molecular weight of the PLGA used, in the body. Hydrophobic drugs, therapeutics could be administered by using the nanoparticle system. The PLGA nanoparticles are basically prepared by Emulsification solvent evaporation techniques. The polymer as is hydrophobic is dissolved in organic liquid and the drug (in case of drug loaded nanoparticles) in aqueous phase. They are mixed together to form a primary emulsion and eventually a secondary emulsion by addition of excess organic phase with agitation to achieve the desired size of the particles, is formed. The solvent is then evaporated from the double emulsion and the precipitation of PLGA nanoparticles is possible. There are different types of PLGA nanoparticles:
Non-targeted Nanoparticles:
The non-targeted PLGA nanoparticles could be a nano-sphere where the drug is dispersed within the core of the PLGA polymer. The nano-capsules are those where the drug is encapsulated within the PLGA polymer. Also, the PEG coated nanoparticles which are only used to increase the hydrophilicity of the PLGA nanoparticles act as the non-target specific moieties.
Targeted Nanoparticles:
These kind of systems are gaining a lot of interest of the researchers. Here, the nanoparticles are either coated/linked with the targeting ligands, antibodies which recognize the target site epitopes (glycoproteins/receptors) as the antigen and bind at these target sites or accumulate near these cells where we want to target the drug release to happen. The target ligands could be the ones which have specifically those ligands which bind to the target receptor which have got expressed on the surface of the target cells. This, kind of treatment works in case of the treatment of cancer. The cancer cells produce or express some particular receptors on its surface which can be targeted. The nanoparticles could be loaded with the cancer therapeutics, i.e. drugs for the treatment or use of biological content the DNA, siRNA, miRNA, and the aptamers which could interfere with the mechanism of growth of the cancer cells leading to apoptosis and cell death.
Theragnostics:
These are the type of targeted nanoparticles which include the diagnostic agents and the imaging agents, where we can note the drug release and the site at which the drug is released in the body. Also, therapy is simultaneously given at a specific site due to targeting nature of these particles.
The nanoparticles of PLGA could be used in the treatment of cancer as due to the nano-size, at the tumour site there are leaky vasculature present due to no proper formation of blood vessels. From the leaky vasculatures, the nanoparticles escape at reach the tumour site thus targeting the drug release at the site of cancer.
PLGA Micelles:

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