PLGA

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Structure of poly(lactic-co-glycolic acid). x= number of units of lactic acid; y= number of units of glycolic acid. PLGA.svg
Structure of poly(lactic-co-glycolic acid). x= number of units of lactic acid; y= number of units of glycolic acid.

PLGA, PLG, or poly(lactic-co-glycolic acid) is a copolymer which is used in a host of Food and Drug Administration (FDA) approved therapeutic devices, owing to its biodegradability and biocompatibility. [1] PLGA is synthesized by means of ring-opening co-polymerization of two different monomers, the cyclic dimers (1,4-dioxane-2,5-diones) of glycolic acid and lactic acid. Polymers can be synthesized as either random or block copolymers thereby imparting additional polymer properties. Common catalysts used in the preparation of this polymer include tin(II) 2-ethylhexanoate, tin(II) alkoxides, or aluminum isopropoxide. During polymerization, successive monomeric units (of glycolic or lactic acid) are linked together in PLGA by ester linkages, thus yielding a linear, aliphatic polyester as a product. [2]

Contents

Copolymer

Depending on the ratio of lactide to glycolide used for the polymerization, different forms of PLGA can be obtained: these are usually identified in regard to the molar ratio of the monomers used (e.g. PLGA 75:25 identifies a copolymer whose composition is 75% lactic acid and 25% glycolic acid). The crystallinity of PLGAs will vary from fully amorphous to fully crystalline depending on block structure and molar ratio. PLGAs typically show a glass transition temperature in the range of 40-60 °C. PLGA can be dissolved by a wide range of solvents, depending on composition. Higher lactide polymers can be dissolved using chlorinated solvents whereas higher glycolide materials will require the use of fluorinated solvents such as HFIP.

PLGA degrades by hydrolysis of its ester linkages in the presence of water. It has been shown that the time required for degradation of PLGA is related to the monomers' ratio used in production: the higher the content of glycolide units, the lower the time required for degradation as compared to predominantly lactide materials. An exception to this rule is the copolymer with 50:50 monomers' ratio which exhibits the faster degradation (about two months). In addition, polymers that are end-capped with esters (as opposed to the free carboxylic acid) demonstrate longer degradation half-lives. [3] This flexibility in degradation has made it convenient for fabrication of many medical devices, such as, grafts, sutures, implants, prosthetic devices, surgical sealant films, micro and nanoparticles. [4]

PLGA undergoes hydrolysis in the body to produce the original monomers: lactic acid and glycolic acid. These two monomers under normal physiological conditions, are by-products of various metabolic pathways in the body. Lactic acid is metabolized in the tricarboxylic acid cycle and eliminated via carbon dioxide and water. Glycolic acid is metabolized in the same way, and also excreted through the kidney. [5] The body also can metabolize the two monomers, which in the case of glycolic acid produces small amounts of the toxic oxalic acid, though the amounts produced from typical applications are minuscule and there is minimal systemic toxicity associated with using PLGA for biomaterial applications. However, it has been reported that the acidic degradation of PLGA reduces the local pH low enough to create an autocatalytic environment. [6] It has been shown that the pH inside a microsphere can become as acidic as pH 1.5. [7]

Biocompatibility

Generally PLGA is considered to be quite biocompatible. Its high biocompatibility results from its composition due to lactic and glycolic acid fermentation from sugars, making them eco-friendly and less reactive in the body. [8] PLGA also degrades into non-toxic and non-reactive products that makes them quite useful for various medical and pharmaceutical applications.

The biocompatibility of PLGA has been tested both in vivo and in vitro. [9] The biocompatibility of this polymer is generally determined by the products that it degrades into, as well as the rate of degradation into degradation products. The way that PLGA degrades is by means of an enzyme known as esterase, which forms lactic acid and glycolic acid. These acids then undergo the Krebs Cycle to be degraded as carbon dioxide (CO2) and water (H2O). [10] These byproducts then get removed from the body through cellular respiration and through the digestive process.

While the byproducts usually do not accumulate in the body, there are instances where these byproducts (lactic and glycolic acid) can be dangerous to the body when accumulated in high local concentrations. [11] There can also be small pieces of the polymers as the polymer degrades, causing an immune response by macrophages. These adverse effects can be reduced by using lower concentrations of the polymer, so that it gets naturally released throughout the body.

Something else to consider regarding PLGA biocompatibility is the location at which the polymer is implanted or placed in the body. There are different immune responses that the body could have depending on where the polymer is placed. For example, in drug delivery systems (DDS), PLGA and PLA implants with high surface area and low volume of injection can increase one's chance of immune response as the polymers degrade in the body.

Biodegradability

The biodegradation of PLGA makes it useful for plenty of medical practices. PLGA undergoes bulk degradation, which is when a catalyst such as water inserts itself throughout the matrix of the polymer. [12] A 75:25 lactide to glycolide PLGA ratio can be made as microspheres that degrade via bulk erosion. [12] This allows degradation throughout the whole polymer to occur equally.

Another injectable form of PLGA was developed to have eroding systems. This form can be used in Lupron Depot. To achieve this, PLGA is mixed with an organic water-miscible solvent approved by the Food and Drug Administration (FDA). Once the PLGA is mixed into the solvent with the drug of choice to create a homogeneous solution or suspension. When this mixture is injected, the PLGA solidifies due to water insolubility and is replaced by the water. Slowly, the drug is delivered from the solution. A problem that may occur is during the initial injection, the drug may be released in a quick burst instead of gradually. [12]

Examples

Specific examples of PLGA's use include:

See also

Related Research Articles

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Polyglycolide or poly(glycolic acid) (PGA), also spelled as polyglycolic acid, is a biodegradable, thermoplastic polymer and the simplest linear, aliphatic polyester. It can be prepared starting from glycolic acid by means of polycondensation or ring-opening polymerization. PGA has been known since 1954 as a tough fiber-forming polymer. Owing to its hydrolytic instability, however, its use has initially been limited. Currently polyglycolide and its copolymers (poly(lactic-co-glycolic acid) with lactic acid, poly(glycolide-co-caprolactone) with ε-caprolactone and poly (glycolide-co-trimethylene carbonate) with trimethylene carbonate) are widely used as a material for the synthesis of absorbable sutures and are being evaluated in the biomedical field.

<span class="mw-page-title-main">Polycaprolactone</span> Chemical compound

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<span class="mw-page-title-main">Polylactic acid</span> Biodegradable polymer

Polylactic acid, also known as poly(lactic acid) or polylactide (PLA), is a thermoplastic polyester with backbone formula (C
3H
4O
2)
n or [–C(CH
3)HC(=O)O–]
n, formally obtained by condensation of lactic acid C(CH
3)(OH)HCOOH with loss of water. It can also be prepared by ring-opening polymerization of lactide [–C(CH
3)HC(=O)O–]
2, the cyclic dimer of the basic repeating unit.

<span class="mw-page-title-main">Organ printing</span> Printing method of creating artificial organs

Organ printing utilizes techniques similar to conventional 3D printing where a computer model is fed into a printer that lays down successive layers of plastics or wax until a 3D object is produced. In the case of organ printing, the material being used by the printer is a biocompatible plastic. The biocompatible plastic forms a scaffold that acts as the skeleton for the organ that is being printed. As the plastic is being laid down, it is also seeded with human cells from the patient's organ that is being printed for. After printing, the organ is transferred to an incubation chamber to give the cells time to grow. After a sufficient amount of time, the organ is implanted into the patient.

<span class="mw-page-title-main">Nanofiber</span>

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<span class="mw-page-title-main">Polydioxanone</span>

Polydioxanone or poly-p-dioxanone is a colorless, crystalline, biodegradable synthetic polymer.

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<span class="mw-page-title-main">Biodegradable polymer</span>

Biodegradable polymers are a special class of polymer that breaks down after its intended purpose by bacterial decomposition process to result in natural byproducts such as gases (CO2, N2), water, biomass, and inorganic salts. These polymers are found both naturally and synthetically made, and largely consist of ester, amide, and ether functional groups. Their properties and breakdown mechanism are determined by their exact structure. These polymers are often synthesized by condensation reactions, ring opening polymerization, and metal catalysts. There are vast examples and applications of biodegradable polymers.

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<span class="mw-page-title-main">Surface modification of biomaterials with proteins</span>

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Poly(ethylene adipate) Chemical compound

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Polyorthoesters are polymers with the general structure –[–R–O–C(R1, OR2)–O–R3–]n– whereas the residue R2 can also be part of a heterocyclic ring with the residue R. Polyorthoesters are formed by transesterification of orthoesters with diols or by polyaddition between a diol and a diketene acetal, such as 3,9-diethylidene-2,4,8,10-tetraoxaspiro[5.5]undecane.

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<span class="mw-page-title-main">Poly(trimethylene carbonate)</span> Polycarbonate

Poly(trimethylene carbonate) (PTMC) is an aliphatic polycarbonate synthesized from the 6-membered cyclic carbonate, trimethylene carbonate (1,3-propylene carbonate or 1,3-Dioxan-2-one). Trimethylene carbonate (TMC) is a colorless crystalline solid with melting point ranging between 45°C and 48 °C and boiling point at 255°C (at 760 mmHg). TMC is originally synthesized from 1,3-propanediol with phosgene or carbon monoxide, which are highly poisonous gases. Another route is from the transesterification of 1,3-propanediol and dialkylcarbonates. This route is considered "greener" compared to the other one, since precursors can be obtained from renewable resources and carbon dioxide.

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References

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  2. ↑ Astete CE, Sabliov CM (2006). "Synthesis and characterization of PLGA nanoparticles". Journal of Biomaterials Science. Polymer Edition. 17 (3): 247–289. doi:10.1163/156856206775997322. PMID   16689015. S2CID   7607080.
  3. ↑ Samadi N, Abbadessa A, Di Stefano A, van Nostrum CF, Vermonden T, Rahimian S, et al. (December 2013). "The effect of lauryl capping group on protein release and degradation of poly(D,L-lactic-co-glycolic acid) particles". Journal of Controlled Release. 172 (2): 436–443. doi:10.1016/j.jconrel.2013.05.034. PMID   23751568.
  4. ↑ Pavot V, Berthet M, Rességuier J, Legaz S, Handké N, Gilbert SC, et al. (December 2014). "Poly(lactic acid) and poly(lactic-co-glycolic acid) particles as versatile carrier platforms for vaccine delivery". Nanomedicine. 9 (17): 2703–2718. doi:10.2217/nnm.14.156. PMID   25529572.
  5. ↑ Crotts G, Park TG (2 July 1998). "Protein delivery from poly(lactic-co-glycolic acid) biodegradable microspheres: release kinetics and stability issues". Journal of Microencapsulation. 15 (6): 699–713. doi:10.3109/02652049809008253. PMID   9818948.
  6. ↑ Zolnik BS, Burgess DJ (October 2007). "Effect of acidic pH on PLGA microsphere degradation and release". Journal of Controlled Release. 122 (3): 338–344. doi:10.1016/j.jconrel.2007.05.034. PMID   17644208.
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  9. ↑ Mir M, Ahmed N, Rehman AU (November 2017). "Recent applications of PLGA based nanostructures in drug delivery". Colloids and Surfaces. B, Biointerfaces. 159: 217–231. doi:10.1016/j.colsurfb.2017.07.038. PMID   28797972.
  10. ↑ Machatschek R, Lendlein A (March 2020). "Fundamental insights in PLGA degradation from thin film studies". Journal of Controlled Release. 319: 276–284. doi: 10.1016/j.jconrel.2019.12.044 . PMID   31884098. S2CID   209511941.
  11. ↑ Ramot Y, Haim-Zada M, Domb AJ, Nyska A (December 2016). "Biocompatibility and safety of PLA and its copolymers". Advanced Drug Delivery Reviews. PLA biodegradable polymers. 107: 153–162. doi:10.1016/j.addr.2016.03.012. PMID   27058154.
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  16. ↑ Fletcher J (6 March 2023). Walton A (ed.). "Lupron (leuprolide acetate) for prostate cancer: What to expect". www.medicalnewstoday.com. Retrieved 2023-04-30.
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