PLGA NANOPARTICLES

The PLGA copolymer is synthesized via random ring-opening copolymerization of the two monomers lactic acid and glycolic acid by ester linkages. Different ratios of glycolic acid to lactic acid can be found (identified with the molar ratio) the most common are 50:50 and 75:25 lactic acid to glycolic acid. This is a determining factor in the final properties of the nanoparticle. On one side, lactic acid has a methyl group which makes it more hydrophobic (thus, it degrades slowly) and stiff. On the other side, glycolic acid is more hydrophilic (degrades faster) and is more flexible. The amount of each will determine the hydrophobicity of the polymer, the rate of degradation (that could go from months to years) and its amorphous structure. The poly(d,l-lactic-co-glycolic acid) polymer can be terminated in a carboxyl group (not end capped) or in an alkyl ester which protects against quick degradation.

Polymeric nanoparticles can be classified in two categories according to their morphology: nanocapsules and nanospheres. Nanocapsules contain an oily or aqueous core surrounded by a polymeric layer. On the contrary, nanospheres, consist of a solid continuous polymeric matrix. In either case, the drug is can be dissolved in the core (nanocapsules) or the polymeric network (nanospheres), or it can be adsorbed onto the nanoparticle surface.

PLGA nanoparticles are synthesized by emulsion-solvent evaporation methods. This is, preparing a single oil-in-water (o/w) emulsion for hydrophobic substances or double water-in-oil-in-water (w/o/w) emulsion for hydrophilic compounds. The emulsification is done using stirring or homogenization, emulsifiers and controlling the temperature which forms the nanoparticles. After that, the solvent is removed via evaporation or extraction and the PLGA drug-containing nanoparticles harden and can be collected.

Gene therapy: Gene therapy is based on the delivery of genetic material to obtain a therapeutical benefit. However, the delivery of genetic information whether in the form of DNA, RNA or aptamers is not an easy task since they are easily susceptible to degradation and have low cell penetration when used in naked form. By encapsulating them in PLGA nanoparticles, many advantages can be obtained like less toxicity than viral vectors, high loading capacity and the protection from enzymatic degradation. PLGA nanoparticles functionalized encapsulating genetic material as siRNA have been used to treat hyperplasia, atherosclerosis, osteocarcinoma, inflammatory lung disease, to name a few. The DNA/RNA can encode many different therapeutic proteins like TNF-α, p53, transferrin or glycoproteins.

Vaccines: Polymeric nanoparticle-based vaccines for in vivo applications have been developed to carry a wide variety of antigens that will be presented to APCs, mainly dentritic cells. While PLGA microspheres have been object of study for a long time, nanoparticles offer the advantage of navigating more freely through organs and physical barriers due their reduced size. This has proved to be an important factor in the outcome of the therapy since just by modifying the diameter, IFN-γ or IL-4 were produced in response.

All these features together with the biocompatibility and biodegradability of the PLGA, have made possible the use with hepatitis B surface antigen, malaria antigen, yersinia pestis antigen, and HIV. PLGA encapsulating bacteria enzymes have also been used against dental caries through intranasal administration. It has also been used for different administration routes like oral, pulmonary, and subcutaneous. Oral administration is made possible thanks to the high nanoparticle take up from M-cells in the intestine epithelium in just a few hours.

Biosensors: PLGA nanospheres have been used in the development and improvement of hemocompatible biosensors that allow the analysis of whole blood with electrochemical techniques. This is relevant to improve diagnostic methods and control the progress of the therapies.

Cancer therapy: PLGA nanospheres have already been successfully used in vitro and in clinical trials. Results show that drugs encapsulated in PLGA nanoparticles have superior accumulation in the tumor environment, reduced tumor size and enhanced inhibition of cell proliferation. This is thanks to increased cell penetration and reduced toxicity of encapsulated compounds. Because of the higher accumulation in tumoral areas PLGA nanoparticles are also useful for cancer diagnosis and imaging which has a key role in clinical oncology to early detection and accurate prognosis. The greater therapeutic index of encapsulated paclitaxel, cisplatin and mitoxantrone among other chemotherapy drugs over their equivalent clinical counterparts has been proved multiple times.

Diabetes treatment: The use of PLGA nanoparticles have been shown to improve the sustained release of insulin. The reduction in the insulin total dose and the release rate is of great interest since it decreases the secondary effects of insulin burst and improves the evolution of the disease. Additionally, studies on the oral administration of insulin have been done with PLGA nanoparticles to replace the typical insulin injections. On the prevention side, the use of PLGA nanoparticles carrying therapeutic genes like IL-10 have been used to reverse the onset of the disease promoting immune tolerance.

Tissue engineering: The delivery of growth factors in PLGA nanocarriers is of great interest to promote the thrive of engineered tissues. It facilitates the interactions between the scaffold and the vascular cells as well as induction of cell proliferation and differentiation. They have been used to load growth factors like TGF-β (BMP-2) and VEGF. PLGA encapsulating IL-2/TFG-β microspheres have also proved effective for the differentiation of T cells into regulatory T cells. Some studies have also shown that even without growth factor encapsulation, specific functionalizations of PLGA nanoparticles ultimately lead to the induction of cells to produce the growth factors themselves.

Ocular drug delivery: PLGA nanoparticles are very well suited for ocular drug delivery since they are able to protect the drug from rapid degradation and provide sustained release. They have been used for the treatment of inflammatory diseases like ocular edema and uveitis by encapsulating anti-inflammatory drugs like pranoprofen and fluocinolone via topical installation targeting the cornea. Other studies show that transport to the retina can be directed with PLGA nanospheres. In the case of pranoprofen PLGA nanoparticles, they showed four times more corneal permeation and higher retention time than its free form. Regardless, chitosan coating of PLGA nanoparticles is normally used for ocular delivery applications to enhance the mucoadhesive properties of these carriers.

Brain drug delivery: Crossing the blood brain barrier remains the main challenge to the treatment central nervous system diseases including Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, schizophrenia, and brain tumors. Modified PLGA nanoparticles have been proved to be a successful approach for the brain drug delivery of multiple drugs in in vitro and in vivo studies. To name some: curcumin, estradiol, doxorubicin, loperamide, docetaxel or coumarin-6. Adding a coating and specific ligand is an essential strategy to target the brain tissue which ensures the safety of PLGA nanoparticles for applications other than this one. Using PLGA nanoparticles increases the cell uptake, the therapeutic efficiency and decreased the cell viability in the case of glioma cells.

Find below some examples of drugs that have been encapsulated in PLGA nanoparticles with their specific applications.