PLGA has become a platform for encapsulating drugs, proteins and DNA in order to enhance their theranostic and therapeutic potential. It is also a promising carrier for inorganic nanomaterials such as gold-, cerium-, carbon- and hydroxyapatite-based ones.

A common method to prepare NPs is the oil-in-water (O/W) double emulsion technique [2]. The polymer and cargo are first dissolved in an organic solvent, then emulsified in an aqueous solution. The organic solvent is then removed under reduced pressure.

Biocompatibility

PLGA is a polymer that can be used for drug delivery applications. Its water solubility and tunable release profile allows for controlled drug delivery. It is also biodegradable and produces nontoxic byproducts upon degradation. In addition to its physical properties, PLGA can be used in conjunction with other nanomaterials for targeted delivery. The interplay between PLGA NPs’ physicochemical characteristics, targeting strategies and treatment modalities resemble a Rubik’s cube (Figure 1).

Despite these advantages, NP formulations remain complex. Tight control of PLGA particle’s size, shape and surface modifications is important to achieve desired biocompatible and safe for internal use. The synthesis method also impacts the physicochemical and functional properties of the final product.

Double emulsions are a popular choice for NP synthesis, but they are often unstable due to the need of heat or vacuum for solvent removal. This process can also lead to leakage of the dissolved drugs into the external phase, resulting in lower drug encapsulation efficiency (EE%).

To overcome this limitation, a new generation of PLGA-based NPs has been developed. These particles are spherical and comprise of a PLGA core, surrounded by an organic or inorganic shell. This system offers the advantages of a W/O/W emulsion without the need for heat or vacuum, and it is easy to manipulate the spheres’ size and composition.

Another advantage of PLGA-based NPs is their excellent stability. This feature allows them to evade phagocytosis and stay in circulation longer than their non-PLGA counterparts, a critical factor for cellular uptake. The ability to manipulate the PLGA-shell interface is also beneficial for targeted drug release and theranosis applications.

For example, PLGA-encapsulated AuNPs have been shown to effectively deliver chemotherapeutic agents into tumor tissues. In a 4T1 tumor model, NPs coated with DOX exhibited reduced tumor growth in comparison to the control group. This was attributed to the combination of magnetic hyperthermia and enhanced drug release.

Another exemplary application involves PLGA-based NPs encapsulating metal NPs with antibacterial properties. PLGA-encapsulated Ag NPs were effective in inhibiting the growth of bacteria by inducing ROS in the bacterial cell membrane and by adhering to the proteins present in the cell wall. In addition, PLGA’s ability to degrade the Ag NPs and promote their dissolution facilitated this antibacterial activity.

Biodegradability

PLGA is one of the most widely used biodegradable polymers, mainly due to its good water solubility and the fact that it can be easily modified to host therapeutically effective drugs. PLGA is an aliphatic copolymer that is typically synthesized by the ring-opening copolymerization of lactic acid (LA) and glycolic acid (GA). Depending on its isomer composition and molecular weight, it can present different intrinsic properties, such as melting points and crystallinity. In general, PLGA degrades through the esterase enzyme in human body organs and is eliminated as lactic and glycolic acids via the Kreb’s cycle into water and carbon dioxide through respiration, feces and urine.

The kinetics of PLGA degradation varies according to the conditions in which it is tested. In general, acidic and basic environments accelerate its degradation compared to neutral or alkaline ones. This is because the incorporated acid and basic drugs secreted by macrophages in the phagolysosome accelerate PLGA degradation by catalyzing its carboxylic end groups.

Another factor that affects PLGA degradation is the ratio of its surface area to volume. Larger devices tend to degrade more quickly than small ones, as they have higher surface areas to volume ratios and more exposed drug surfaces. In addition, bulk degradation rather than pure surface degradation has been shown to be a more efficient way for PLGA to release its drug load.

PLGA is often combined with other biocompatible and nontoxic materials to make nano- or microparticulate systems that are suitable for various medical applications, including theranosis (MRI-guided delivery). These include inorganic nitrides such as zirconium dioxide and calcium phosphates. In addition to these, a variety of biomolecules such as antibodies, genes, peptides and proteins can be incorporated into the PLGA-based particles. These can be used to deliver therapeutics such as vaccines, drugs or genes with high specificity and effectiveness. Alternatively, the PLGA-based microparticles can be combined with magnetic nanoparticles to generate MRI contrast agents and other diagnostic imaging tools. Lastly, the synthesis method of the PLGA-based particles also has an impact on their biocompatibility and biodegradability. Specifically, the W/O/W emulsion method is the most commonly used method to prepare PLGA-based micro- and nanoparticulate systems for therapeutic application.

Toxicity

PLGA-based micro- and nanoparticles (MPs and NPs) have been used for different medical applications. Several studies have shown that they meet the biocompatibility requirements and cause only mild tissue responses. These systems are suitable for intravascular, intratracheal, and intracochlear implantations. They also show good pharmacokinetic properties and are compatible with other administration sites. However, further research is needed to optimize these systems.

The synthesis of PLGA is a complex process that requires large amounts of heat and vacuum to remove solvent. This is a disadvantage because it affects the drug encapsulation efficiency (EE%) and can lead to poor aggregation of drugs. In addition, the use of solvents can lead to oxidative damage. In addition, the synthesis of PLGA particles is time-consuming and expensive. Consequently, a new metabolic engineering approach is being investigated to synthesize PLGA without using any organic solvents. This method uses E. coli to catalyze the chemical reactions of D-lactic acid and glycolic acid, and then convert them into coenzyme A (CoA) intermediates. These intermediates are then copolymerized to form PLGA by polyhydroxyalkanoate synthase.

In recent years, researchers have developed a variety of PLA-based delivery systems for various clinical applications. These include PLGA-based drug delivery systems for anticancer drugs, cell adhesion and proliferation, angiogenesis, and osteogenesis. However, there are still many challenges in this area, such as adjusting the drug release kinetics and reducing the fluctuation of blood drug concentrations.

Another issue is that PLGA-based DDS can trigger immune responses, depending on the location of the injection or implantation. However, this can be overcome by modifying the surface of the polymer. In addition, introducing a magnetic element into the system can increase the stability and cellular uptake of PLGA-based NPs.

Furthermore, PLGA-based MPs have been shown to be a promising platform for the delivery of cancer therapy agents. Specifically, a core-shell PLGA@Au nanocomposite was used to deliver the chemotherapy agent doxorubicin (DTX) and demonstrated that it could be used for tumor-targeted chemophotothermal therapy and X-ray imaging. This system was able to reduce toxicity to normal cells and inhibit the formation of metastases. In addition, PLGA-based NPs were able to induce significant cytotoxicity in cancer cells by targeting the lysosome and disrupting cellular membranes.

Safety

PLGA is widely used in designing drug delivery systems due to its biocompatibility and favorable degradation characteristics. However, conventional synthesis methods often produce particles with wide size distribution and imprecise drug loading. This can negatively affect their drug release kinetics and ability to co-deliver drugs with different solubility properties. Fortunately, new fabrication techniques offer improved control over particle size, shape and drug load. Microfluidics technology, for example, has been shown to be capable of producing PLGA micro/nanospheres with a narrow size distribution, high drug loading efficiency and significantly less agglomeration.

Another significant advantage of PLGA-based DDS is their elasticity and mechanical strength. These factors allow for intravascular, intraparenchymal and intratracheal delivery to the target site. In addition, PLGA-based DDS are capable of being loaded with various inorganic nanomaterials to enhance their therapeutic effects and equip them with novel abilities (e.g., MRI contrast agents, magnetic resonance imaging dyes, superparamagnetic iron oxides) [81].

In order to design specific release profiles, PLGA can be modified with pH-responsive polymers. These compounds contain a b-amino ester linkage, which makes the polymer sensitive to alterations in pH. Hence, the particles will only release their payload upon reaching an optimum pH window in a particular organ, intracellular compartment or tumor microenvironment, for instance.

Similarly, the stability of PLGA-based nanoparticles can be tailored by adjusting their polymer composition and crystallinity. For instance, increasing the amount of glycolide monomer in the polymer backbone decreases its crystallinity and promotes amorphous regions. This can help to reduce the degradation time and improve the overall stability of PLGA-based nanoparticles (Mitchell and Hirt 2015).

In addition, the surface of PLGA-based particles can be functionalized with various ligands for targeting purposes. This can be accomplished by conjugating the ligands to the polymer using a PEG-linker. This allows the ligands to bind with the cytoplasmic domain of a target cell or tumor tissue and thus, allow the particles to be targeted to the desired location. Moreover, it is also possible to incorporate other polymers into the PLGA-based DDS to increase their therapeutic activity and to enhance their biocompatibility and biodegradability.