PLGA is a copolymer composed of lactic acid and glycolic acid that is widely used in drug delivery applications. Its unique blockiness and end group characteristics allow for tunable degradation periods that vary from months to years.
Several factors have been found to affect protein release from encapsulated PLGA. However, the reason for differences in release kinetics remains unclear.
1. Hydrophobic Effect
The hydrophobic effect is responsible for a wide variety of biological processes that affect the organization of membranes; the distribution of drugs, metabolites, and other molecules; and the structure and function of proteins. It is also the driving force behind protein aggregation, a phenomenon that contributes to many neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. The hydrophobic effect is an extremely important concept that you should learn, because it will help you understand a broad range of biochemical phenomena.
Hydrophobic interactions are governed by the free energy of the water molecules and their interaction with hydrophobic ligands, which is driven by the entropy of mixing (Stokes–Fischer). If you can estimate the entropy of mixing, you can predict the strength of hydrophobic interactions. The entropy of mixing increases with temperature, and the strength of hydrophobic interactions decreases at higher temperatures.
When PLGA sustained and controlled release of therapeutic agents, the water molecules form a clathrate cage around them. The clathrate cage has a low energy of dissociation, which means that the water molecules have a large amount of cohesive energy. This energy is released as they break down the hydrogen bonds and interact with the surrounding PLGA molecule.
As the PLGA molecule breaks down, it releases drug into the water phase. Typically, the release rate is controlled by the concentration of the drug in the water phase and the polymer degradation mechanism. Other factors that control the release rate include the lipid composition of the PLGA, its molecular weight, and monomer composition, as well as its degree of crystallinity, porosity, and end-group functionalization (Washington et al., 2018).
Moreover, a number of methods have been developed to evaluate the release kinetics of drug from PLGA MPs. These methodologies can be used to compare the behavior of different formulations or pharmacokinetic models and identify the best one for the given application. The resulting data can be fitted with mathematical models such as zero order, first-order, Higuchi, Korsmeyer-Peppas Weibull, and Gompertz (Casalini et al., 2014).
Besides the physicochemical properties of PLGA, the type and amount of drugs loaded on a PLGA MP can be controlled by using different excipients such as porogen agents, osmotic agents, stabilizers, surfactants, and so on. For instance, Ni et al., have successfully combined the O/W emulsion technique with PVA as a novel extractable porogen agent to prepare large porous PLGA MPs for the targeted delivery of Cinaciguat for the treatment of pulmonary hypertension via inhalation. They found that the PVA-PLGA encapsulation process not only increases the pore size but also the amount of deposited drug. In addition, they showed that the presence of PVA enhances the permeability of PLGA MPs in human skin. Hence, they can be a valid delivery platform for HDT against tuberculosis (Tb). This pathology is one of the world’s most dangerous infectious diseases.
2. Hydrophilic Effect
PLGA is highly water-soluble and readily forms solutions with water in a wide range of solvents. Hence, it is an ideal drug carrier for encapsulating drugs with low water solubility. Additionally, PLGA is also biodegradable and can be used for prolonged delivery of drugs, peptides or proteins. Drug loading efficacy and release kinetics can be controlled by altering the size of PLGA particles, polymer molecular weight and co-polymer composition. Furthermore, a cationic excipient like the lipid 1,2-dioleoyl-3-trimethylammoniumpropane (DOTAP) can be added to PLGA MPs to enhance the solubility of proteins and peptides.
The hydrophobic effect is the tendency of different hydrophobic molecules or regions of a large macromolecule to cluster together in order to minimize their interaction with water molecules. This is because water molecules do not form hydrogen bonds with nonpolar surfaces. This interaction imposes an unfavorable free energy penalty on the molecules/regions, as the resulting structured water cage or clathrate hinders their movement.
In PLGA, the hydrophobic effect is enhanced by its copolymer composition. Specifically, the ratio of lactide to glycolide determines how much PLGA is resistant to degradation. This is because lactic acid is more hydrophobic than glycolic acid, thereby slowing down the degradation process.
One of the most common methods for preparing PLGA microspheres is by using single or double emulsion solvent evaporation techniques. These methods are fast, convenient and can yield high-quality spheres with uniform size. However, agglomeration and instability issues can occur during this step. A more reliable method for producing PLGA particles is through membrane emulsification and microfluidics systems. These systems allow for a more controlled working conditions, such as shear stress and osmotic pressure. This results in more stable and well-defined morphology, better dispersibility and faster encapsulation efficacy.
Regardless of the preparation method, the final morphology of PLGA MPs will depend on the conditions of emulsion formation and stabilization. To avoid unwanted reactions, it is important to use a good emulsifier with a low viscosity to ensure that the emulsion stays in suspension during evaporation. It is also important to choose a good solvent, such as tetrahydrofuran, tetramethylacetone, chloroform or acetone.
Once PLGA MPs have been prepared, they can be loaded with drugs and other materials. The stability of the encapsulated materials in PLGA MPs depends on a number of factors, including polymer molecular weight, co-polymer ratio and solubility. It is also important to add a steric stabilizer such as trehalose or cyclodextrin to the formulation to prevent agglomeration and aggregation during storage.
Moreover, the encapsulation efficiency of hydrophilic compounds in PLGA microspheres is influenced by the surface area of the PLGA particles. To achieve higher encapsulation efficiency, smaller PLGA particles should be used. The encapsulation efficiency can be further increased by using a double-emulsion technique, such as the water-in-oil/oil-in-water (W/O/W) emulsification method.
3. Electrostatic Effect
As an atom, a molecule has an electrical charge, which is either positive or negative. Depending on the number of electrons and protons, the charge is distributed over different parts of the particle, which determines its electrostatic force of interaction with other particles or molecules. This force is described by Coulomb’s law, which states that a charged molecule will attract other positively charged ions and negatively charged atoms. The size of the molecule and the distance between its parts can also influence this electrostatic effect. A smaller molecule will be attracted to more positively charged atoms, and a larger molecule will be attracted to more negatively charged atoms.
In drug-loaded PLGA MPs, the electrostatic force between the drug and PLGA depends on the number of protons in the polymer chain and its structure. In order to obtain a controlled release, it is important to control the number of protons in the polymer. This is done by modifying the polymer’s molecular weight and monomer composition.
Another factor that affects the electrostatic force between the drug and pPLGA is the surface properties of the polymer. Generally, a smooth surface has higher surface energy and lower frictional forces than a rough one. The surface energy and frictional forces can be reduced by using a surfactant or nanoparticle coating.
The electrostatic force between a ligand and the polymer is also dependent on the charge and size of the ligand. A large molecule has a greater electrostatic attraction with the pPLGA than a small ligand, because a bigger ligand is closer to the polymer than a smaller ligand. This is why it is essential to use a large ligand and the right pPLGA copolymer to obtain a controlled drug release.
In the process of preparing a PLGA based encapsulation system, it is necessary to take into account many parameters such as the production method (Busatto et al. 2018), the nature of the drug (Capan et al. 2003), the morphology of the PLGA particle (Wang et al. 2015), and the presence of different excipients including porogen agents, osmogens, stabilizers, and surfactants.
Among the most common techniques for preparing drug-loaded PLGA microparticles are the single and double emulsion techniques. However, the single emulsion technique suffers from low encapsulation efficiency for hydrophilic drugs such as proteins and nucleic acids. In this regard, double emulsion is the preferred preparation method. It allows for a better dispersion of the encapsulated biomolecules and the formation of pores in the PLGA matrix. This enables for a more rapid onset of the encapsulated drug release. Moreover, the pore formation mechanism can be modulated by varying the ionic strength and concentration of the ionic liquids used to form the emulsion (Koushik and Kompella 2004), the lipid composition of the emulsion (Tran et al. 2013), and the pH of the ionic liquid (Tran et al. 2015).