PLGA based drug delivery systems offer excellent biocompatibility with minimal tissue responses and biodegradability. Incorporation of inorganic nanomaterials in a core-shell structure can further enhance their utility by improving their targeting ability and enhancing drug release kinetics.
Various synthesis techniques can be used for PLGA MPs/NPs, and each method has its own advantages and disadvantages. Some of the more common methods include emulsification-solvent evaporation, spray-drying and double emulsion (W/O/W).
1. Water Solubility
In the context of drug delivery, PLGAs are advantageous as they allow for prolonged drug release by using the pH gradient of the body. During degradation, the polymer breaks down to its constituent monomers, which are endogenous to the body, and thus cause minimal toxicity. Moreover, the monomers can be easily metabolized in the body to form pyruvate which can then enter the Krebs cycle.
Moreover, the drug-releasing behavior of PLGAs can be controlled by functionalizing the surface of the polymer with drugs. This allows the encapsulation of drugs and peptides with specific properties and enhances the targeting ability of PLGA-based drug delivery systems by limiting their entrance into healthy cells. This enables chemotherapeutic drugs to be delivered in higher concentrations and extends their therapeutic window while minimizing unwanted side effects brought on by elevated toxicity of the cytotoxic agent.
The morphology of PLGAs can be modified by adjusting the processing parameters, which allows for the encapsulation of hydrophobic and hydrophilic drugs and the sustained and controlled release over weeks. Furthermore, PLGAs can be formulated into nanoparticles, microspheres, and millimeter-sized implants to encapsulate drugs or peptides over long periods of time. Various methods for the preparation of PLGAs have been developed including the emulsification-solvent evaporation method, the double or multiple emulsion technique, and the nanoprecipitation method.
Another important property of PLGAs is their ability to be crosslinked to form biodegradable scaffolds. This can be achieved by chemically crosslinking or by using photoinitiators that activate under UV light. Crosslinking can enhance the structural stability and modulus of a PLGA matrix, as well as modify its degradation kinetics. This can be controlled by varying the ratio of the two monomers used to make the copolymer. For instance, a 50:50 mixture of LA and GA has a faster degradation rate than a 75:25 mixture due to its greater hydrophilicity.
2. Biocompatibility
The biodegradability of PLGAs allows for controlled release of drugs over long periods, thereby extending their therapeutic window. Additionally, the degrading products of PLGAs are non-toxic and less reactive to cells, making them a valuable material for many medical applications.
Various methods are employed to fabricate PLGA-based hydrogels for the delivery of various therapeutic agents, such as drugs, peptides, and proteins. In general, PLGAs are fabricated using physical or chemical crosslinking to achieve a pliable matrix that can load and release hydrophobic molecules. These PLGAs can be fabricated with different water contents, different ratios of lactide to glycolide, and molecular weight to optimize drug loading capacity and pharmacokinetic profile.
A tunable drug release profile is also possible through the modification of the surface morphology of PLGAs and the incorporation of additives. The addition of surfactants can be used to alter the surface chemistry of the polymer and improve drug load efficiency. The selection of a suitable additive can also impact the degradation behavior and zero-order release rate of the PLGA hydrogel.
PLGA micro- and nanoparticles can be used to target specific cell types, as well as enable the encapsulation of other small molecules that cannot easily cross the plasma membrane. For example, PLGA-MPs encapsulating Fe3O4 have been shown to be phagocytosed by macrophages, as well as stimulate dendritic cell differentiation in vitro.
Furthermore, the tunable drug release characteristics of PLGA can be further augmented by using a non-toxic and soluble drug carrier such as a glucose molecule. This approach can be particularly useful in the delivery of a therapeutic agent for long-term treatment in diabetes.
3. Biodegradability
A key property of PLGAs is their biodegradability. This is mainly determined by the degradation products that they produce during their in-vivo breakdown and removal from the body (via cellular respiration). Typically, these byproducts include lactide and glycolic acid, carbon dioxide and water. This allows for a natural and slow degradation process within the body, making it suitable for long-term treatments and minimizing adverse reactions such as metabolic acidosis (i.e. excess acidity in the local microenvironment).
PLGAs can be made to degrade through bulk degradation or through the use of a specific isomer composition, which can help control the rate of degradation. For example, a 75:25 lactide-to-glycolic acid ratio can be used to create PLGA microspheres that undergo bulk degradation at a constant rate of about 5-10 nm/day. This allows for a consistent degradation rate, which is essential for many applications where a steady release of drug molecules is required (Kamaly et al., 2017).
Another way that a tunable degradation kinetics can be achieved is by the specific incorporation of inorganic nanomaterials into the PLGA matrices. This has been particularly useful in developing multifunctional PLGAs for theranostic, therapeutic and diagnostic applications. Several inorganic materials such as gold-, silver- and iron-based nanomaterials have been incorporated into PLGA matrices to improve a range of biological functions.
This has also been demonstrated with PLGA/inorganic nanoparticulate composites. For instance, Singh et al. [80] produced a PLGA MP/NP/scaffold nanocomposites that encapsulated cerium oxide NPs (nanoceria-CNPs). The inorganic particles were shown to reduce ROS production in vivo and counteract oxidative stress, while the PLGA provided a stable environment for cell attachment and proliferation. The resulting PLGA-nanoceria-SOD nanocomposites reduced oxidative damage to cells and tissues and were ideal for use in the treatment of a number of inflammatory diseases.
4. Tunable Drug Release
As a result of its ring-opening copolymerization, PLGAs have many inherent properties that can be modulated and tuned for specific applications. For instance, the polymer molecular weight and ratio of lactide to glycolide can be controlled to achieve desired drug concentrations in the resulting DDSs. Moreover, the degradation of the polymer matrix can also be controlled to alter the release rate and interval based on the intended application.
The physical properties of PLGAs can be further tuned by incorporating other materials and components into the polymer matrix, increasing the encapsulation capacity and enhancing the drug release mechanism. For example, combining the highly sensitive and responsive MR contrast agent MnO2 with a chemotherapeutic drug to produce a multimodal imaging and therapy platform for tumors has been demonstrated using PLGA-based INPs. This approach enables a highly sensitive MR signal due to the MnO2’s rapid surface degradation triggered by acidic environments, while at the same time, providing a therapeutic effect through the localized delivery of chemotherapeutic drugs via the PLGA-MnO2 interface.
Moreover, the incorporation of a mannosyl group into PLGA significantly enhances the uptake and release by phagocytes and increases the biodistribution within target tissues and organs. This approach is particularly useful for theranostic applications, as it allows the encapsulation of therapeutic molecules in the form of a microsphere and the delivery of other agents such as radiofrequency (RF) hyperthermia, MRI contrast, or optical pharmacology to improve specificity and accuracy.
Another way to optimize PLGA-based DDSs for long-term drug release is by coating them with hydrophilic polymers. For instance, the use of PEG or poloxamers greatly reduces opsonization and phagocytosis by endothelial cells, thereby enabling the stable circulation of PLGA NPs in the body.
5. Bioavailability
As a functional polymer, PLGA degrades into non-toxic and non-reactive products that are easily cleared from the body. It is also compatible with many drug substances and has been shown to be a superior delivery system for peptides, proteins, toxins and medicines (see Figure below).
Due to the good biocompatibility of PLGA, it can be used in combination with various types of drugs and other material to develop a range of different therapeutic applications. For example, encapsulating contrast agents in a PLGA matrix can enhance their magnetic properties to enable better imaging with MRI and CT. Incorporating nanoparticles into a PLGA matrix can improve the targeting ability of the particles and enhance their bioavailability.
Moreover, PLGAs can be block-polymerized with copolymers such as PEG to modify their physicochemical properties and drug-release characteristics. The resulting diblock and triblock copolymers are stable against degradation and offer a wide range of drug-encapsulation efficiencies.
Furthermore, PLGA can be modified to make it more hydrophobic or to add receptors to facilitate the encapsulation of hydrophilic substances. These alterations can increase the circulation time of a drug and/or help it target specific disease tissues.
For instance, Ye et al. developed a PLGA-based composite that encapsulates inorganic imaging materials such as manganese-doped zinc sulfide quantum dots and silver-tagged superparamagnetic iron oxide nanoparticles (SPION). The resulting PLGA-SPION-Mn:ZnS-QD-Busulfan (PLGA-SPION-Mn:ZnS-QD) nanocomposites are capable of producing T2 contrast in MRI due to the differences in longitudinal and transverse relaxation times of water molecules near the NPs. This is an important step towards the use of NPs in clinical diagnosis. Despite their advantages, however, more research is needed to evaluate the cytotoxicity of NPs and their impact on the physiological response at the cellular level.