Poly (D, L-lactide-co-glycolide) (PLGA) is a widely used biodegradable copolymer that is widely used in drug delivery applications because it is biocompatible, biodegradable and granularly tunable in degradation rates. Systems based on PLGA have been widely studied for controlled, sustained and selective drug delivery, such as in cancer therapy, tissue engineering or vaccine delivery. There is also a new molecule of PLGA — HOOC-PLGA-COOH — that adds carboxyl groups on either end of the polymer chain. This change increases the reactivity and efficiency of the polymer and opens new possibilities for more efficient and functional drug delivery. These free carboxyl groups do not only make the polymer more responsive to a broader set of therapeutic molecules, but also provide better control over drug release, which makes the polymer more therapeutically efficacious with fewer side effects. HOOC-PLGA-COOH is different from standard PLGA, it contains carboxyl groups at the polymer's two ends. Such free carboxyls also give the polymer more hydrophilicity and can change the way the polymer interacts with the capsulated drug and the living world. One of the biggest strengths of this structure is that it can bind in covalent mode to a variety of biologically useful molecules. Targeting ligands, peptides, proteins and so on can be covalently linked to these carboxyl groups, for instance, to improve their targeting to specific tissues or cells. This functionalization capability can be especially helpful in drug delivery applications where a targeted approach is required (e.g., cancer therapies in which the drug has to be delivered to the tumours so that it has less overall side-effects). Moreover, due to the greater hydrophilicity of HOOC-PLGA-COOH, drugs remain stable and solubilized in the nanoparticles with better encapsulation and release profiles of drugs.
Figure 1. Conjugation reaction of PLGA-COOH with sulfadiazine carbodiimide and N-hydroxysuccinimide. (Guimarães PP, et al. 2015)
As well as helping in drug loading and targeting, the carboxyl groups on HOOC-PLGA-COOH gives a huge amount of control on the drug release rate. PLGA degradation rate is known to depend on hydrophilicity of the polymer and thus the hydrolysis rate of the ester bonds in the polymer chain. HOOC-PLGA-COOH's carboxyl groups at the end can be used to make hydrolysis more rapid at the target location. Such fast degradation can be very advantageous for purposes like cancer therapy where a fast clearance of the drug is typically needed for the kill of the tumour. Alternately, by modifying the number of carboxyl groups or the molecular weight of the polymer, the release profile can be tuned to give long-term release (beneficial for treatments that involve extended drug release, like hormone therapy or vaccination). Because of the variability in the degradation rate, HOOC-PLGA-COOH can be adapted to larger range of therapeutics. Also, by adding free carboxyl groups to the PLGA sequence it becomes more feasible to develop combination therapy. For example, in the treatment of cancer, HOOC-PLGA-COOH nanoparticles can be used to deliver chemotherapeutics and biologics, such as nucleic acids or proteins, together for improved therapy. Carboxyl groups give us the ability to fuse multiple therapeutics together in one delivery system that can be tuned to release those therapeutics in a controlled way. This combination of drug delivery – drugs that have distinct release profiles – can increase efficacy, while decreasing the chance of drug resistance, which is a major problem with cancer treatment. It is a property that can be applied to other fields of therapeutics, like gene therapy, in which the application of nucleic acids and proteins both needs careful planning to bring about the therapeutic effect. Biocompatibility and biodegradability of HOOC-PLGA-COOH also lend it an advantage as a delivery agent. As the polymer breaks down, it disintegrates into lactic acid and glycolic acid, both of which are natural byproducts safely flushed from the body. This attribute limits the risk of chronic toxicity of non-biodegradable materials, and HOOC-PLGA-COOH is therefore safe to use in clinical conditions. Also, with biodegradable carriers such as HOOC-PLGA-COOH the drug is delivered over time without having to re-dosage which makes the patient more responsive. The polymer's established safety profile and versatility to be tailored to various drugs and therapeutic uses make HOOC-PLGA-COOH the most promising candidate for the next generation of drug delivery devices.
The HOOC-PLGA-COOH is well suited for the delivery of poorly soluble or hydrophobic drugs as recent studies indicate. Because the polymer allows for more soluble and stable drugs of this kind in nanoparticles. In addition, drug bioavailability (one of the key aspects of drug effectiveness ) is enhanced. This makes HOOC-PLGA-COOH a candidate for the delivery of drugs that would otherwise be confined to the bench because they were poorly solubilised or stable. Additionally, functionalisation of HOOC-PLGA-COOH nanoparticles with targeted ligands (antibodies, peptides, or aptamers) has proven effective for targeting specificity and off-target effect reduction as well as therapeutic improvements in preclinical models. With the ability to tailor the size, surface charge and amount of drug these nanoparticles can carry, scientists can tailor the pharmacokinetics and biodistribution essential for drug delivery to maximise its performance. HOOC-PLGA-COOH is also catching on for vaccine delivery. Nanoparticles could enable both antigens and adjuvants to be more stable and efficient in a vaccine environment that is vulnerable to cold chain storage and transport. Moreover, regulated dispersal of vaccine molecules from the HOOC-PLGA-COOH nanoparticles might extend the immune response to maximise vaccine effectiveness. that's hugely important to improving both infectious disease vaccines and cancer immunotherapies. The broad therapeutic application range of HOOC-PLGA-COOH and its versatility to be designed for a variety of therapies make it a very attractive candidate for the future of vaccine delivery systems.
Alternate Names:
Poly(D,L-lactide-co-glycolide) Di-COOH
PLGA Dicarboxylic Acid
PLGA Dicarboxyl-terminated
Dicarboxylate PLGA
PLGA with Two Carboxyl End Groups
PLGA Double Carboxyl
References:
1. Guimarães PP, et al. Development of sulfadiazine-decorated PLGA nanoparticles loaded with 5-fluorouracil and cell viability. Molecules. 2015, 20(1):879-99.
Biodegradable PLGA based nanoparticles for sustained regional lymphatic drug delivery
J Pharm Sci.
Authors: Rao DA, Forrest ML, Alani AW, Kwon GS, Robinson JR.
Abstract
The purpose of this work is to evaluate biodegradable drug carriers with defined size, hydrophobicity, and surface charge density for preferential lymphatic uptake and retention for sustained regional drug delivery. PLGA-PMA:PLA-PEG (PP) nanoparticles of defined size and relative hydrophobicity were prepared by nanoprecipitation method. These were compared with PS particles of similar sizes and higher hydrophobicity. PLGA-PMA:PLGA-COOH (PC) particles at 80:20, 50:50, and 20:80 ratios were prepared by nanoprecipitation for the charge study. Particle size and zeta potential were characterized by dynamic light scattering and laser doppler anemometry, respectively. Particles were administered in vivo to rats subcutaneously. Systemic and lymph node uptake was evaluated by marker recovery. Lymphatic uptake and node retention of PP nanoparticles was shown to be inversely related to size. Lymphatic uptake and node retention of PP particles, as compared to PS particles, was shown to be inversely related to hydrophobicity. Lastly, lymphatic uptake and node retention of PC nanoparticles were directly related to the anionic charge on the particles. In vivo lymphatic uptake and retention in a rat model indicates that the 50 nm PP particles are ideal for sustained regional delivery into the lymphatics for prevention/treatment of oligometastases.
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