Poly(caprolactone-co-L-lactide)

Poly(caprolactone-coL-lactide) or P(CLco-LLA) is a copolymer composed of two monomers, one being caprolactone (CL), a cyclic ester that gives the polymer flexibility and slow biodegradability, and one being L-lactide (LLA), which gives it stiffness and quick biodegradability. This created a copolymer P(CL-co-LLA) that has multiple applications depending on the split of the two monomers and thus is extremely adaptable to various drug delivery systems. Because the polymer could produce nanoparticles, microspheres and other carriers, it was useful in numerous therapeutic solutions for hydrophilic and hydrophobic drugs, proteins and genes. Biodegradability is another reason for the success of P(CL-co-LLA) as a drug delivery system. P(CL-co-LLA) as a copolymer metabolizes into harmless byproducts – lactic acid and caprolactone – that can be quickly metabolized and expelled from the body, so you never have to worry about long-term toxic effects. That makes P(CL-co-LLA) a perfect candidate for controlled-release drug delivery systems. The degradation rate of the polymer can be modified by altering the copolymer content so scientists can tailor the release rate of the encapsulated drug. There is more to the versatility of P(CL-co-LLA) than just biodegradability. Because the polymer self-assembles into all sorts of nanostructures, from micelles to nanoparticles to microspheres, it is very effective at encapsulating drugs. These self-assembling structures are ideal carriers for the transport of low-water soluble drugs. P(CL-co-LLA) nanoparticles, for example, allow us to encapsulate hydrophobic drugs and the hydrophilic domains in the polymer matrix enable aqueous-soluble drugs to be incorporated. P(CL-co-LLA) has also been shown to be promising in gene delivery where it can bind nucleic acids stable and shield them from degradation by enzymes. So it could be a platform for new drug and gene delivery systems.

Figure 1. Synthesis of poly(caprolactone-co-lactide) by ring opening polymerization. (V G R, et al.; 2022)

P(CLco-LLA) has many special advantages as a material for drug delivery. Its best attribute is the possibility of creating drug delivery systems with accurate control of the release profile. The caprolactone to lactide ratio in the polymer chain is directly related to the hydrophobicity, crystallinity, and degradation activity of the polymer. The more caprolactone a polymer contains, the more malleable and hydrophobic it will be; therefore the slower its degradation and the longer its drug life. However, the higher the amount of L-lactide, the more hydrophilic and rapid degrading polymer, which is useful for use cases where a fast release of drugs is required. Depending on the therapy, we can tune these parameters to deliver either immediate short-term delivery or sustained long-term delivery of P(CL-co-LLA). The control of the degradation rate of the polymer can be key to the administration of drugs. Specifically, P(CL-co-LLA) has been extensively employed in controlled-release drugs in which the release of the drug is coupled to degradation of the polymer matrix. This is a beautiful system because the drug is delivered in a controlled rate over a pre-defined time. In cancer treatment, for instance, P(CL-co-LLA) nanoparticles could be shaped to release chemotherapeutic drugs slowly and specifically to the tumor, allowing therapeutic drug concentrations to persist for a long time. This is not only for improved efficacy but for lowering systemic toxicity. And so, too, for protein drugs, the polymer's capability to shield the encapsulated protein from the degradation in the bloodstream and manage its release at the site of the attack is key to maintaining protein function and achieving the best therapeutic results. What's more, P(CL-co-LLA) is readily modifiable to act against particular tissues or cells, which also gives it even more precision medicine potential. The surface of the polymer particles can be customized with targeting ligands, antibodies or peptides that bind specifically to receptors or antigens on the surface of target cells (eg, cancer cells, cells in inflamed tissues). Such a personalized treatment makes it more likely to get the drug right to the target, especially relevant in disorders such as cancer, where the target's immune system is under great pressure to reduce exposure of healthy tissues to toxins. Further, targeting molecules in P(CL-co-LLA) delivery systems can be combined with a drug, imaging and targeting ligands-in-one nanoparticle for treatment and diagnostic applications that would revolutionize therapies as well as enhancing the efficacy of drugs and minimizing their side effects.

P(CL-co-LLA) has some notable advantages, but there are still issues to overcome for the clinical adoption of the drug. Among the most important considerations is the instability of the polymer degradation rate. The degradation speed is controlled by changing the monomer ratio, but temperature, pH and enzyme concentration in the biological milieu also affect the rate of polymer breakdown, and the precise kinetics of the drug's release profile cannot be predicted in vivo. Also, the breakdown products of P(CL-co-LLA) are not toxic but it's also not clear whether such byproducts will accumulated for a long time when we use large quantities of the polymer in medicine. As a result, further study of how P(CL-co-LLA) is biodegraded and what are the long-term consequences of its degradation products will be needed to improve its safety and effectiveness in the clinic. Another hurdle is the immunogenicity of P(CL-co-LLA), particularly in the repeated-dose long-term treatment. Although P(CL-co-LLA) is a widely accepted non-toxic, biocompatible polymer material, immune reactions to some of its polymer components have been reported, especially when polymer materials are applied in large quantities or for long periods of time. As a solution to this problem, scientists are now working on more bioresorbable versions of P(CL-co-LLA) that break down more accurately and don't provoke immunity. Even then, if the copolymers are produced with additional functional groups or contain natural biodegradable polymers, they could make the material more biocompatible. These additions might also boost the polymer's toxicity against cells or tissues to increase its therapeutic index. Future for P(CL-co-LLA) drug delivery is very bright. Nanotechnological advances in the nanocarrier space should make P(CL-co-LLA) more versatile and effective for drug delivery. For instance, the synthesis of stimuli-responsive P(CL-co-LLA) devices, that release drugs in response to ambient conditions (e.g., pH, temperature, or enzyme activity) is a work in progress. This kind of controlled release might allow for more targeted treatment protocols in which drugs only come into the system at the point of action after a specific stimulus, minimizing systemic effects and improving therapeutic efficacy. And if you pair P(CL-co-LLA) with high-definition imaging, perhaps "smart" delivery systems can track drug delivery and the fate of the drug within the body on an ever-changing basis.

Alternate Names:
PCL-co-LLA copolymer
PCL-L-lactide copolymer
Poly(ε-caprolactone-co-L-lactic acid)
Poly(caprolactone-co-L-lactic acid)
Poly(ε-caprolactone-co-L-lactide)
PCL-L-lactide blend
Caprolactone-lactide copolymer
PCL/LLA copolymer

References:
1. V G R, et al.; Assessing the 3D Printability of an Elastomeric Poly(caprolactone-co-lactide) Copolymer as a Potential Material for 3D Printing Tracheal Scaffolds. ACS Omega. 2022, 7(8):7002-7011.

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