BioCoStent

Chemistry

Retinoic acid

Retinoic acid (RA) is a derivative of retinol (vitamin A). It is a natural component of the human body but is also used as an active medicinal ingredient.

RA is a retinoid (or retinoid). Retinoids are a class of natural and synthetic substances with a chemical structure similar to that of retinol (vitamin A). They are absorbed from the human diet either from plants in the form of provitamins A, such as β-carotene, or from animal foods mainly as preformed retinol or retinol esters.

The skeleton of natural retinoids consists of a six-carbon non-aromatic ring with an 11-carbon polyisoprenoid side chain that terminates in a functional group (Figure 1). The characteristic group in the chain in the case of retinol is hydroxyl (-OH), in retinal carbonyl (-CH=O) and in retinoic acid carboxyl (-COOH).

Figure 1: Chemical structure and metabolism of some biologically important retinoids. β-Carotene (i) is enzymatically cleaved into two molecules of all-trans-retinal (v). Retinal can be oxidized to retinoic acid (iii) or reduced to retinol (v) (vitamin A). Retinol, as an alcohol, can form esters (vi) with various carboxylic acids. Source: Kiser PD et al, 2014 [1].

Figure 2: Chemical structure of the major isomers of retinoic acid. Source: Tsuji M et al (2015) [2]

Retinol is a primary alcohol which in cells can be oxidized to an aldehyde or an acid in two steps. In the first step retinol is oxidized to retinal, a component that plays a role in the vision process. In a second step, retinal is oxidized to retinoic acid.

The existence of the five conjugated double bonds in the retinoid molecule allows for the existence of geometric isomers and in particular one all-trans-isomer and four cis-isomers. Both retinol and retinal and retinoic acid can exist as geometric isomers. In nature and in the human body, the all trans isomers dominate quantitatively, but there are special biological roles for the cis isomers as well. The most important retinoids of biological interest are 1-cis retinal, and all-trans, 9-cis and 13-cis retinoic acids.

Retinoic acid is the active form of vitamin A that acts through specific nuclear receptors (RAR and RXR) to influence gene expression [3]. Retinoids contribute to the homeostasis of cell differentiation and proliferation and are successfully used to treat diseases associated with cell proliferation such as acne as well as in the treatment of acute myeloid leukemia [4,5]. [4,5].

Retinoic acid affects gene expression through specific cellular receptors. Retinoid receptors are divided into two main families, the Retinoic Acid Receptors (RAR) and the Retinoic X Receptors (RXR). Each family includes three subtypes (alpha, beta, gamma) and their activation depends on ligands. The normal ligand for RARs is all-trans retinoic acid, while for RXRs 9-cis retinoic acid, although the latter has the ability to bind to RAs as well [6]

Retinoids have been found to inhibit cell proliferation and induce differentiation in various cell systems while research has shown promising results regarding their use in the treatment of various diseases, such as malignant neoplasms [7]

REFERENCES

[1] Kiser, PD, Golczak, M., & Palczewski, K. (2014). of the retinoid (visual) cycle. Chemical reviews, 114(1), 194–232. https://doi.org/10.1021/cr400107q

[2] Tsuji, M., Shudo, K., & Kagechika, H. (2015). Docking simulations suggest that all-trans retinoic acid could bind to retinoid X receptors. Journal of computer-aided molecular design, 29(10), 975–988. https://doi.org/10.1007/s10822-015-9869-9

[3] D. R. Soprano, P. Qin, and K. J. Soprano, “Retinoic acid receptors and cancers,” Annu. Rev. Nutr., vol. 24, pp. 201–221, 2004.

[4] R. Wyss, “Chromatographic and electrophoretic analysis of biomedically important retinoids,” J. Chromatogr. B Biomed. Sci. Appl., vol. 671, no. 1–2, pp. 381–425, 1995.

[5] M. Marchetti, A. Vignoli, M. R. Bani, D. Balducci, T. Barbui, and A. Falanga, “All-trans retinoic acid modulates microvascular endothelial cell hemostatic properties,” Haematologica, vol. 88, no. 8, pp. 895–905, 2003.

[6] J. Marill, N. Idres, C. Capron, E. Nguyen, and G. Chabot, “Retinoic Acid Metabolism and Mechanism of Action: A Review,” Curr. Drug Metab., vol. 4, no. 1, pp. 1–10, 2005.

[7] Siddikuzzaman, C. Guruvayoorappan, and V. M. Berlin Grace, “All trans retinoic acid and cancer,” Immunopharmacol. Immunotoxicol., vol. 33, no. 2, pp. 241–249, 2011.

 

 

 

 

Biodegradable polymers

Coronary Arterial Disease (CAD) is characterized by narrowing or even blockage of the arteries of the heart due to atherosclerosis, the deterioration of the inside of the vessels with the deposition of cholesterol and other lipids and the concentration of cells of the immune system there. Drug Eluting Stents (DES) are a leading treatment option for coronary artery disease. Stents are implanted with the help of an air chamber at the point where the artery has damage (narrowing or blockage) to maintain the patency of the artery. Other treatment options for arterial disease are the use of intravascular balloons (balloons) with or without medication, arterial bypass surgery, and pharmacotherapy.

A drug-eluting stent consists of a (usually) metal mesh on which a drug that inhibits cell proliferation is placed. A polymer or polymer system is usually used for the retention and controlled release of the drug. The role of the polymer is to ensure that the drug remains on the surface of the stent during implantation and to release the drug with a specific pharmacokinetic, specific rate. First-generation DES and many of those available today have stable, non-biodegradable polymers that, after releasing the drug, remain with the implant in the patient’s vasculature. The existence of these non-biodegradable polymers has been linked to the possibility of complications such as late stenosis or thrombosis months or years after surgery. The new generations of DES use biodegradable polymers, which after the release of the drug, are broken down and absorbed by the body without leaving residues that can potentially create complications such as delayed stenosis.

The main biodegradable polymers are polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PC), while other related polymers are emerging for use in medical technology products. Copolymers of the above, such as polylactic-co-glycolic acid (PLGA), in which the two monomers (lactic and glycolic acid) can be found in various proportions, are also in use.

Lactic acid, chemical name 2-hydroxy-propanoic acid, is a hydroxy acid that exists in two stereochemical configurations (forms), L- and D-. These stereoisomeric forms (L-lactate and D-lactate) have a relationship of object and mirror image. The ester bond dimerization of lactic acid gives a cyclic di-ester, lactide. The polymer of lactic acid is called polylactic acid (PLA) or polylactide. Polymerization of L-lactic acid gives poly-L-lactic acid (poly-L-lactic acid, PLLA), of D-lactic acid poly-D-lactic acid (PDLA). Polymerization of a mixture of L- and D-lactic acids gives poly-DL-lactic acid (PDLLA).

Copolymerization of lactic and glycolic acid gives polylactic polyglycolic copolymer (PLGA).

Glycolic acid (glycolic acid), chemical name hydroxy-ethanoic acid or hydroxy-acetic acid is also a hydroxy acid.

The polymerization of hydroxy acids takes place through ester bonds with the final formation of polylactones. The difference of these polylactones from polymers with carbon-carbon bonds is that the ester bonds can be hydrolyzed at various pH by cellular enzymes to their non-toxic monomers. This property makes these polymers biodegradable and even bioabsorbable, as their monomers can be absorbed and further metabolized by the body. For example, lactic acid through catabolic processes can eventually be broken down into carbon dioxide and water.

Figure 1: Synthesis of polylactic acid. Source: Middleton et al, 2000

 

Figure 2: Synthesis of polyglycolic acid. Source: Middleton et al, 2000

 

The current trend in DESs, supported by preclinical and clinical data, is the use of biodegradable polymers.

In the BioCoStent project, different biodegradable polymers are evaluated to select the polymer system with the best biocompatibility and pharmacokinetic properties for the creation of retinoic acid-eluting stents.

 

REFERENCES

Rebagay, G., Bangalore, S. Biodegradable Polymers and Stents: the Next Generation?. Curr Cardiovasc Risk Rep 13, 22 (2019). https://doi.org/10.1007/s12170-019-0617-x

Middleton, J. C., & Tipton, A. J. (2000). Synthetic biodegradable polymers as orthopedic devices. Biomaterials, 21(23), 2335–2346. https://doi.org/10.1016/s0142-9612(00)00101-0