Entrevista al Abogado Miguel Morachimo

Although polymer matrices make for good delivery vehicles for drugs, the commonly used polymers are hydrophobic and best accommodate hydrophobic drug molecules. However, this eliminates the use of a range of hydrophilic drugs of therapeutic benefit. In particular, proteins are a large class of therapeutics which are typically water-soluble and sensitive agents that can be challenging to deliver effectively.

The biological activity of a protein can be difficult to maintain until reaching its target. Oral delivery of proteins is limited by the gastric system and thus multiple injections or intravenous infusions become the delivery methods of choice [93]. Local drug delivery of protein therapeutics would overcome the difficulties of patient compliance and also help to retain the protein activity, increasing its efficacy.

Early-time Approximation Late-time

Incorporating a protein drug into a polymer matrix can protect the protein from

proteolysis and antibody neutralization in vivo in addition to providing a controlled

release vehicle [94]. Design of a controlled release system for a protein drug should take into consideration properties of the protein including molecular size, biological half-life, immunogenicity, conformational stability, dose requirement, site and rate of administration, pharmocokinetics, and pharmacodynamics [93, 95].

It can be a challenge to incorporate proteins into a polymer matrix. Complications that may be encountered during manufacturing include protein denaturing by chemicals used, leaching out of the protein in aqueous solutions while removing porogens from the polymer matrix, and loss of protein activity when chemically tethering to the polymer backbone [96]. To avoid these problems, hydrogels with high water content are viewed as protein friendly delivery materials. Water-soluble proteins can easily diffuse through a hydrogel matrix with only its size as a restriction [96]. Swollen hydrogels offer more effective area for diffusion of larger macromolecular drugs [93]. The downfall of using hydrogels for controlled release applications is that the release rate is often rapid, but there are tactics to alleviate this. For instance, the crosslinking density can be increased to decrease the diffusion of the protein [96].

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Polymers are thus far the material of choice for DES coatings. The coating of a DES has several roles including being a surface that is friendly in the blood-contacting cardiovascular environment as well as being able to control the release of the drug it contains. These devices are implanted in direct contact with the bloodstream, therefore they must not only be biocompatible, but also preferably be hemocompatible. Hemocompatibility means that the material properties will not change blood functions, transform blood components or form thromboses [97]. The interaction between blood and a foreign material can initiate protein adsorption, platelet adhesion and activation, leukocyte adhesion and activation, and the activation of the complement and coagulation

pathways [98]. However, in general all synthetic polymers are blood incompatible, thus the challenge becomes to use materials and techniques to increase their blood compatibility. To aid in hemocompatibility, materials with a surface that is non- thrombogenic are crucial. The surface properties of a material greatly influence its thrombogenicity. These include surface energy, wettability, texture, and charge [53, 99]. Hydrophobic surfaces tend to absorb more plasma proteins than uncharged hydrophilic surfaces. And, smooth surfaces are less likely to adsorb protein while rough surfaces can be strong activators of blood platelets.

Several approaches have been undertaken to modify a material’s surface to enhance its hemocompatibility. Three approaches to this are surface passivation to minimize blood-material interaction, immobilization of bioactive molecules on the surface, and promotion of endothelialization [100]. Passive coatings can be biologically inert materials that act as a barrier between stent and the bloodstream, including gold, carbon, and silicon carbide [19, 53]. Heparin, an anti-coagulant, is a frequently employed molecule that can be immobilized on the surface by endpoint attachment for improved hemocompatibility [54]. Additionally, the promotion of endothelialization of a surface has gained some attention in recent years as a method to create a hemocompatible surface that mimics nature. This can be achieved by two different approaches. The first approach is to seed a materials surface with ECs with the help of cell adhesion proteins or peptide sequences, allowing a confluent layer to cover the surface before implantation. The second approach is to either immobilize a molecule to the surface or release

molecules that attract ECs from the bloodstream in vivo. This includes antibodies that

capture endothelial precursor cells to encourage endothelialization [51].

In addition to surface properties, some other important criteria exist for the materials used to coat stents. This encompasses the stent and coating stability after placement, the solubility compatibility between polymer, solvent and drug during coating process, the coating stability, expandability and integrity during stent deployment, and the materials must be sterilizable [101, 102].

Another major design criterion for the DES coating material is its ability to provide controlled drug delivery. These devices contain an active ingredient to help reduce restenosis. Therefore, the polymer coating must allow the drug to be delivered in a timely method, ensuring consistent dosing and release kinetics that are controlled and predictable [102]. Later sections of this thesis will discuss controlled release factors in further detail.

The first DESs are coated with hydrophobic elastomers. However, Medtronic’s Endeavor stent takes a new approach using phosphorylcholine (PC) as a coating material and Abbott’s Xience V stent uses a fluorinated copolymer. Biodegradable coatings and materials for fully degradable stents are currently being researched intensely.