Polymers derived from the amino acid l-tyrosine: polycarbonates, polyarylates and copolymers with poly(ethylene glycol)

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Abstract

The natural amino acid l-tyrosine is a major nutrient having a phenolic hydroxyl group. This feature makes it possible to use derivatives of tyrosine dipeptide as a motif to generate diphenolic monomers, which are important building blocks for the design of biodegradable polymers. Particularly useful monomers are desaminotyrosyl-tyrosine alkyl esters (abbreviated as DTR, where R stands for the specific alkyl ester used). Using this approach, a wide variety of polymers have been synthesized. Here, tyrosine-derived polycarbonates, polyarylates, and polyethers are reviewed with special emphasis on recent developments relating to cellular and in vivo responses, sterilization techniques, surface characterization, drug delivery, and processing and fabrication techniques. The commercial development of tyrosine-derived polycarbonates is most advanced, with one polymer, poly(DTE carbonate) (E=ethyl), being under review by the USA Federal Drug Administration.

Section snippets

An historic overview of amino-acid-derived polymers

Over the last 25 years, significant efforts have been devoted to the development of polymeric biomaterials. Historically, the vast majority of these efforts were focused on identifying ‘off the shelf’ polymers that were biologically inert and stable under physiological conditions. These materials were used as permanent prosthesis such as bone and joint replacements, dental devices and cosmetic implants. However, the emerging field of tissue engineering and the need for advanced drug and gene

Design and synthesis of tyrosine-derived diphenolic monomers

Diphenols, such as Bisphenol A, are frequently used in industry, since their aromatic backbone structures can significantly increase the stiffness and mechanical strength of polymers. However, Bisphenol A and other industrially used diphenols are cytotoxic and can therefore not be used as monomers in degradable biomaterials. There was a significant need for a non-cytotoxic, diphenolic monomer that could be used as a building block in the design of degradable implant materials. This need was

Properties of tyrosine-derived polymers

The basic design, synthesis, and material properties of tyrosine-derived polycarbonates and polyarylates have been reviewed in detail [13], [47], [48], [49]. These properties are therefore reviewed here only very briefly.

Cellular and in vivo response

The cellular responses to polycarbonates and polyarylates indicate no sign of cytotoxicity. The ability of cells to attach and proliferate on these polymer surfaces was strongly correlated with the hydrophobicity of the polymers [45], [61], [80]. Tyrosine-containing poly(DTR–PEG carbonate)s are also non-cytotoxic. However, the presence of PEG leads to low or no cell attachment in short-term cell culture [76]. It is reasonable to assume that poly(DTR–PEG ether)s are also non-cytotoxic, but, at

Sterilization

To further evaluate tyrosine-derived polycarbonates for clinical use, the ability of selected polycarbonates and PLLA to maintain their properties after ethylene oxide or γ-irradiation sterilization was determined by Hooper et al. [87]. Ethylene oxide was found to induce less structural damage to the polymers than γ-irradiation based on measurements of molecular weight, surface composition, mechanical properties, and in vitro degradation rate. Ethylene oxide was determined to be a feasible

Surface characterization

The surface properties of polymeric biomaterials are of interest because they play a significant role in the cell, blood, and tissue responses observed both in vitro and in vivo. Therefore, Pérez-Luna et al. [88] characterized the surface of five tyrosine-derived polycarbonates (pendent chain: DTE, DTB, DTH, DTO and DT-benzyl) by using contact angle measurements, electron spectroscopy for chemical analysis (ESCA) and static secondary ion mass spectrometry (SIMS).

Results showed that the

Drug delivery

Poly(DTH carbonate) was selected for the design of a long-term controlled-release device for the intracranial administration of dopamine [89], [90]. The potential advantages of poly(DTH carbonate) over other degradable polymers include the ease with which dopamine can be physically incorporated into the polymer (due to its relatively low processing temperature and the structural similarity between the drug and the polymer), the apparent protective action of the polymeric matrix on dopamine, the

Processing and fabrication

Polycarbonates and polyarylates have sufficient thermal stability to be processed by conventional polymer fabrication techniques such as extrusion, compression molding and injection molding. Additionally, high solubility in a wide range of organic solvents allows for the use of solvent casting to fabricate films, fibers, sponges and coatings. So far, films [45], rods [94], porous scaffolds (sponges) [56], [95], pins [56], [81] and fibers [96], [97], [98] have been processed by one or more of

Conclusions and outlook

The amino acid l-tyrosine was shown to be a versatile building block for biodegradable and biocompatible polymers. The incorporation of derivatives of tyrosine dipeptide, such as the desaminotyrosyl-tyrosine alkyl esters (DTR), into the backbone of different polymer systems results in versatile polymers with interesting properties. Contrary to most conventional poly(amino acid)s, tyrosine-derived pseudo-poly(amino acid)s exhibit excellent engineering properties and polymer systems can be

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