LYSINE COPOLYMER

To produce biodegradable poly(lactic acid-co-lysine) copolymers (for cell adhesion), it was first necessary to synthesize the monomer 3-[4-(A-benzyloxycarbonyl)aminobutyl]-6-methylmorpholine-2,5-dione (4, Scheme 4). During the final ring-closure step, a minor amount of epimerization occurs. However, the diastereomeric purity of 4 is in excess of 95%. The monomer 4 is copolymerized with L,L-lactide (3,6-dimethyl-l,4-dioxane-2,5-dione, 5) (Scheme 5) in tin(II) 2-ethylhexanoate at 100 °C for 24 hours. 

Synthesis of Biodegradable Poiy(lactic acid-co-lysine) Copolymers Linked to Cell Adhesive Peptide Sequences General Procedure 27 ... 

Sawhney, A.S. and Hubbell, J.A., Poly(ethylene oxide)-graft-poly(L-lysine) copolymers to enhance the biocompatibility of poly(L-lysine)-alginate microcapsule membranes. Biomaterials, 13, 863 870, 1992. 

Bioresorbable copolymers between linear aliphatic polyesters in (1) and monomers other than Unear aUphatic polyesters like, poly(glycoUde-trimethylene carbonate) copolymer, poly(L-lactic acid-L-lysine) copolymer, tyrosine-based polyarylates or polyiminocarbonates or polycarbonates, poly(DJL-lactide-urethane), and poly(ester-amide). 

D. Ma, Q.M. Lin, L.M. Zhang, YY Liang, and W. Xue, A star-shaped porphyrin-arginine functionalized poly(l-lysine) copolymer for photo-enhanced drug and gene co-dehvery. Biomaterials, 35 (14), 4357-67,2014. 

Poly(lactic acid-co-lysine) copolymers were synthesized to benefit from the biodegradabihty of PLA while using the amino-groups of lysine as grafting sites for RGD peptides, which are known to be recognized by mammalian cell receptors. XPS was used to determine the lysine and the peptide densities at the surface. This was made possible by the incorporation of diiodotyrosine into the peptide. The RGD-containing polymer was later found to promote the spreading of bovine aortic endothelial ceUs. ... 

Deng X, Liu Y, Yuan M (2002), Study on biodegradable polymer, 3. Synthesis and characterization of poly(DL-lactic acid)-co-poly(ethylene glycol)-co-poly(L-lysine) copolymer , Eur. Pol. J., 38 (7), 1435-1441. 

Recently, Gallot et al. succeeded in preparing well characterized block copolymers by polymerization of 7-benzyl-L-glutamate NCA and e-carbobenzoxyl-L-lysine NCA with a primary amine ended polystyrene or polybutadiene in dioxane or ben-... 

A series of poly(ester-urethane) urea triblock copolymers have been synthesized and characterized by Wagner et al/ using PCL, polyethylene glycol, and 1,4 diisocyanatobutane with either lysine ethyl ester or putrescine, as the chain extender. These materials have shown the elongation at break from 325% to 560% and tensile strengths from 8 to 20 MPa. Degradation products of this kind of materials did not show any toxicity on cells. 

Unfortunately, the modification of the side chain is not a generally applicable approach. Among the major, naturally occurring amino acids, only L-lysine has a chemically reactive side chain that would be as readily available for chemical modification as the side chain of glutamic or aspartic acid. Since, however, poly (L-lysine) is known to be toxic (10), its derivatives cannot be candidates for generally applicable biomaterials. Thus, most of the poly(amino acids) that have so far been suggested as biomaterials are derivatives of gluteunic or aspartic acid or copolymers of such derivatives with leucine, methionine, or a limited number of additional amino acids (11). 

Cardinaux F, Howard JC, Taylor GT, Scheraga HA (1977) Block copolymers of amino-acids. 1. Synthesis and stmcture of copolymers of L-alanine or L-phenylalanine with D, L-lysine-D7 or D, L-lysine. Biopolymers 16 2005-2028... 

Fig. 1 Vesicle construct formed from poly(L-lysine)-i)-poly(L-leucme) polypeptides where the poly(L-leucine) block corresponds to the a-helical hydrophobic segments and the poly (L-lysine) block corresponds to the random coil hydrophilic segments. Note that this is one specific example and not all vesicle constructs have a-helical and random coil blocks. Moreover, the amphiphilic copolymer can be comprised of either a pure block copolypeptide or a macromolecule consisting of a polypeptide and another type of polymer. Adapted from [20] with permission. Copyright 2010 American Chemical Society...

VandeVondele S, Voros J, Hubbell JA (2003) Rgd-grafted poly-l-lysine-graft- (polyethylene glycol) copolymers block non-specific protein adsorption while promoting cell adhesion. Biotechnol Bioeng 82 784—790... 

Synthetic Polymers. Synthetic polymers are versatile and offer promise for both targeting and extracellular-intracellular drug delivery. Of the many soluble synthetic polymers known, the poly(amino acids) [poly(L-lysine), poly(L-aspartic acid), and poly(glutamic acid)], poly(hydroxypropylmethacrylamide) copolymers (polyHPMA), and maleic anhydride copolymers have been investigated extensively, particularly in the treatment of cancers. A brief discussion of these materials is presented. 

In ref. [74] it is emphasized that N-acetylimidazole reacts with all tyrosyl residues in copolymers and denatured proteins but only with free tyrosyl residues in native proteins. In ref. [75] it is noted that Af-acetylimidazole reacts extensively with both lysine and tyrosine chains. 

Multiblock copolymers of poly(L-lysine) and PEG were prepared following the reaction sequence illustrated in Scheme 66. N-carboxy-(AT -benzyloxy... 

Muller M, Reihs T, Ouyang W (2005) Needlelike and spherical polyelectrolyte complex nanoparticles of poly(L-lysine) and copolymers of maleic acid. Langmuir 21 465 -69... 

Copolymers of a-hydroxy acids and a-amino acids are one type of poly(ester-amide)s and are called polydepsipeptides (PDPs) [17]. Since some of natural occurring a-amino acids, typically Asp, Glu, lysine (Lys), cysteine (Cys), serine (Ser), and threonine (Thr), possess reactive (hydrophilic) side-chain groups, PDPs... 

Many polymers have been studied for their usefulness in producing pharmacologically active complexes with proteins or drugs. Synthetic and natural polymers such as polysaccharides, poly(L-lysine) and other poly(amino acids), poly(vinyl alcohols), polyvinylpyrrolidinones, poly(acrylic acid) derivatives, various polyurethanes, and polyphosphazenes have been coupled to with a diversity of substances to explore their properties (Duncan and Kopecek, 1984 Braatz et al., 1993). Copolymer preparations of two monomers also have been tried (Nathan et al., 1993). 

Nathan, A., Zalipsky, S., Ertel, S.I., Agathos, S.N., Yarmush, M.L., and Kohn, J. (1993) Copolymers of lysine and polyethylene glycol A new family of functionalized drug carriers. Bioconjugate Chem. 4, 54-62. 

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