BIOADHESIVE COMPOUNDS AND METHODS OF SYNTHESIS AND USE
The invention describes new synthetic medical adhesives and antifouling coatings which exploit the key components of natural marine mussel adhesive proteins.
1 . A compound comprising the formula (I)
wherein
each L 2 , L 3 and L 4 independently, is a linker;
each L 1 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 L 12 and L 13 , independently, is a linker or a suitable linking group selected from amine, amide, ether, ester, urea carbonate or urethane linking groups;
each X 1 , X 2 , X 3 and X 4 independently, is an oxygen atom or NR;
R, if present, is H or a branched or unbranched C 1 -C 10 alkyl group;
each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 independently, is a branched or unbranched C1-C15 alkyl group;
each PD ii and PD jj , independently, is a phenyl derivative residue;
aa is a value from 0 to about 80;
bb is a value from 0 to about 80;
cc is a value from 0 to about 80;
dd is a value from 1 to about 120;
ee is a value from 1 to about 120;
ff is a value from 1 to about 120;
gg is a value from 1 to about 120; and
hh is a value from 1 to about 80.
2 . The compound of claim 1 , wherein L 2 is a residue of a C1-C15 alkyl lactone or lactam, a poly C1-C15 alkyl lactone or lactam, a polyester, or a compound comprising the formula Y 4 —R 17 —C(═O)—Y 6 , wherein Y 4 is OH, NHR, a halide, or an activated derivative of OH or NHR; R 17 is a branched or unbranched C1-C15 alkyl group; and Y 6 is NHR, a halide, or OR.
3 . The compound of claim 2 , wherein the polylactone is a polycaprolactone.
4 . The compound of claim 1 , wherein L 3 is a residue of an alkylene diol, an alkylene diamine or a poly(alkylene oxide) polyether or derivative thereof.
5 . The compound of claim 4 , wherein L 3 is a poly(alkylene oxide) or —O—CH 2 CH 2 —O—CH 2 CH 2 —O—.
6 . The compound of claim 1 , wherein L 2 or L 4 is a residue of a C1-C15 alkyl lactone or lactam, a poly C1-C15 alkyl lactone or lactam, or a compound comprising the formula Y 4 —R 17 —C(═O)—Y 6 , wherein Y 4 is OH, NHR, a halide, or an activated derivative of OH or NHR; R 17 is a branched or unbranched C1-C15 alkyl group; and Y 6 is NHR, a halide, or OR.
7 . The compound of claim 6 , wherein the polylactone is polycaprolactone.
8 . The compound of claim 1 , wherein X 1 , X 2 , X 3 and X 4 are each O or NH.
9 . The compound of claim 1 , wherein R 3 , R 6 , R 10 and R 13 are each —CH 2 CH 2 —.
10 . The compound of claim 1 , wherein X 1 , X 2 , X 3 and X 4 are each O.
11 . The compound of claim 1 , wherein R 4 , R 5 , R 9 and R 12 are each —CH 2 —.
12 . The compound of claim 1 , wherein R 1 , R 2 , R 7 , R 8 , R 11 and R 14 are a branched or unbranched alkane.
13 . The compound of claim 16 , wherein R 1 , R 2 , R 7 , R 8 , R 11 and R 14 are —CH 2 —CH 2 — or CH 2 —CH 2 —CH 2 —.
14 . The compound of claim 1 , wherein L 1 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 , L 12 , and L 13 form an amide, ester or carbamate.
15 . The compound of claim 1 , wherein each PD xx and PD dd , independently, is a residue of a formula comprising:
wherein Q is an OH or OCH3;
“z” is 1 to 5;
Each X 1 , independently, is H, NH 2 , OH, or COOH;
Each Y 1 , independently, is H, NH 2 , OH, or COOH;
Each X 2 , independently, is H, NH 2 , OH, or COOH;
Each Y 2 , independently, is H, NH 2 , OH, or COOH;
Z is COOH, NH 2 , OH or SH;
aa is a value of 0 to about 4;
bb is a value of 0 to about 4; and
optionally provided that when one of the combinations of X 1 and X 2 , Y 1 and Y 2 , X 1 and Y 2 or
Y 1 and X 2 are absent, then a double bond is formed between the C aa and C bb , further provided that aa and bb are each at least 1 to form the double bond when present.
16 . The compound of claim 1 , wherein PD xx and PD dd residues are selected from the group consisting of 3,4-dihydroxyphenylalanine (DOPA), 3,4-dihydroxyphenethylamine (dopamine), 3,4-dihydroxyhydrocinnamic acid (DOHA), 3,4-dihydroxyphenyl ethanol, 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylamine, 3,4-dihydroxybenzoic acid, 3-(3,4-dimethoxyphenyl)propionic acid, 3,4-dimethoxyphenylalanine, 2-(3,4-dimethoxyphenyl)ethanol, 3,4-dimethoxyphenethylamine, 3,4-dimethoxybenzylamine, 3,4-dimethoxybenzyl alcohol, 3,4-dimethoxyphenylacetic acid, 3-(3,4-dimethoxyphenyl)-2-hydroxypropanoic acid, 3,4-dimethoxybenzoic acid, 3,4-dimethoxyaniline, 3,4-dimethoxyphenol, 3-(4-Hydroxy-3-methoxyphenyl)propionic acid, homovanillyl alcohol, 3-methoxytyramine, 3-methoxy-L-tyrosine, homovanillic acid, 4-hydroxy-3-methoxybenzylamine, vanillyl alcohol, vanillic acid, 5-amino-2-methoxyphenol, 2-methoxyhydroquinone, 3-hydroxy-4-methoxyphenethylamine, 3-hydroxy-4-methoxyphenylacetic acid, 3-hydroxy-4-methoxyphenylacetic acid, 3-hydroxy-4-methoxybenzylamine, 3-hydroxy-4-methoxybenzyl alcohol, isovanillic acid.
17 . The compound of claim 1 , wherein
L 2 is a residue of a polycaprolactone, a caprolactone, a polylactic acid, a polylactone or a lactic acid or lactone;
L 3 is a residue of polyethylene glycol;
L 4 is a residue of a polycaprolactone, a caprolactone, a polylactic acid, a polylactone or a lactic acid or lactone;
X 1 , X 2 , X 3 and X 4 are each O or NH;
R 1 , R 3 , R 6 , R 8 , R 10 , and R 13 are each —CH 2 CH 2 —;
R 4 , R 5 , R 9 and R 12 are each —CH 2 —;
R 2 , R 7 , R 11 and R 14 are each —(CH 2 ) n —, wherein n is 3;
L 1 , L 5 , L 7 , L 8 , L 10 , L 12 form an ester;
L 6 , L 9 , L 11 , and L 13 form an amide; and
PD xx and PD dd are residues selected from the group consisting of 3,4-dihydroxyhydrocinnamic acid (DOHA), hydroferulic acid (HFA), or 3,4-dimethoxyhydrocinnamic acid (3,4-DMHCA).
18 . The compound of claim 1 , wherein
L 2 is a residue of a polycaprolactone, a caprolactone, a polylactic acid, a polylactone or a lactic acid or lactone;
L 3 is a residue of polyethylene glycol;
L 4 is a residue of a polycaprolactone, a caprolactone, a polylactic acid, a polylactone or a lactic acid or lactone;
X 1 , X 2 , X 3 and X 4 are each O or NH;
R 3 , R 6 , R 10 , and R 13 are each —CH 2 CH 2 —;
R 1 , R 8 , R 4 , R 5 , R 9 and R 12 are each —CH 2 —;
R 2 , R 7 , R 11 and R 14 are each —(CH 2 ) n —, wherein n is 2 or 3;
L 1 , L 5 , L 7 , L 8 , L 10 , L 12 form an ester;
L 6 , L 9 , L 11 , and L 13 form an amide; and
PD xx and PD dd are residues selected from the group consisting of 3,4-dihydroxyphenylethylamine, 3-methoxytyramine.
19 . A bioadhesive construct, comprising:
a support suitable for tissue repair or reconstruction; and
a coating comprising a phenyl derivative (PD) functionalized polymer (PDp) of claim 1 .
20 . The bioadhesive construct of claim 20 , further comprising an oxidant.
21 . The bioadhesive construct of claim 21 , wherein the oxidant is formulated with the coating.
22 . The bioadhesive construct of claim 21 , wherein the oxidant is applied to the coating.
23 . The bioadhesive construct of claim 20 , wherein the support is a film, mesh, a membrane, a nonwoven or a prosthetic.
24 . A blend of a polymer and a compound of claim 1 .
25 . The blend of claim 24 , wherein the polymer is present in a range of about 1 to about 50 percent by weight.
26 . The blend of claim 25 , wherein the polymer is present in a range of about 30 percent by weight.
27 . A bioadhesive construct comprising:
a support suitable for tissue repair or reconstruction; and
a coating comprising the blend of claim 24 .
28 . The bioadhesive construct of claim 27 , further comprising an oxidant.
29 . The bioadhesive construct of claim 28 , wherein the oxidant is formulated with the coating.
30 . The bioadhesive construct of claim 28 , wherein the oxidant is applied to the coating.
31 . The bioadhesive construct of claim 27 , wherein the support is a film, a mesh, a membrane, a nonwoven or a prosthetic.
32 . A bioadhesive construct comprising:
a support suitable for tissue repair or reconstruction;
a first coating comprising a phenyl derivative (PD) functionalized polymer (PDp) of claim 1 and a polymer; and
a second coating coated onto the first coating, wherein the second coating comprises a phenyl derivative (PD) functionalized polymer (PDp) of claim 1 .
33 . A bioadhesive construct comprising:
a support suitable for tissue repair or reconstruction;
a first coating comprising a first phenyl derivative (PD) functionalized polymer (PDp) of claim 1 and a first polymer; and
a second coating coated onto the first coating, wherein the second coating comprises a second phenyl derivative (PD) functionalized polymer (PDp) of claim 1 and a second polymer, wherein the first and second polymer may be the same or different and wherein the first and second PDp can be the same or different.
34 . A bioadhesive construct comprising:
a support suitable for tissue repair or reconstruction;
a first coating comprising a first phenyl derivative (PD) functionalized polymer (PDp) of claim 1 ; and
a second coating coated onto the first coating, wherein the second coating comprises a second phenyl derivative (PD) functionalized polymer (PDp) of claim 1 , wherein the first and second PDp can be the same or different.