DISCRETE PEG CONSTRUCTS
Disclosed are linear discrete PEG constructs, which can be created and produced in a precise and reproducible way. Key to being able to do these things, where x in the discrete PEG x can vary from about 2 to about 64, is that the processes used to make each linear portion is controlled to give essentially one oligomer/one compound. Having a variable length linear discrete PEG construct that is (a) primarily an linear discrete PEG construct with diagnostic or therapeutic groups attached along a chain of attachment cores, which is attached to a preferential locator; (b) is an m-discrete PEG as the terminal construct on the linear portion, and “hidden”; (c or linear discrete PEG with a terminus group that can be either negatively or positively charged, or neutral; and any of the discrete PEG portions can be designed to be cleaved after entering the cell.
1 .- 13 . (canceled)
14 . A linker comprising:
wherein,
(a) each AC is an amino acid attachment core;
(b) each is a linear hydrocarbon chain independently comprising a discrete PEG residue;
(c) A is a chemically reactable group or a chemically reactive group;
(d) is a terminal linear discrete PEG-containing chain comprising from 2 to 96 ethylene oxide residues, said terminal linear discrete PEG-containing chain ending with a non-reactive moiety; and
(e) n is from 1-10.
15 . The linker of claim 14 , wherein each is a linear hydrocarbon chain independently comprising a discrete PEG residue comprising from 2 to 72 ethylene oxide groups.
16 . The linker of claim 14 , wherein each is a linear hydrocarbon chain independently comprising a discrete PEG residue comprising from 2 to 12 ethylene oxide groups.
17 . The linker of claim 16 , wherein the terminal linear discrete PEG, independently comprises from 8 to 24 ethylene oxide groups.
18 . The linker of claim 14 , wherein each AC independently comprises
19 . The linker of claim 14 , wherein each AC independently comprises a linear hydrocarbon chain comprising a chemically reactive or reactable group that is independently reactive or reactable from A.
20 . The linker of claim 19 , wherein the chemically reactive or reactable group comprises an amine, a protected amine, an azide, a carboxylic acid, an ester, a ketone, an amide, an alkyne, a carbonate, a thiol, an aldehyde, an aminooxy, a protected aminooxy, a tetrazine, an alkene, a maleimide or derivative thereof, haloacetamide, vinyl sulfone or derivative thereof, peptide substrate, or combination thereof.
21 . The linker of claim 14 , wherein each AC is a natural or unnatural amino acid residue comprising a side chain.
22 . The linker of claim 14 , wherein A comprises an amine, a protected amine, an azide, a carboxylic acid, an ester, a ketone, an amide, an alkyne, a carbonate, a thiol, an aldehyde, an aminooxy, a protected aminooxy, a tetrazine, an alkene, a maleimide or derivative thereof, haloacetamide, vinyl sulfone or derivative thereof, peptide substrate, or combination thereof.
23 . The linker of claim 14 , wherein A is a chemically reactable group or a chemically reactive group selected from the group consisting of —NH 2 , —NH(Boc),
24 . The linker of claim 14 , having the structure:
25 . A linker comprising:
wherein,
(a) each AC is an amino acid attachment core;
(b) each connecting an A to an AC is a linear hydrocarbon chain;
(c) each connecting an AC to a G is a linear hydrocarbon chain;
(d) G is a targeting group, therapeutic agent, or diagnostic agent;
(e) A is a chemically reactable group or a chemically reactive group;
(f) is a terminal linear discrete PEG-containing chain comprising from 2 to 96 ethylene oxide residues, said terminal linear discrete PEG-containing chain ending with a non-reactive moiety; and
(g) n is from 1-10;
wherein A and G are independently reactive or reactable.
26 . The linker of claim 25 , wherein each linear hydrocarbon chain connecting an A to an AC independently comprises a discrete PEG residue comprising from 2 to 72 ethylene oxide residues.
27 . The linker of claim 25 , wherein each linear hydrocarbon chain connecting an A to an AC independently comprises a discrete PEG residue comprising from 2 to 12 ethylene oxide residues.
28 . The linker of claim 27 , wherein each solid line, , independently comprises from 8 to 24 ethylene oxide groups.
29 . The linker of claim 25 , wherein each linear hydrocarbon chain connecting an AC to a G independently comprises one or more ethylene oxide residues, aryl groups, alkyl groups, and/or amino acid residues.
30 . The linker of claim 25 , wherein each linear hydrocarbon chain connecting an AC to a G is independently a natural or unnatural amino acid residue comprising a side chain.
31 . The linker of claim 25 , wherein A comprises an amine, a masked amine, an azide, a carboxylic acid, an ester, a ketone, an amide, an alkyne, a carbonate, a thiol, an aldehyde, an aminooxy, a protected aminooxy, a tetrazine, an alkene, a maleimide or derivative thereof, haloacetamide, vinyl sulfone or derivative thereof, peptide substrate, or combination thereof.
32 . The linker of claim 25 , wherein A is a chemically reactable group or a chemically reactive group selected from the group consisting of —NH 2 , —NH(Boc),
33 . The linker of claim 25 , wherein G is a therapeutic agent.
34 . The linker of claim 33 , wherein the therapeutic agent is a small molecule, peptide, protein, antibody, antibody fragment, nucleic acid, nucleic acid fragment, or recombinant virus.
35 . The linker of claim 25 , wherein the therapeutic agent is an anticancer agent.
36 . The linker of claim 35 , wherein the anticancer agent is a cytotoxin selected from the group consisting of combretastatins, duocarmycins, the CC-1065 anti-tumor antibiotics, anthracyclines and related compounds, mycotoxins, ricin and its analogues, calicheamycins, doxirubicin and maytansinoids.
37 . The linker of claim 25 , wherein G is a diagnostic agent.
38 . The linker of claim 37 , wherein the diagnostic agent is a radiolabel, chromogenic and fluorescent dye, biotin or a derivative thereof, or a combination thereof.
39 . The linker of claim 25 , wherein the targeting group is an antibody, antibody fragment, peptide, or aptamer.
40 . The linker of claim 25 , having the structure:
41 . The linker of claim 25 , wherein the linker is in a biological system.
42 . The linker of claim 41 , wherein the biological system comprises a target cell.