Discrete PEG Constructs

Abstract

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.

I claim: 
     
         1 . A construct, which comprises at least one attachment core (AC) substituted with:
 (a) one or more of a reactive or reactable group (A);   (b) a terminal linear discrete PEG-containing chain ( ) having between about 2 and 64 ethylene oxide residues and having a terminal moiety that is not an ethylene oxide residue; and   (c) a linear chain ( ) containing a discrete PEG residue, optionally substituted with one or more of N, S, Si, Se, or P, and optionally having one or more side chains from one or more attachment cores (AC) which can be the same or different; and terminated with a reactive or reactable group (A).   
     
     
         2 . The substantially pure construct of  claim 1  represented by one or more of: 
       
         
           
           
               
               
           
         
       
       where,
 (a) A is a biologically active group or a chemically reactable moiety; 
 (b) AC is an attachment core; 
 (c) G is a chemically or biologically reactable moiety, where n=1 to 10; 
 (d) the wavy line,  , is a linear discrete polyethylene glycol chain containing between 4 and 72 discrete ethylene oxide residues optionally substituted with N, S, Si, Se, or P, aryl groups or alkyl groups; and having one or more of chemically reactive or reactable end groups that are independently reactable, or cleavable groups; and 
 (e) the solid line,  , is a linear discrete polyethylene glycol chain that has between 4 and 96 ethylene oxide residues and has a terminal moiety, wherein the terminal moiety can be neutral or charged. 
 
     
     
         3 . The substantially pure compound of  claim 1 , wherein A is one or more of a cell surface and matrix antigen, transport protein, receptor protein, an antibody, antibody fragment, engineered antibody, engineered fragment, peptide, peptide substrate, peptomimetic substrate, cytokine, aptamer, siRNA, vitamin, steroid, a nanoparticle, microparticle, engineered molecular scaffold that contains multiple functionalities, or an engineered chemically reactable group. 
     
     
         4 . The substantially pure compound of  claim 1 , wherein A is a chemically moiety reactable with thiols, carbonyls, carboxylic acid, amines, strained alkenes, strained alkynes, or azides. 
     
     
         5 . The substantially pure compound of  claim 1 , wherein the solid line,  , is terminated by a charged group that is either negative, positive, or zwitterionic. 
     
     
         6 . The substantially pure compound of  claim 1 , wherein each wavy line,  , contains between about 2 and 24 ethylene oxide groups. 
     
     
         7 . The substantially pure compound of  claim 1 , wherein each solid line,  , independently, contains between about 0 and 64 ethylene oxide groups. 
     
     
         8 . The substantially pure compound of  claim 7 , wherein each wavy line,  , attached to AC contains, independently, between about 3 and 64 ethylene oxide groups. 
     
     
         9 . The substantially pure compound of  claim 1 , wherein G is one or more of:
 (a) a diagnostic group, being one or more of radiolabels, chelated radiolabels, chromogenic and fluorescent dyes, biotin and its derivatives, and combinations thereof; or   (b) a therapeutic group being one or more of radionuclides, toxic drugs, cytotoxins, cytokines, enzymes, antibiotic, and combinations thereof.   
     
     
         10 . The substantially pure compound of  claim 1  represented by: 
       
         
           
           
               
               
           
         
       
     
     
         11 . A substantially pure compound of  claim 1  being one or more of:
 A-dPEG x -AC(G)-OH; x=2-64; 
 A-dPEG x -AC(G)-m-dPEG x ; x same or different; x=2-64; 
 A-dPEG x -AC(-dPEG x -G)-m-dPEG x ; x same or different; x=2-64; 
 A-dPEG x -AC(G)-dPEG x -CO 2 H; x same or different; x=2-64; 
 A-dPEG x -AC(-dPEG x -G)-dPEG x -CO 2 H; x same or different; x=2-64; 
 A-dPEG x -AC(-G)-dPEG x -AC(-G)-dPEG x -AC(-G)-m-dPEG x ; x same or different; x=2-64; (=A-(dPEG x -AC(-G)) 3 -)-m-dPEG x ); 
 A-dPEG x -AC(-G)-dPEG x -AC(-G)-dPEG x -AC(-G)-dPEG x -CO 2 H; x same or different; x=2-64 (=A-(dPEG x -AC(-G)) 3 -)-dPEG x -CO 2 H); 
 A-(dPEG x -AC(-G)) y -)-m-dPEG x ; AC same or different; G same or different; x same or different, y=2-10; x=2-64; 
 A-(dPEG x -AC(-G)) y -)-dPEG x -CO 2 H; AC same or different; G same or different x same or different; y=2-10; x=2-64; 
 A-dPEG x -Tyr(G)-OH; x=2-64; 
 A-dPEG x -Tyr(G)-m-dPEG x ; x same or different; x=2-64; 
 A-dPEG x -Tyr(-dPEG x -G)-m-dPEG x ; x same or different; x=2-64; 
 A-dPEG x -Tyr(G)-dPEG x -CO 2 H; x same or different; x=2-64; 
 A-dPEG x -Tyr(-dPEG x -G)-dPEG x -CO 2 H; x same or different; x=2-64; 
 A-dPEG x -Tyr(-G)-dPEG x -Tyr(-G)-dPEG x -Tyr(-G)-m-dPEG x ; x same or different; x=2-64; (=A-(dPEG x -Tyr(-G)) 3 -)-m-dPEG x ); 
 A-dPEG x -Tyr(-G)-dPEG x -Tyr(-G)-dPEG x -Tyr(-G)-dPEG x -CO 2 H; x same or different; x=2-64 (=A-(dPEG x -Tyr(-G)) 3 -)-dPEG x -CO 2 H); 
 A-(dPEG x -Try(-G)) y -)-m-dPEG x ; G same or different, x same or different, y=2-10; x=2-64; or 
 A-(dPEG x -Tyr(-G)) y -)-dPEG x -CO 2 H; G same or different x same or different; y=2-10 x=2-64. 
 
     
     
         13 . The substantially pure compound of claim  14 , being one or more of:
 PhthN-dPEG x -Tyr(OH)-OBn; x=2-24;   t-boc-NH-dPEG x -Tyr(OH)-OBn; x=2-24;   Fmoc-NH-dPEG x -Tyr(OH)—OH; x=2-24;   PhthN-dPEG x -Tyr(OTBA)-OBn; x=2-24;   t-boc-NH-dPEG x -Tyr(OTBA)-OBn; x=2-24;   Fmoc-NH-dPEG x -Tyr(OTBA)-OH; x=2-24;   PhthN-dPEG x -Tyr(O-dPEG m -TBE)-OBn; x=2-24; m=1-24;   t-boc-NH-dPEG x -Tyr(O-dPEG m -TBE)-OBn; x=2-24; m=1-24;   Fmoc-NH-dPEG x -Tyr(O-dPEG m -TBE)-OH; x=2-24 m=1-24;   PhthN-dPEG x -Tyr(-O-propargyl)-CO 2 H;   PhthN-dPEG x -Tyr(-O-propargyl)-dPEG m ; x=2-24; y=4-48;   PhthN-dPEG x -Tyr(-O-propargyl)-dPEG y -CO 2 R; x=2-24; y=4-48;   PhthN-dPEG x -Tyr(-O-propargyl)-dPEG y -FG; x=2-24; y=2-48;   Fmoc-NH-dPEG x -Tyr(-O-propargyl)-CO 2 H; x=2-24;   Fmoc-NH-dPEG x -Tyr(-O-propargyl)-dPEG y -m; x=2-24; y=4-48;   Fmoc-NH-dPEG x -Tyr(-O-propargyl)-dPEG y -CO 2 R; x=2-24; y=4-48;   Fmoc-NH-dPEG x -Tyr(-O-propargyl)-dPEG y -FG; x=2-24; y=2-48;   PhthN-((dPEG x -Tyr(O-dPEG m -TBE)) z -OH; x=2-24; m=1-24; z=1-10;   t-boc-NH-(dPEG x -Tyr(O-dPEG m -TBE)) z -OH; x=2-24; m=1-24; z=1-10;   Fmoc-NH-(dPEG x -Tyr(O-dPEG m -TBE)) z -OH; x=2-24 m=1-24; z=1-10;   PhthN-((dPEG x -Tyr(O-dPEG m -propargyl)) z -OH; x=2-24; m=0-24; z=1-10;   t-boc-NH-(dPEG x -Tyr(O-dPEG m -propargyl)) z -OH; x=2-24; m=0-24; z=1-10;   Fmoc-NH-(dPEG x -Tyr(O-dPEG m -propargyl)) z -OH; x=2-24 m=0-24; z=1-10;   t-boc-NH(-dPEG x -Tyr(OTBA)) z -OH; x=2-24; z=1-10;   Fmoc-NH-(dPEG x -Tyr(OTBA)) z -OH; x=2-24; z=1-10;   t-boc-NH(-dPEG x -Tyr(OTAA)) z -OH; x=2-24; z=1-10;   NH 2 (-dPEG x -Tyr(OTAA)) z -OH; x=2-24; z=1-10;   Fmoc-NH-(dPEG x -Tyr(OTAA)) z -OH; x=2-24; z=1-10;   t-boc-NH(-dPEG x -Tyr(OTAA)) z -m-dPEG y ; x=2-24; y=2-48; z=1-10;   Fmoc-NH-(dPEG x -Tyr(OTAA)) z -m-dPEG y ; x=2-24; y=2-48; z=1-10;   NH 2 -(dPEG x -Tyr(OTAA)) z -m-dPEG y ; x=2-24; y=2-48; z=1-10; or   MAL-(dPEG x -Tyr(OTFP ester)) z -m-dPEG y ; x=2-24; y=2-48; z=1-10.