Polymer-carbohydrate-lipid conjugates

Abstract

The invention comprises compounds, methods of making, and methods of using. The compounds may have a backbone and three appended functional groups: one lipid, one hydrophilic polymer, and one carbohydrate. Specific functional groups may be selected for specific applications in formulating pharmaceuticals, cosmetics, nutriceuticals, and the like. A variety of linkers between the backbone and functional groups may also be selected to optimize performance.

1 . A method of making a Polymer-carbohydrate-lipid conjugate with three defined carriers and represented by the formula: 
       
         
           
           
               
               
           
         
         wherein X 1  and X 2  are the same or different linkers, said method comprising the steps of: 
         (a) selecting a central backbone with at least three available binding positions or sites for the conjugation of a first carrier, a second carrier, and a third carrier, each said available binding position or site comprising an expendable amino, hydroxyl, or carboxylic group; 
         (b) selecting a lipid comprising an expendable amino, hydroxyl, or carboxylic group as said first carrier; 
         (c) selecting a polymer comprising an expendable amino, hydroxyl, or carboxylic group as said second carrier; 
         (d) selecting a sugar comprising an expendable amino, hydroxyl, or carboxylic group as said third carrier; 
         (e) protecting one of said expendable amino, hydroxyl, or carboxylic groups of said central backbone with a protecting group; 
         (f) bonding said first carrier to said central backbone at one of said unprotected binding positions or sites by one of 1) and 2), wherein:
 1) bonding said expendable amino, hydroxyl, or carboxylic group of said first carrier with said expendable amino, hydroxyl, or carboxylic group of said central backbone forming a linker therebetween; 
 2) attaching a linker to said expendable amino, hydroxyl, or carboxylic group of said first carrier and bonding said linker to said expendable amino, hydroxyl, or carboxylic group of said central backbone; 
 
         (g) bonding said second carrier to said central backbone at the other of said unprotected binding positions or sites by one of 1) and 2), wherein:
 1) bonding said expendable amino, hydroxyl, or carboxylic group of said second carrier with said expendable amino, hydroxyl, or carboxylic group of said central backbone forming a linker therebetween; 
 2) attaching a linker to said expendable amino, hydroxyl, or carboxylic group of said second carrier and bonding said linker to said expendable amino, hydroxyl, or carboxylic group of said central backbone; 
 
         (h) removing said protecting group from one said binding position or site of said central backbone; and 
         (i) bonding said third carrier to said central backbone at said binding position or site of said central backbone having said protecting group removed therefrom by one of 1) and 2), wherein:
 1) bonding said expendable amino, hydroxyl, or carboxylic group of said third carrier with said expendable amino, hydroxyl, or carboxylic group of said central backbone forming a linker therebetween; 
 2) attaching a linker to said expendable amino, hydroxyl, or carboxylic group of said third carrier and bonding said linker to said expendable amino, hydroxyl, or carboxylic group of said central backbone. 
 
       
     
     
         2 . The process of  claim 1  wherein two of said binding positions or sites on said central backbone are identical and said process steps (e)-(i) further comprise:
 (e) protecting said expendable amino, hydroxyl, or carboxylic group of one said identical binding position or site with a protecting group; 
 (f) bonding said first carrier to said central backbone at said unprotected identical binding position or site or said non-identical binding position or site; 
 (g) bonding said second carrier to said central backbone at the other of said unprotected identical binding position or site or said non-identical binding position or site 
 (h) removing said protecting group from one said identical binding position or site of central backbone; and 
 (i) bonding said third carrier to said central backbone at said identical binding position or site of central backbone having said protecting group removed therefrom. 
 
     
     
         3 . The method of  claim 1  wherein said backbone is selected from the group consisting of glycerol or glycerol-like analogues, polyamines (tri- or tetra-amines), amino acids having three available binding sites, triols, triacids, glucoheptonic acid, tartaric acid, and combinations thereof. 
     
     
         4 . The method of  claim 1  wherein said central backbone comprises a compound with two said available binding positions or sites selected from the group consisting of ethylenediamine, diaminopropane, ethanolamine, and aminopropanol, said compound being chemically extended and modified to provide said third available binding position or site. 
     
     
         5 . The method of  claim 1  wherein said second carrier comprises a single PEG chain having between 5 and 45 subunits or a branched PEG having 2 or more subchains wherein each said subchain has between 5 and 45 subunits. 
     
     
         6 . The method of  claim 1  wherein said lipid is selected from the group consisting of diacylglycerols, saturated lipids, unsaturated lipids, and steroid acids. 
     
     
         7 . The method of  claim 1  wherein said sugar is selected from the group consisting of monosaccharide or disaccharides, trisaccharides, tetrasaccharides, fructooligosaccharide, galacto-oligosaccharides, mannan-oligosaccharides, and polysaccharides. 
     
     
         8 . The method of  claim 1  wherein said linker is selected from the group consisting of oxy, amino, succinylamino, acetamido, aminopentanamido, aminoacetyl, thiopropanoayl, N-(mercaptomethyl)propionamido, mercaptopropylthio)-propanoyl, (1,2-dihydroxy-3-mercaptopropylthio)propanoyl, succinyl, acetyl, oxopentanoyl, carbamoyl, aminoalkyl, glutaramido, aminoethanethiol, mercaptopropanol, (hydroxypropylthio)propanoayl, 3-((2-propionamidoethyl)disulfanyl)propanoayl, (((acetamidoethyl)disulfanyl)propanoyloxy)-glutaramido, aminoethanethioate, and 2-hydroxyacetic proprionic anhydride. 
     
     
         9 . The method of  claim 1  wherein said linker is selected from the group consisting of Proline, Glycine, Alanine, Lysine, Cysteine, Valine, Isoleucine, Leucine, Methionine, Phenylalanine, Histidine, Tryptophan, Tyrosine, Selenocysteine, and Arginine. 
     
     
         10 . The method of  claim 1  wherein said central backbone is selected from the group consisting of 3-amino-1,2-propanediol, 3-bromo-1,2-propanediol, 3-chloro-1,2-propanediol, 3-fluoro-1,2-propanediol, DL-glyceric acid, diaminopropionic acid, tartaric acid, glucoheptonic acid and, 2,4-butanetriol, 2,2-Bis(hydroxymethyl)butyric acid, 1,3-Diamino-2-propanol and 2-(3-Aminopropylamino)-ethanol. 3-amino-1,2-propanediol, 3-bromo-1,2-propanediol, 3-chloro-1,2-propanediol, 3-fluoro-1,2-propanediol, DL-glyceric acid, diaminopropionic acid, tartaric acid, glucoheptonic acid and, 2,4-butanetriol, 2,2-bis(hydroxymethyl)butyric acid, 1,3-Diamino-2-propanol, 2-(3-Aminopropylamino)ethanol, and 3-((3-aminopropyl)-amino)propanol. 
     
     
         11 . The method of  claim 1  wherein said central backbone is selected from the group consisting of diethylenetriamine, spermidine, triethylenetetramine, spermine, norspermidine, bis(3-aminopropyl)-1,3-propanediamine, and bis(hexamethylene)triamine. 
     
     
         12 . The method of  claim 1  wherein said central backbone is selected from the group consisting of aspartic acid, glutamic acid, asparagine, glutamine, ornithine, serine and threonine. 
     
     
         13 . The method of  claim 1  wherein said polymer is selected from the group consisting of polyethylene glycol, polymethylene glycol, polypropylene glycol, and copolymers comprised of at least two monomers, wherein said monomers are selected from the group consisting of methylene glycol, propylene glycol, and ethylene glycol. 
     
     
         14 . The method of  claim 1  wherein said polymer comprises PEG with a terminal (R) group that is easily polarized or negatively or positively charged. 
     
     
         15 . A method of making a Polymer-carbohydrate-lipid conjugate with three defined carriers and represented by the formula: 
       
         
           
           
               
               
           
         
         wherein X 1 , X 2  and X 3  are the same or different linkers, said method comprising the steps of: 
         (a) selecting a central backbone with at least three available binding positions or sites for the conjugation of a first carrier, a second carrier, and a third carrier, each said available binding position or site comprising an expendable amino, hydroxyl, or carboxylic group; 
         (b) selecting a lipid comprising an expendable amino, hydroxyl, or carboxylic group as said first carrier; 
         (c) selecting a polymer comprising an expendable amino, hydroxyl, or carboxylic group as said second carrier; 
         (d) selecting a sugar comprising an expendable amino, hydroxyl, or carboxylic group as said third carrier; 
         (e) bonding said first carrier to said central backbone at one of said binding positions or sites by one of 1), 2), and 3) wherein:
 1) bonding said expendable amino, hydroxyl, or carboxylic group of said first carrier with said expendable amino, hydroxyl, or carboxylic group of said central backbone; 
 2) bonding said expendable amino, hydroxyl, or carboxylic group of said first carrier with said expendable amino, hydroxyl, or carboxylic group of said central backbone forming a linker therebetween; 
 3) attaching a linker to said expendable amino, hydroxyl, or carboxylic group of said first carrier and bonding said linker to said expendable amino, hydroxyl, or carboxylic group of said central backbone; 
 
         (f) bonding said second carrier to said central backbone at one available of said binding positions or sites wherewith by one of 1), 2), and 3) wherein:
 1) bonding said expendable amino, hydroxyl, or carboxylic group of said second carrier with said expendable amino, hydroxyl, or carboxylic group of said central backbone; 
 2) bonding said expendable amino, hydroxyl, or carboxylic group of said second carrier with said expendable amino, hydroxyl, or carboxylic group of said central backbone forming a linker therebetween; 
 3) attaching a linker to said expendable amino, hydroxyl, or carboxylic group of said second carrier and bonding said linker to said expendable amino, hydroxyl, or carboxylic group of said central backbone; and 
 
         (g) bonding said third carrier to said central backbone at one available of said binding positions or sites by one of 1), 2), and 3) wherein:
 1) bonding said expendable amino, hydroxyl, or carboxylic group of said third carrier with said expendable amino, hydroxyl, or carboxylic group of said central backbone; 
 2) bonding said expendable amino, hydroxyl, or carboxylic group of said third carrier with said expendable amino, hydroxyl, or carboxylic group of said central backbone forming a linker therebetween; 
 3) attaching a linker to said expendable amino, hydroxyl, or carboxylic group of said third carrier and bonding said linker to said expendable amino, hydroxyl, or carboxylic group of said central backbone. 
 
       
     
     
         16 . The method of  claim 15  wherein said first carrier is bonded to said central backbone before said second carrier or said third carrier. 
     
     
         17 . The method of  claim 15  wherein said central backbone comprises a compound with two said available binding positions or sites selected from the group consisting of ethylenediamine, diaminopropane, ethanolamine, and aminopropanol, said compound being chemically extended and modified to provide said third available binding position or site of said central backbone. 
     
     
         18 . The method of  claim 15  wherein said second carrier comprises a single PEG chain having between 5 and 45 subunits or a branched PEG having 2 or more subchains wherein each said subchain has between 5 and 45 subunits. 
     
     
         19 . A method of delivering a compound comprising:
 (a) determining a therapeutic target;   (b) determining a mode of administration;   (c) determining the physiological conditions the compound will encounter during administration;   (d) providing a polymer-carbohydrate-lipid conjugate(s) based delivery vehicle comprising a PEG-carbohydrate-lipid conjugate backbone having three carrier groups and one or more linkers between each carrier group and the backbone, said carrier groups comprising a PEG chain, a carbohydrate, and a fatty acid or steroid acid, said backbone comprising an amino acid or linear multiamine portion, said delivery vehicle being configured to deliver the compound to the therapeutic target within the physiological conditions to be encountered during administration by the determined administration mode;   (e) formulating the compound with the delivery vehicle; and   (f) administering the compound to the a therapeutic target.   
     
     
         20 . The method of  claim 19  wherein the compound is Propofol and the weight ratio of the polymer-carbohydrate-lipid conjugate(s) based delivery vehicle to the compound is between about 1 and 3.