Asymmetric biofunctional silyl monomers and particles thereof as prodrugs and delivery vehicles for pharmaceutical, chemical and biological agents

Abstract

Asymmetric bifunctional silyl (ABS) monomers comprising covalently linked pharmaceutical, chemical and biological agents are described. These agents can also be covalently bound via the silyl group to delivery vehicles for delivering the agents to desired targets or areas. Also described are delivery vehicles which contain ABS monomers comprising covalently linked agents and to vehicles that are covalently linked to the ABS monomers. The silyl modifications described herein can modify properties of the agents and vehicles, thereby providing desired solubility, stability, hydrophobicity and targeting.

That which is claimed: 
     
         1 . A functionalized drug delivery monomer, comprising:
 an asymmetric bifunctional silyl pro-drug monomer having a formula   
       
         
           
           
               
               
           
         
         wherein R 1′  and R 2′  are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, and a hydrophobic group; 
         wherein M is a residue of one of the following selected from the group consisting of a hydrogel, 2-Hydroxyethyl acrylate, 2-Hydroxyethyl methacrylate, vinyl pyrrolidone, acrylic acid, ethylene oxide or Poly(ethylene oxide) monomers, vinyl alcohol, a protein, an amino acid, and a polysaccharide; 
         wherein X a  and X b  are each independently selected from the group consisting of O, NH, S, and a carboxyl; and 
         wherein R 3′  is selected from the group consisting of a drug, a biologic, or fragments thereof. 
       
     
     
         2 . The monomer of  claim 1 , wherein at least one of X a  and X b  is O. 
     
     
         3 . The monomer of  claim 1 , wherein X a  and X b  are each O. 
     
     
         4 . A molded particle, comprising a crosslinked network of the monomers of  claim 1 . 
     
     
         5 . The molded particle of  claim 4 , wherein the drug comprises a ratio of 0.1 mg of drug to 1 mg of particle. 
     
     
         6 . The molded particle of  claim 4 , wherein the asymmetric bifunctional silyl pro-drug comprises between 1 wt. % and 50 wt. % of the particle. 
     
     
         7 . The molded particle of  claim 4 , wherein the asymmetric bifunctional silyl pro-drug comprises between 1 wt. % and 40 wt. % of the particle. 
     
     
         8 . The molded particle of  claim 4 , wherein asymmetric bifunctional silyl pro-drug comprises between 2 wt. % and 20 wt. % of the particle. 
     
     
         9 . The molded particle of  claim 4 , wherein the molded particle further comprises a three-dimensional shape substantially mimicking the mold shape and a size less than about 50 micrometers in a broadest dimension. 
     
     
         10 . The molded particle of  claim 4 , wherein R 1  and R 2  are ethyl and the particle has a release rate of 2.87 at pH 7.4 relative to a release rate at pH 5.0 of a particle having R 1  and R 2  of ethyl. 
     
     
         11 . The molded particle of  claim 10 , wherein the particle has a first dimension of less than about 200 nanometers and a second dimension greater than about 200 nanometers. 
     
     
         12 . The molded particle of  claim 4 , wherein R 1  and R 2  are isopropyl and the particle has a release rate of 50.4 at pH 5.0 and 201 at pH 7.4 relative to a release rate at pH 5.0 of a particle having R 1  and R 2  of ethyl. 
     
     
         13 . The molded particle of  claim 12 , wherein the particle has a first dimension of less than about 200 nanometers and a second dimension greater than about 200 nanometers. 
     
     
         14 . The molded particle of  claim 4 , wherein R 1  and R 2  are t-butyl and the particle has a release rate of 4968 at pH 5.0 and 9675 at pH 7.4 relative to a release rate at pH 5.0 of a particle having R 1  and R 2  of ethyl. 
     
     
         15 . The molded particle of  claim 14 , wherein the particle has a first dimension of less than about 200 nanometers and a second dimension greater than about 200 nanometers. 
     
     
         16 . A plurality of substantially identically sized and shaped molded particles of  claim 4 . 
     
     
         17 . A method for making a polymer, comprising:
 i. covalently linking a monomer and a silyl via an O, N, S or carboxyl of a monomer to prepare a silyl monomer;   ii. covalently linking a drug to said silyl monomer to prepare a drug-silyl monomer;   iii. cross-linking at least one of said drug-silyl monomers to another said drug-silyl monomer, to form a polymer,
 wherein said monomer and said drug can be different in each drug-silyl monomer, wherein each of said covalent linkages is reversible. 
   
     
     
         18 . The method of  claim 17 , wherein said covalently linking said monomer with said silyl is via a Si—O bond. 
     
     
         19 . A method for reversibly modifying a characteristic of a particle, comprising:
 i. reversibly bonding a silyl group with said particle through a covalent bond,
 wherein said particle comprises a drug; and 
   ii. reversibly bonding to said silyl group a lipid or polymer through a covalent bond;
 wherein said lipid or polymer modifies a characteristic of said particle, 
 wherein i. and ii. can be performed in any order. 
   
     
     
         20 . The method of  claim 19 , wherein said lipid or polymer modifies a hydrophobic or hydrophilic characteristic of said particle. 
     
     
         21 . The method of  claim 19 , further comprising reversing one or more of said covalent bonds. 
     
     
         22 . A molded particle comprising:
 two or more asymmetric bifunctional silyl pro-drug monomers having a formula   
       
         
           
           
               
               
           
         
         wherein, in each monomer, R 1′  and R 2′ , in each instance, are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, and a hydrophobic group; 
         wherein, in each monomer, M is a residue of one of the following selected from the group consisting of a hydrogel, 2-Hydroxyethyl acrylate, 2-Hydroxyethyl methacrylate, vinyl pyrrolidone, acrylic acid, ethylene oxide or Poly(ethylene oxide) monomers, vinyl alcohol, a protein, an amino acid, and a polysaccharide; 
         wherein, in each monomer, X a  and X b , in each instance, are each independently selected from the group consisting of O, NH, S, and a carboxyl; and 
         wherein, in each monomer, R 3′  in each instance, is selected from the group consisting of a drug, a biologic, or fragments thereof, 
         wherein in each monomer, M and said drug can be independently selected from each other monomer. 
       
     
     
         23 . The molded particle of  claim 22 , comprising
 a first asymmetric bifunctional silyl pro-drug monomer having the structure   
       
         
           
           
               
               
           
         
       
       and
 a second asymmetric bifunctional silyl pro-drug monomer having the structure 
 
       
         
           
           
               
               
           
         
         wherein, in each monomer, R 1′  and R 2′ , in each instance, are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, and a hydrophobic group; 
         wherein, in each monomer, M 1  or M 2  is a residue of one of the following selected from the group consisting of a hydrogel, 2-Hydroxyethyl acrylate, 2-Hydroxyethyl methacrylate, vinyl pyrrolidone, acrylic acid, ethylene oxide or Poly(ethylene oxide) monomers, vinyl alcohol, a protein, an amino acid, and a polysaccharide; 
         wherein, in each monomer, X a  and X b , in each instance, are each independently selected from the group consisting of O, NH, S, and a carboxyl; and 
         wherein, in each monomer, R 3′A  or R 3′B , in each instance, is selected from the group consisting of a drug, a biologic, or fragments thereof, 
         wherein, 
         i. M 1  and M 2  are different, 
         ii. R 3′A  and R 3′B  are different, 
         iii. M 1  and M 2  are the same, and R 3′A  and R 3′B  are different, 
         or 
         iv. M 1  and M 2  are different, and R 3′A  and R 3′B  are the same. 
       
     
     
         24 . The molded particle of  claim 23 , further comprising a third asymmetric bifunctional silyl pro-drug monomer having the structure 
       
         
           
           
               
               
           
         
         wherein, in each monomer, R 1′  and R 2′ , in each instance, are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, and a hydrophobic group; 
         wherein, in each monomer, M 3  is a residue of one of the following selected from the group consisting of a hydrogel, 2-Hydroxyethyl acrylate, 2-Hydroxyethyl methacrylate, vinyl pyrrolidone, acrylic acid, ethylene oxide or Poly(ethylene oxide) monomers, vinyl alcohol, a protein, an amino acid, and a polysaccharide; 
         wherein, in each monomer, X a  and X b , in each instance, are each independently selected from the group consisting of O, NH, S, and a carboxyl; and 
         wherein, in each monomer, R 3′C , in each instance, is selected from the group consisting of a drug, a biologic, or fragments thereof, 
         wherein, 
         i. M 1  and M 2  are different than M 3 , or
 ii. R 3′A  and R 3′B  are different than R 3′C .