Porphyrin modified telodendrimers

Abstract

The present invention provides amphiphilic telodendrimers that aggregate to form nanocarriers characterized by a hydrophobic core and a hydrophilic exterior. The nanocarrier core may include amphiphilic functionality such as cholic acid or cholic acid derivatives, and the exterior may include branched or linear poly(ethylene glycol) segments. Nanocarrier cargo such as hydrophobic drugs and other materials may be sequester in the core via non-covalent means or may be covalently bound to the telodendrimer building blocks. Telodendrimer structure may be tailored to alter loading properties, interactions with materials such as biological membranes, and other characteristics.

1 .- 19 . (canceled) 
     
     
         20 . A nanocarrier having an interior and an exterior, the nanocarrier comprising a plurality of first conjugates wherein each conjugate comprises
 a polyethylene glycol (PEG) polymer;   at least two amphiphilic compounds having both a hydrophilic face and a hydrophobic face;   at least one porphyrin;   optionally at least two crosslinking groups; and   a dendritic polymer covalently attached to the PEG, the amphiphilic compounds, the porphyrin and the crosslinking groups,   wherein each conjugate self-assembles in an aqueous solvent to form the nanocarrier such that a hydrophobic pocket is formed in the interior of the nanocarrier by the orientation of the hydrophobic face of each amphiphilic compound towards each other, wherein the PEG of each conjugate self-assembles on the exterior of the nanocarrier.   
     
     
         21 . The nanocarrier of  claim 20 , wherein each conjugate is a compound of formula I:
   (B) k -(PEG) m -A(Y 1 ) p -L 1 -D-[Y 2 -L 2 -R] n   (I)
   
       wherein
 B is a binding ligand; 
 each PEG is the polyethyleneglycol (PEG) polymer having a molecular weight of 1-100 kDa; 
 A comprises at least one branched monomer unit X and is linked to at least one PEG group; 
 D is the dendritic polymer having a single focal point group, a plurality of branched monomer units X and a plurality of end groups; 
 each Y 1  and Y 2  is absent or the crosslinkable group independently selected from the group consisting of boronic acid, dihydroxybenzene and a thiol; 
 each L 1  and L 2  is independently a bond or a linker, wherein L 1  is linked to the focal point group of the dendritic polymer; 
 each R is independently selected from the group consisting of the end group of the dendritic polymer, the porphyrin, a hydrophobic group, a hydrophilic group, the amphiphilic compound and a drug, wherein at least one R group is a porphyrin;
 subscript k is 0 or 1; 
 
 subscript m is an integer from 0 to 20; 
 subscript n is an integer from 2 to 20, wherein subscript n is equal to the number of end groups on the dendritic polymer; and 
 subscript p is from 0 to 8. 
 
     
     
         22 . The nanocarrier of  claim 20 , wherein the nanocarrier further comprises a hydrophobic drug or an imaging agent, such that the hydrophobic drug or imaging agent is sequestered in the hydrophobic pocket of the nanocarrier. 
     
     
         23 . The nanocarrier of  claim 20 , wherein at least one of the monomer units is optionally linked to a member selected from the group consisting of an optical probe, a radionuclide, a paramagnetic agent, a metal chelate and a drug. 
     
     
         24 . The nanocarrier of  claim 22 , wherein the hydrophobic drug is selected from the group consisting of bortezomib, paclitaxel, SN38, camptothecin, etoposide and doxorubicin, docetaxel, daunorubicin, VP16, prednisone, dexamethasone, vincristine, vinblastine, temsirolimus, carmusine, sorafinib, lapatinib, and bortezomiob. 
     
     
         25 . The nanocarrier of  claim 20 , wherein the nanocarrier further comprises a metal cation chelated to the porphyrin. 
     
     
         26 . The nanocarrier of  claim 20 , wherein the nanocarrier further comprises a radio-metal cation selected from the group consisting of  64 Cu,  67 Cu,  177 Lu,  67 Ga,  111 In, and  90 Yt, wherein the radio-metal is chelated to the porphyrin. 
     
     
         27 . The nanocarrier of  claim 20 , wherein the conjugates are crosslinked via the crosslinking groups. 
     
     
         28 . The nanocarrier of  claim 20 , wherein each conjugate comprises:
 at least two cholic acids;   at least two pyropheophorbide-a groups; and   at least two crosslinking groups, wherein the conjugates of the nanocarrier are crosslinked via the crosslinking groups.   
     
     
         29 . The nanocarrier of  claim 28 , further comprising a metal chelated to at least one of the pyropheophorbide-a groups. 
     
     
         30 . The nanocarrier of  claim 20 , further comprising at least one binding conjugate comprising:
 a polyethylene glycol (PEG) polymer;   a binding ligand linked to the PEG polymer;   at least two amphiphilic compounds having both a hydrophilic face and a hydrophobic face;   a dendritic polymer covalently attached to the PEG and the amphiphilic compounds,   wherein each binding conjugate self-assembles with the first conjugates in an aqueous solvent to form the nanocarrier such that a hydrophobic pocket is formed in the interior of the nanocarrier by the orientation of the hydrophobic face of each amphiphilic compound towards each other, wherein the PEG of each conjugate self-assembles on the exterior of the nanocarrier.   
     
     
         31 .- 37 . (canceled) 
     
     
         38 . The nanocarrier of  claim 21 , wherein each branched monomer unit X is a diamino carboxylic acid. 
     
     
         39 . The nanocarrier of  claim 38 , wherein each diamino carboxylic acid is independently selected from the group consisting of 2,3-diamino propanoic acid, 2,4-diaminobutanoic acid, 2,5-diaminopentanoic acid (ornithine), 2,6-diaminohexanoic acid (lysine), (2-Aminoethyl)-cysteine, 3-amino-2-aminomethyl propanoic acid, 3-amino-2-aminomethyl-2-methyl propanoic acid, 4-amino-2-(2-aminoethyl) butyric acid and 5-amino-2-(3-aminopropyl) pentanoic acid. 
     
     
         40 . The nanocarrier of  claim 38 , wherein the diamino carboxylic acid is an amino acid. 
     
     
         41 . The nanocarrier of  claim 38 , wherein each branched monomer unit X is lysine. 
     
     
         42 . The nanocarrier of  claim 21 , wherein linkers L 1  and L 2 , when present, are independently selected from the group consisting of polyethylene glycol, polyserine, polyglycine, poly(serine-glycine), aliphatic amino acids, 6-amino hexanoic acid, 5-amino pentanoic acid, 4-amino butanoic acid and beta-alanine. 
     
     
         43 . The nanocarrier of  claim 21 , wherein linkers L 1  and L 2 , when present, have the formula: 
       
         
           
           
               
               
           
         
       
     
     
         44 . The nanocarrier of  claim 21 , wherein each remaining R is independently selected from the group consisting of cholic acid, (3α, 5β, 7α, 12α)-7,12-dihydroxy-3-(2,3-dihydroxy-1-propoxy)-cholic acid (CA-4OH), (3α, 5β, 7α, 12α)-7-hydroxy-3,12-di(2,3-dihydroxy-1-propoxy)-cholic acid (CA-5OH), (3α, 5β, 7α, 12α)-7,12-dihydroxy-3-(3-amino-2-hydroxy-1-propoxy)-cholic acid (CA-3OH—NH 2 ), cholesterol formate, doxorubicin, and rhein. 
     
     
         45 . The nanocarrier of  claim 21 , wherein each remaining R is cholic acid. 
     
     
         46 . The nanocarrier of  claim 21 , wherein the compound of formula I has the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 PEG is PEG5k; 
 each branched monomer unit X is lysine; 
 A is lysine; 
 each L 2  is a bond or linker Ebes; 
 each Y 2  is absent or is cysteine; and 
 each R is a cholic acid or a porphyrin. 
 
     
     
         47 . The nanocarrier of  claim 46 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein
 each R′ is selected from the group consisting of cholic acid (CA), (3α, 5β, 7α, 12α)-7,12-dihydroxy-3-(2,3-dihydroxy-1-propoxy)-cholic acid (CA-4OH), (3α, 5β, 7α, 12α)-7-hydroxy-3,12-di(2,3-dihydroxy-1-propoxy)-cholic acid (CA-5OH) and (3α, 5β, 7α, 12α)-7,12-dihydroxy-3-(3-amino-2-hydroxy-1-propoxy)-cholic acid (CA-3OH—NH 2 ); and 
 each R″ is a porphyrin selected from the group consisting of pyropheophorbide-a, pheophorbide, chlorin e6, purpurin and purpurinimide. 
 
     
     
         48 . The nanocarrier of  claim 47 , wherein the porphyrin is pyropheophorbide-a. 
     
     
         49 . The nanocarrier of  claim 47 , wherein the compound is selected from the group consisting of:
 (1) each L 2  is a bond, each Y 2  is absent, each R′ is cholic acid, each R″ is pyropheophorbide-a, and subscript k is 0;   (2) each L 2  is the linker Ebes, each Y 2  is absent, each R′ is cholic acid, each R″ is pyropheophorbide-a, and subscript k is 0;   (3) each L 2  is a bond, each Y 2  is cysteine, each R′ is cholic acid, each R″ is pyropheophorbide-a, and subscript k is 0;   (4) each L 2  is the linker Ebes, each Y 2  is cysteine, each R′ is cholic acid, each R″ is pyropheophorbide-a, and subscript k is 0;   (5) each L 2  is a bond, each Y 2  is absent, each R′ is cholic acid, each R″ is pyropheophorbide-a, and subscript k is 1;   (6) each L 2  is the linker Ebes, each Y 2  is absent, each R′ is cholic acid, each R″ is pyropheophorbide-a, and subscript k is 1;   (7) each L 2  is a bond, each Y 2  is cysteine, each R′ is cholic acid, each R″ is pyropheophorbide-a, and subscript k is 1; and   (8) each L 2  is the linker Ebes, each Y 2  is cysteine, each R′ is cholic acid, each R″ is pyropheophorbide-a, and subscript k is 1.