Photoactivatable caged tamoxifen and tamoxifen derivative molecules and methods of use thereof

Abstract

Provided herein are compositions containing photoactivatable caged tamoxifen and tamoxifen derivative molecules. Also provided are kits containing one of these compositions and a light source. Also provided are methods of optically inducing nuclear translocation of a fusion protein containing a mammalian estrogen receptor ligand binding domain in a eukaryotic cell and methods of optically inducing recombination in a eukaryotic cell that include contacting a eukaryotic cell with at least one of these compositions. Also provided are methods of treating breast cancer in a subject that include administering a photoactivatable caged tamoxifen or tamoxifen derivative molecule to a subject having breast cancer.

1 . A composition, comprising: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The composition of  claim 1 , wherein the composition comprises 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The composition of  claim 2 , wherein the composition is formulated as a liquid. 
     
     
         4 . A kit comprising:
 one or more doses of the composition of  claim 1 ; and   a light source that emits light of a wavelength of between 350 nm to 410 nm.   
     
     
         5 . A method of inducing nuclear translocation of a fusion protein comprising a human estrogen receptor ligand binding domain in a eukaryotic cell, the method comprising:
 providing a eukaryotic cell that contains a fusion protein comprising a human estrogen receptor ligand binding domain,   contacting the eukaryotic cell with the composition of  claim 1 ; and   irradiating the eukaryotic cell with a wavelength of light between 350 nm to 410 nm for a period of time sufficient to release 4-hydroxycyclofen from the composition,   wherein the released 4-hydroxycyclofen induces the nuclear translocation of the fusion protein.   
     
     
         6 . The method of  claim 5 , wherein the eukaryotic cell is in a mammal. 
     
     
         7 . The method of  claim 6 , wherein the eukaryotic cell is present in the mammary gland or the skin. 
     
     
         8 . The method of  claim 6 , wherein the composition is locally administered to a target tissue in the mammal that contains the eukaryotic cell. 
     
     
         9 . The method of  claim 5 , wherein the eukaryotic cell comprises a nucleic acid encoding the fusion protein, and the nucleic acid is stably integrated into a chromosome of the cell. 
     
     
         10 . The method of  claim 9 , wherein the nucleic acid encoding the fusion protein is:
 operably linked to a tissue-specific promoter sequence; or   operably linked to an inducible promoter sequence, and the eukaryotic cell is further contacted with a chemical inducing agent.   
     
     
         11 . The method of  claim 5 , wherein the fusion protein comprises:
 a sequence of a recombinase, and the fusion protein has recombinase enzymatic activity;   a sequence of a transcription factor, and the fusion protein is capable of promoting gene transcription in the nucleus of the eukaryotic cells;   a sequence of a transcription repressor, and the fusion protein is capable of repressing transcription of a gene in the nucleus of the eukaryotic cell;   a sequence of a histone deacetylase and the fusion protein has histone deacteylase activity;   a sequence of a histone acetyltransferase and the fusion protein has histone deacetylase activity;   a sequence of an O-6-methylguanosine-DNA methyltransferase and the fusion protein O-6-methylguanine-DNA methyltransferase activity;   a sequence of a telomerase, and the fusion protein has telomerase activity; or   a sequence of an oncogene.   
     
     
         12 . The method of  claim 5 , wherein the eukaryotic cell is an undifferentiated cell, and the fusion protein comprises a sequence of a transcription factor or transcription repressor that induces cellular differentiation. 
     
     
         13 . A method of inducing recombination in a eukaryotic cell, the method comprising:
 providing a eukaryotic cell that comprises (i) a nucleic acid encoding a fusion protein comprising a sequence of a recombinase and a sequence of a human estrogen receptor ligand binding domain, wherein the fusion protein has recombinase activity, and (ii) a recombinase recognition sequence that is specifically recognized by the fusion protein, wherein both the nucleic acid encoding the fusion protein and the recombinase recognition sequence are integrated into a chromosome within the nucleus of the eukaryotic cell;   contacting the eukaryotic cell with a composition of  claim 1 ; and   irradiating the eukaryotic cell with a wavelength of light between 350 nm to 410 nm for a period of time sufficient to release 4-hydroxycyclofen from the composition,   wherein the 4-hydroxycyclofen stimulates the nuclear importation of the fusion protein and the fusion protein stimulates recombination at the recombinase recognition sequence.   
     
     
         14 . The method of  claim 13 , wherein the eukaryotic cell is in a mammal. 
     
     
         15 . The method of  claim 14 , wherein the eukaryotic cell is present in the mammary gland or the skin. 
     
     
         16 . The method of  claim 14 , wherein the composition is locally administered to a target tissue in the mammal that contains the eukaryotic cell. 
     
     
         17 . The method of  claim 13 , wherein the recombination results:
 in a decrease in the expression of a transgene located between two recombinase recognition sequences in the chromosome;   in the replacement of a sequence between two recombinase recognition sequences with a new transgenic sequence; or   in the increase in the proximity of a promoter or enhancer sequence to a transgene, wherein the recombination results in increased expression of the transgene.   
     
     
         18 . The method of  claim 13 , wherein the nucleic acid encoding the fusion protein is:
 operably linked to tissue specific promoter sequence in the chromosome of the eukaryotic cell; or   operably linked to an inducible promoter in the chromosome of the eukaryotic cell, and the eukaryotic cell is further contacted with a chemical inducing agent.   
     
     
         19 . A method of treating breast cancer in a subject diagnosed as having breast cancer, the method comprising:
 administering to the subject an amount of the composition of  claim 1  sufficient to treat breast cancer in a subject, and   irradiating the mammary tissue of the subject with light between 350 nm and 410 nm,   wherein the irradiating mediates the release of 4-hydroxytamoxifen in the irradiated mammary tissue.   
     
     
         20 . The method of  claim 19 , wherein the composition is locally administered to the mammary tissue of the subject.