Color-Coded Polymeric Particles of Predetermined Size for Therapeutic and/or Diagnostic Applications and Related Methods

Abstract

Various embodiments are directed to color-coded and size-calibrated polymeric particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising polyphosphazenes of formula I, useful for various therapeutic and/or diagnostic procedures. In various embodiments, the color-coded and size-calibrated polymeric particles can be employed in any particle-mediated procedure, including as embolic agents, dermal fillers, and various implantable devices for a broad range of clinical and cosmetic applications. The incorporation of a particular chromophore formulation that correlates with a pre-determined size specificity for implantable and loadable polymeric particles (“color-coded and size-calibrated”) enables the visual detection and identification of particles exhibiting a particular size of interest, and minimizes the probability of user-introduced or procedural errors.

We claim: 
     
         1 . Color-coded and size-calibrated polymeric particles, each particle comprising:
 an acrylate-based hydrogel core incorporating one or more chromophores; and   an outer shell comprising a polyphosphazenes having the general formula (I):   
       
         
           
           
               
               
           
         
         in which the n value is an integer from 2 to ∞; 
         R 1  to R 6  are independently selected from the group consisting of: 
         a substituted or unsubstituted alkyl, alkoxy, aryl, aryloxy, silyl, silyloxy, alkylsulfonyl, alkyl amino, dialkyl amino, ureido, carboxylic acid ester, alkylmonoamidine, alkylbisamidine, alkoxymonoamidine, or alkoxybisamidine, aminoalkyl, haloalkyl, thioalkyl, thioaryl, haloalkoxy, aryloxy, haloaryloxy, alkylthiolate, arylthiolate, alkylsulphonyl, alkylamino, dialkylamino, heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, and combinations thereof, heteroaryl comprising one or more heteroatoms selected from nitrogen, oxygen, sulfur, phosphorus, and combinations thereof. 
       
     
     
         2 . The color-coded and size-calibrated polymeric particles of  claim 1 , wherein R 1  to R 6  are selected independently from the group consisting of OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCF 3 , OCH 2 CF 3 , OCH 2 CH 2 CF 3 , OCH 2 CF 2 CF 3 , OCH(CF 3 ) 2 , OCCH 3 (CF 3 ) 2 , OCH 2 CF 2 CF 2 CF 3 , OCH 2 (CF 2 ) 3 CF 3 , OCH 2 (CF 2 ) 4 CF 3 , OCH 2 (CF 2 ) 5 CF 3 , OCH 2 (CF 2 ) 6 CF 3 , OCH 2 (CF 2 ) 7 CF 3 , OCH 2 CF 2 CHF 2 , OCH 2 CF 2 CF 2 CHF 2 , OCH 2 (CF 2 ) 3 CHF 2 , OCH 2 (CF 2 ) 4 CHF 2 , OCH 2 (CF 2 ) 5 CHF 2 , OCH 2 (CF 2 ) 6 CHF 2 , OCH 2 (CF 2 ) 7 CHF 2 , OCH 2 CH═CH 2 , OCH 2 CH 2 CH═CH 2 , and any combinations thereof. 
     
     
         3 . The color-coded and size-calibrated polymeric particles of  claim 1 , wherein the polyphosphazene is poly[bis(2,2,2-trifluoroethoxy)]phosphazene or a derivative of poly[bis(2,2,2-trifluoroethoxy)]phosphazene. 
     
     
         4 . The color-coded and size-calibrated polymeric particles of  claim 1 , wherein the acrylate-based hydrogel core comprises a polymer selected from the group consisting of poly(methacrylic acid), poly(methyl acrylate), poly(methyl methacrylate), poly(ethyl methacrylate), poly(hexamethyl methacrylate), poly(hydroxyethyl methacrylate), poly(acrylic acid), poly(butyl acrylate), poly(2-ethylhexyl acrylate), poly(ethyl acrylate), poly(acrylonitrile), poly(trimethylolpropane triacrylate), copolymers thereof, and combinations thereof. 
     
     
         5 . The color-coded and size-calibrated polymeric particles of  claim 1  calibrated to have an average diameter selected from the group consisting of: from about 10 μm to about 1500 μm; from about 10 μm to about 1100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μm to about 600 μm; from about 10 μm to about 500 μm; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 120 μm; from about 10 μm to about 80 μm; and from about 10 μm to about 40 μm. 
     
     
         6 . The color-coded and size-calibrated polymeric particles of  claim 1 , wherein the acrylate-based hydrogel core comprises an agent of interest selected from the group consisting of barium sulfate, an imaging agent, a bioactive agent, a pharmaceutical agent, a contrast agent, a steroid, a hormone, a nucleic acid, an antibiotic, an antiseptic, an analgesic, an anti-neoplastic, an anesthetic, and combinations thereof. 
     
     
         7 . A method of making color-coded and size-calibrated polymeric particles, the method comprising:
 incorporating one or more chromophores into an acrylate-based hydrogel core; and   coating the acrylate-based hydrogel core with a polyphosphazene having the general formula (I):   
       
         
           
           
               
               
           
         
         in which the n value is an integer from 2 to ∞; 
         R 1  to R 6  are independently selected from the group consisting of: 
         a substituted or unsubstituted alkyl, alkoxy, aryl, aryloxy, silyl, silyloxy, alkylsulfonyl, alkyl amino, dialkyl amino, ureido, carboxylic acid ester, alkylmonoamidine, alkylbisamidine, alkoxymonoamidine, or alkoxybisamidine, aminoalkyl, haloalkyl, thioalkyl, thioaryl, haloalkoxy, aryloxy, haloaryloxy, alkylthiolate, arylthiolate, alkylsulphonyl, alkylamino, dialkylamino, heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, and combinations thereof, heteroaryl comprising one or more heteroatoms selected from nitrogen, oxygen, sulfur, phosphorus, and combinations thereof. 
       
     
     
         8 . The method of  claim 7 , wherein R 1  to R 6  are selected independently from the group consisting of OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCF 3 , OCH 2 CF 3 , OCH 2 CH 2 CF 3 , OCH 2 CF 2 CF 3 , OCH(CF 3 ) 2 , OCCH 3 (CF 3 ) 2 , OCH 2 CF 2 CF 2 CF 3 , OCH 2 (CF 2 ) 3 CF 3 , OCH 2 (CF 2 ) 4 CF 3 , OCH 2 (CF 2 ) 5 CF 3 , OCH 2 (CF 2 ) 6 CF 3 , OCH 2 (CF 2 ) 7 CF 3 , OCH 2 CF 2 CHF 2 , OCH 2 CF 2 CF 2 CHF 2 , OCH 2 (CF 2 ) 3 CHF 2 , OCH 2 (CF 2 ) 4 CHF 2 , OCH 2 (CF 2 ) 5 CHF 2 , OCH 2 (CF 2 ) 6 CHF 2 , OCH 2 (CF 2 ) 7 CHF 2 , OCH 2 CH═CH 2 , OCH 2 CH 2 CH═CH 2 , and combinations thereof. 
     
     
         9 . The method of  claim 7 , wherein the acrylate-based hydrogel core comprises a polymer selected from the group consisting of poly(methacrylic acid), poly(methyl acrylate), poly(methyl methacrylate), poly(ethyl methacrylate), poly(hexamethyl methacrylate), poly(hydroxyethyl methacrylate), poly(acrylic acid), poly(butyl acrylate), poly(2-ethylhexyl acrylate), poly(ethyl acrylate), poly(acrylonitrile), poly(trimethylolpropane triacrylate), copolymers thereof, and combinations thereof. 
     
     
         10 . The method of  claim 7 , wherein the color-coded and size-calibrated polymeric particles are calibrated to have an average diameter selected from the group consisting of: from about 10 μm to about 1500 μm; from about 10 μm to about 1100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μm to about 600 μm; from about 10 μm to about 500 μm; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 120 μm; from about 10 μm to about 80 μm; and from about 10 μm to about 40 μm. 
     
     
         11 . The color-coded and size-calibrated polymeric particles of  claim 1 , wherein the acrylate-based hydrogel core comprises an agent of interest selected from the group consisting of barium sulfate, an imaging agent, a bioactive agent, a pharmaceutical agent, a contrast agent, a steroid, a hormone, a nucleic acid, an antibiotic, an antiseptic, an analgesic, an anti-neoplastic, an anesthetic, and combinations thereof. 
     
     
         12 . A method of selective embolization at a site in need of, the method comprising,
 administering color-coded and size-calibrated particles of  claim 1  to a patient in need of.