Fucoidan nanogels and methods of their use and manufacture

Abstract

Described herein are polymeric drug-carrying nanogels that are capable of targeting to P-selectin for the treatment of cancer and other diseases and conditions associated with P-selectin. Furthermore, in certain embodiments, the nanogels presented here offer a drug release mechanism based on acidic pH in the microenvironment of a tumor, thereby providing improved treatment targeting capability and allowing use of lower drug doses, thereby reducing toxicity.

What is claimed is: 
     
         1 . A polymeric nanogel with affinity to P-selectin, the nanogel comprising:
 (i) a sulfated polymer species comprising free hydroxyl moieties and sulfate moieties capable of targeting P-selectin; and   (ii) a drug.   
     
     
         2 . The nanogel of  claim 1 , wherein the sulfated polymer species is selected from the group consisting of a sulfated polysaccharide, protein, and a fucoidan. 
     
     
         3 . The nanogel of  claim 1 , wherein the drug is a cationic drug. 
     
     
         4 . The nanogel of  claim 2 , wherein the fucoidan is a sulfated polysaccharide comprising sulfated ester moieties of fucose. 
     
     
         5 . The nanogel of  claim 1 , comprising nanoparticles having a core comprising albumin and a surface comprising fucoidan. 
     
     
         6 . The nanogel of  claim 1 , comprising polyethylene glycol (PEG), wherein the drug is conjugated to the polyethylene glycol via hydrozone linkages. 
     
     
         7 . The nanogel of  claim 1 , wherein the drug is not chemically conjugated to the sulfated polymer species, but is electrostatically bound to the sulfated polymer species. 
     
     
         8 . The nanogel of  claim 7 , wherein the sulfated polymer species is a fucoidan. 
     
     
         9 . The nanogel of  claim 1 , wherein the drug is selected from the group comprising doxorubicin (DOX) and vincristine. 
     
     
         10 . The nanogel of  claim 1 , wherein the drug is a cationic drug that comprises one or more members selected from the group consisting of DOX, vincristine, paclitaxel, MEK162, ispinesib, daunorubicin (daunomycin), doxorubicin (adriamycin), epirubicin, idarubicin, valrubicin, mitoxantrone, vinblastine, vindesine, vinorelbine, bleomycin, actinomycin D, sorafenib, camptothecin, topotecan, and irinotecan. 
     
     
         11 . The nanogel of  claim 1 , comprising fucoidan and DOX-PEG-DOX constructs. 
     
     
         12 . The nanogel of  claim 1 , comprising fucoidan on the surface of nanoparticles of the nanogel. 
     
     
         13 . The nanogel of  claim 1 , wherein the nanogel comprises particles having an average particle diameter selected from the group consisting of: from about 20 nm to about 400 nm, from about 100 nm to about 200 nm, and from about 150 nm to about 170 nm. 
     
     
         14 . The nanogel of  claim 1 , wherein the nanogel further comprises a fluorophore. 
     
     
         15 . The nanogel of  claim 1 , wherein the fluorophore is a near infra-red dye, and wherein the infra-red dye is IR783. 
     
     
         16 . A method of treating a P-selectin associated disease, the method comprising a step of:
 administering, to a subject in need of treatment, a formulation comprising the nanogel of  claim 1 ,
 wherein the nanogel binds to P-selectin and translocates an active endothelial barrier. 
   
     
     
         17 . The method of  claim 16 , wherein the subject is human and the formulation is a therapeutic agent. 
     
     
         18 . The method of  claim 16 , wherein the P-selectin associated disease is a member selected from the group consisting of carcinoma, sarcoma, lymphoma, leukemia, sickle cell disease, arterial thrombosis, rheumatoid arthritis, ischemia, and reperfusion. 
     
     
         19 . The method of  claim 16 , comprising administering a radiotherapeutic, wherein the nanogel provides improved P-selectin targeting and activity. 
     
     
         20 . The method of  claim 19 , wherein, upon delivery of the drug to P-selectin, a local environment having an acidic pH causes release of the drug from the nanogel. 
     
     
         21 . The method of  claim 20 , wherein the nanogel comprises PEG and the local acidic pH environment results in breakage of hydrozone linkages between the PEG and the drug. 
     
     
         22 . A method for manufacturing a nanogel comprising contacting fucoidan and a drug-PEG construct in the presence of a salt to form hydrogel aggregates, and agitating, by sonicating, the hydrogel aggregates to form nanoparticles. 
     
     
         23 . The method of  claim 22 , wherein the drug-PEG construct is DOX-PEG-DOX. 
     
     
         24 . The method of  claim 22 , wherein the salt is a phosphonobile salt (PBS). 
     
     
         25 . A method for manufacturing a nanogel comprising:
 contacting albumin, fucoidan, and sorafenib in an aqueous salt solution to form hydrogel aggregates; and   agitating, by sonicating, the hydrogel aggregates to form nanoparticles.   
     
     
         26 . The method of  claim 25 , wherein the albumin is Human Serum Albumin. 
     
     
         27 . The method of  claim 25 , wherein the salt solution is a phosphonobile salt (PBS). 
     
     
         28 . A method for manufacturing a nanogel comprising:
 contacting fucoidan and paclitaxel in an aqueous solution to form hydrogel aggregates; and   agitating, by sonicating, the hydrogel aggregates to form nanoparticles.   
     
     
         29 . A polymeric fucoidan-based nanogel with affinity to P-selectin, the nanogel comprising a non-covalent assembly of fucoidan and a hydrophobic drug.