Cationic polysaccharides for delivery of phosphoinositides to cells for therapeutic purpose
The present invention provides a complex comprising at least one phosphoinositide and at least one positively charged modified polysaccharide, pharmaceutical compositions comprising the complex, methods for treatment of a disease, disorder or condition associated with impaired phosphoinositide-mediated signaling comprising administering the complex to an subject in need, and methods for delivery of a phosphoinositide into cells, comprising contacting the cells with the complex of the invention.
1. A complex comprising at least one phosphoinositide and at least one positively charged modified polysaccharide, wherein said positively charged modified polysaccharide is quaternized starch, wherein the molar ratio of positively charged amine groups on said at least one positively charged modified polysaccharide to negatively charged phosphate groups in the at least one phosphoinositide is at least 2.
2. The complex according to claim 1 , wherein the molecular weight of said quaternized starch is in a range selected from the group consisting of 10 3 to 10 8 daltons, 10 4 to 10 5 daltons, and 10 4 to 5×10 4 daltons, or the molecular weight is about 26,500 daltons.
3. The complex according to claim 1 , wherein said phosphoinositide is selected from the group consisting of phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 4-phosphate (PI4P) phosphatidylinositol 5-phosphate (PI5P), phosphatidylinositol 3,4-bisphosphate (PI(3,4)P 2 ), phosphatidylinositol 3,5-bisphosphate (PI(3,5)P 2 ), phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ), and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P 3 or PIP 3 ).
4. The complex according to claim 3 , wherein said phosphoinositide is PI3P or PIP 3 .
5. The complex according to claim 1 , wherein the molar ratio of the positively charged amine groups on said at least one positively charged modified polysaccharide to the negatively charged phosphate groups in the at least one phosphoinositide is about 2.
6. The complex according to claim 1 in the form of a nanoparticle.
7. The complex according to claim 1 , further comprising a targeting ligand.
8. A method for enhanced localization of a phosphoinositide to cell membranes, comprising contacting cells with a complex comprising at least one phosphoinositide and at least one positively charged modified polysaccharide, wherein said positively charged modified polysaccharide is quaternized starch, and wherein the molar ratio of positively charged amine groups on said at least one positively charged modified polysaccharide to negatively charged phosphate groups in the at least one phosphoinositide is at least 2; or a pharmaceutical composition comprising the complex.
9. The method of claim 8 , wherein said cells are mammalian cells, including muscle cells, liver cells, fat cells, macrophages, keratinocytes, or stem cells.