Compositions and methods for enhancing receptor-mediated cellular internalization

Abstract

Compositions and methods for improving cellular internalization of one or more compounds are disclosed. The compositions include a compound to be delivered and a biocompatible viscous material, such as a hydrogel, lipogel, or highly viscous sol. The composition also include, or are administered in conjunction with, an enhancer in an amount effective to maximize expression of or binding to receptors and enhance RME of the compound into the cells. This leads to high transport rates of compounds to be delivered across cell membranes, facilitating more efficient delivery of drugs and diagnostic agents. Compositions are applied topically orally, nasally, vaginally, rectally, and ocularly. The enhancer is administered with the composition or separately, either systemically or preferably locally. The compound to be delivered can also be the enhancer.

1. A composition for the administration of an agent to a cell comprising
 a viscous material and an agent to be delivered, wherein the viscous material comprises a polysaccharide in a concentration range of between 1.0 and 2.0% (w/w), and wherein the agent is selected from the group consisting of proteins, peptides, nucleotide molecules, saccharides, polysaccharides, lipids, synthetic chemotherapeutic agents, and diagnostic compounds, wherein the composition has an apparent viscosity of less than 10 Poise or greater than 2000 Poise at a shear stress of between approximately 1 and 200 Pascal.    
     
     
       2. The composition of  claim 1 , wherein the composition has approximately the same apparent viscosity, at a shear stress of between approximately 1 and 1000 Pascal and at a strain rate approximately that of endocytosis, as the cytosolic fluid of the cell to which the agent is to be delivered. 
     
     
       3. The composition of  claim 1  wherein the concentration of the polysaccharide is less than or equal to 1.75% (w/w). 
     
     
       4. The composition of  claim 1 , wherein the agent is selected from the group consisting of insulin, alpha interferons, beta interferon, follicle stimulating hormone, and growth factors. 
     
     
       5. A method for delivering an agent to cells at a site where uptake is desired comprising administering to the cells at the site where uptake is desired a composition comprising
 (a) a viscous material comprising a polysaccharide in a concentration range of between 1.0 and 2.0% (w/w), and    (b) the agent to be delivered, wherein the agent is selected from the group consisting of proteins, peptides, nucleotide molecules, saccharides, polysaccharides, lipids, synthetic chemotherapeutic agents, and diagnostic compounds,    wherein the composition has an apparent viscosity of less than 10 Poise or greater than 2000 Poise at a shear stress of between approximately 1 and 200 Pascal.    
     
     
       6. The method of  claim 5 , wherein the cells to which the agent is to be delivered are in the nose, rectum, mouth, ear, eye, or lungs. 
     
     
       7. The method of method of  claim 5 , wherein the composition is administered topically. 
     
     
       8. The method of  claim 5 , wherein the site is mucosal tissue. 
     
     
       9. The method of  claim 5 , wherein the site is lower gastrointestinal tract mucosal tissue. 
     
     
       10. The method of  claim 5 , wherein site is the vagina or rectum. 
     
     
       11. The method of  claim 5 , wherein the site is the nose, eye, or mouth. 
     
     
       12. The method of  claim 5 , wherein the site is the respiratory or pulmonary system. 
     
     
       13. The composition of  claim 1  wherein the polysaccharide is selected from the group consisting of celluloses, dextrans and alginates. 
     
     
       14. The method of  claim 5  wherein the polysaccharide is selected from the group consisting of celluloses, dextrans and alginates. 
     
     
       15. The composition of  claim 13  wherein the polysaccharide is methylcellulose. 
     
     
       16. The method of  claim 14  wherein the polysaccharide is methylcellulose. 
     
     
       17. A composition for delivering a hormone to cells at a site where uptake is desired comprising
   a viscous fluid selected from the group consisting of hydrogels, lipogels and sols having a viscosity of between  2  and  200  Poise when measured at  37 ° C. with a standard rheometer at an applied stress ranging from  1  to  100  Pascals; and        the hormone,        wherein the viscous fluid comprises a polysaccharide.     
     
     
       18. The composition of  claim 17 , wherein the hormone is a reproductive hormone. 
     
     
       19. The composition of  claim 18 , wherein the reproductive hormone is selected from the group consisting of estrogen, estradiol and progesterone. 
     
     
       20. The composition of  claim 17 , wherein the viscous material is a hydrogel. 
     
     
       21. The composition of  claim 17 , wherein the viscous fluid is  1 -   2   % ( w/w )  methocel.   
     
     
       22. The composition of  claim 17 , wherein the polysaccharide is a cellulose. 
     
     
       23. The composition of  claim 22 , wherein the cellulose is methylcellulose. 
     
     
       24. The composition of  claim 18 , wherein the reproductive hormone is gonadotropin releasing hormone ( GnRH )  or an analog of GnRH.   
     
     
       25. The composition of  claim 24 , wherein the viscous fluid is  1 -   2   % ( w/w )  methocel.   
     
     
       26. The composition of  claim 17 , wherein the composition is in a formulation suitable for administration to mucosa of tissue. 
     
     
       27. The composition of  claim 26 , wherein the tissue is lower gastrointestinal tract mucosal tissue. 
     
     
       28. The composition of  claim 17 , wherein the composition is in a form suitable for administration to the vagina or rectum. 
     
     
       29. The composition of  claim 26 , wherein the tissue is selected from the group consisting of tissue of the nose, the rectum, the vagina, the mouth, the ear, the eye, and the lungs.