Utilization of Glycosaminoglycans/Proteoglycans as Carriers for Targeted Therapy Delivery

Figure 9

Exploitation of HA-CD44 interaction for anticancer therapy. Left panel represents the internalization of HA-drug conjugate that ultimately releases the drug that inhibits DNA synthesis of cancer cells. CD44 on the cell membrane binds the HA-drug conjugate and is internalized by endocytosis. The endosome formed is moved to the lysosome and fused. Here the HA in the conjugate is degraded first by hyaluronidase 1 (Hyal-1) into small HA oligosaccharides and next by lysosomal glycosidases to monosaccharides followed by release of the drug. The drug inhibits the DNA synthesis in the nucleus. Right panel exemplifies the steps that target the CD44v6mRNA in cancer cells by CD44v6shRNA. Plasmids producing CD44v6shRNA are coated with transferrin containing nanoparticles to target transferrin receptors of the cells. The particles are then internalized and form an endosome from which the plasmids are released to the nucleus where activation of DNA pol III occurs that results in CD44v6shRNA production. Through exportin, the newly produced CD44v6shRNA come out into cytoplasm where it is converted into CD44v6siRNA by dicer enzyme. One of the strands of siRNA will bind to CD44v6mRNA and forms RNA-induced silencing complex (RISC) which is ultimately degraded.