By Dr. Shruti Bhat
Several routes viz. ocular, nasal, buccal, respiratory, stomach, colon, rectal and vaginal have already been explored for peptide based drugs such as angiotensins, badykinin, calcitonin, t-PA, urokinase, neuropeptide Y, enkephalin, interferon, insulin, oxytocin, gonadotrophins, etc. Presently, there are over 250 products formulated using biotechnology based peptide actives pending the USFDS marketing approval.
Alongside development of new delivery presentations as well as biotech based actives such as peptides, a new biochemical pathway based on carbohydrates uptake and metabolism using cell surface “landscape” engineering technique is currently being investigated. This route promises a novel approach to tissue engineering and presents variety of applications in bringing about modifications of tumor cells that could increase their uptake of drugs. The groups of sialic acid derivatives- “landscape cell” that is chemically unique to the cell surface is being used as a “ chemical handle” for attaching molecular probes or various bio molecules. These cells revolutionize the ability to interface biological tissues since they selectively bind to synthetic/ natural drug moieties and deliver drugs on site. The hypothesis based on the fact that breast, colorectal and lung cancer cells produce unusually large amounts of receptor chemicals CD 44 and RHAMM- involved in initiating a cascade of events that lead to proliferation of both defense and cancer cells. This finding is particularly exciting since one of the technical barriers to effective use of gene therapy approach is targeting the antisepses (molecule) to the site of pathology. Hyaluronic acid, a disaccharide has been studied as a carrier for several drugs viz. diclofenac, cyclosprorine, paclitaxel, DNA as well as RNA (gene medications). Animal studies have shown that hyaluronan bound cyclosporine is more effective than cyclosporine alone in promoting cell death in colorectal tumors.
In studies in vitro, hyaluronan-anti sense RNA combination has proved 10-0 times more effective than antisense RNA alone in inhibiting cell proliferation of rat hepatoma cells. Similar was the observation with diclofenac sodium complexed with hyaluronan; the complex showing increased anti-inflammatory activity than diclofenac alone.
On a different front, researchers have unraveled the mechanism of protein carbohydrate interactions among cells involved in the inflammation process. It has been found that 3 proteins (so far identified) viz. L-selectin (on leukocyte), E-selectin and P-selectin (on endothelial cell wall) participate in the inflammatory response, each interacting with specific glycoprotein ligands. Knowing that the affinity and specificity of protein- carbohydrate interactions often depend on the formation of multiple receptor-ligand complexes, the researchers decided to use open ring polymerization technique to synthesize biologically active ligands containing multiple sulfated sugars (sulfated neoglycopolymers) that might target specific selections. The multi-valent saccharide derivatives may lead to completely new strategies for the modulation of cell –cell recognition.
In conclusion, it can be stated that pharmaceutical science and technology have progressed since 80’s on both the fronts – (i) new moieties/ pathways as well as (ii) novel presentation forms. Continued success to both !!
In the next post I shall take up challenges in Controlled release drug delivery systems.
By Dr. Shruti Bhat
Shruti U. Bhat