Receptor Mediated Targeting To Enhance Therapeutic Efficacy Of Chemotherapeutic Agents PDF Download

Dr. Paul Ehlrich introduced the concept of targeted drug delivery in 1904. With the advancement in technology, and molecular biology techniques, several new targeting moieties have been developed in the past two decades. These targeting molecules improve the therapeutic efficacy of the drug, and alleviate systemic toxicity. Drug delivery devices, including, nanoparticles and polymer-drug pendant chains have been thoroughly investigated for targeting applications. Cancer has been the focus for development of efficient targeted drug delivery devices and new therapies because of poor prognosis, and socio-economic impact. One of the main aims of this research is to design and develop a targeted drug delivery device with the goal of achieving receptor mediated targeting to the tumor and alleviate systemic toxicity. Therefore, peptide targeted nanoparticles and hyaluronan based self-targeting polymer-chain pendant system have been developed and tested with two novel chemotherapeutic agents, resveratrol and MOMIPP. Peptides Lyp1 and p160 have been chosen for targeting L-tyrosine polyphosphate nanoparticles because of their ability to selectively bind with certain breast cancers. Lyp1 targeted nanoparticles show 5 and 7 fold greater attachment to MB157 and MB231 cells, while p160 targeted nanoparticles exhibit 3-fold greater attachment to MCF7 cells, under physiological flow compared to untargeted nanoparticles or non-cancerous cells. This attachment is stable since the attached nanoparticles do not detach at shear stresses encountered in the tumor interstitium. Hyaluronan, a hydrophilic biopolymer plays an important role in tumor development and metastasis, hence, several cancers over-express hyaluronan binding receptors, CD44 and RHAMM. The availability of multiple functional groups on hyaluronan allows for attachment of drugs, therefore, hyaluronan is an ideal candidate for development of self-targeted drug delivery device. Hyaluronan conjugates exhibit enhanced attachment to CD44 over-expressing MB157 cells compared to non-conjugated drug. Further, hyaluronan conjugated resveratrol and MOMIPP exhibit up to 12-fold greater toxicity against certain cancers in vitro. Hyaluronan also shows enhanced attachment to breast cancer cells under physiological flow conditions compared to noncancerous cells. Animals injected with hyaluronan conjugates via tail-vein show greater accumulation in the tumors compared to kidneys and livers, which translates to a reduced tumor mass. Thus, these hyaluronan conjugates suggest hyaluronan's potential as a "magic bullet" to target and deliver therapeutic agents specifically to the cell of interest.