Dr. David Sanabria

Inter-American University of Puerto Rico

Metropolitan Campus

dsanabria@intermetro.edu

 

“Development of NPs containing Dxtl an NChalc for controlled chemotherapy”

PROJECT SUMMARY

The importance of this project is underscored by the problem of the prostate cancer (PC) resistance to the currents anticancer chemotherapies which causes that 1.7% of 2 million people diagnosed with PC die as a result of this disease. Although the knowledge about cancer disease has advanced greatly, death rates have been only falling 1.5% each year over 2002-2011, being PC the second leading cause of cancer related deaths in male in the United States. Docetaxel (Dtxl) is a potent antitumor agent, which has been widely used in chemotherapy against androgen dependent and androgen independent PCs. Despite Dtxl currently represents the most active chemotherapeutic agents, it only gives a modest survival advantage, since most patients eventually acquire resistance towards this drug creating a critical need to develop more enhanced and effective therapeutic options for treating highly metastatic PC. Recent investigations agrees that the development of nanoparticle (NP) drug delivery vehicles offers an unprecedented opportunity for targeted drug delivery to the tumor and tumor supportive cells of the microenvironment. Some advantages such as preferential accumulation in tumors and controlled release have been attributed to NPs, which make this approach suitable for chemotherapy applications. Recently, our group encapsulated a nitrochalcone (NChalc) using the poly (lactic-co-glycolic acid)-NP (PLGA-NP) approach and demonstrated that this PLGA NP system enhanced the anticancer activity against the highly metastatic prostate cancer cell line PC-3 when compared to NChalc alone. Although the mechanism of action PC inherency remains unknown, several studies have shown that the inhibition of the NFkB is linked with the enhanced sensitivity of tumors to cytotoxic anticancer drugs, while other studies demonstrated that the NFkB is related to chemoresistance of PC cells. Therefore, our central hypothesis is that the combination of both Dtxl PLGA NPs and NChalc PLGA NPs will enhance the anticancer activity in PC-3 when compared to Dtxl through the inhibition of the transcriptional activity of NFkB. Our main goal is to investigate whether the combination of both Dtxl PLGA NPs and NChalc PLGA NPs will enhance the anticancer activity against PC-3 by inhibiting the transcriptional activity of the NFkB protein. Our long-term goal is to develop more effective and less toxic PLGA-NP-based chemotherapy for treating patient with highly metastatic PC. This project will pursue the following two related, yet independent specific aims. In Aim 1, we will investigate whether the combination of both Dtxl PLGA NPs and NChalc PLGA NPs will enhance the anticancer activity of Dtxl in PC-3. In Aim 2, we will measure the inhibitory effect of the combination of both Dtxl PLGA NPs and NChalc PLGA NPs on the transcriptional activity of the NFkB. The proposed work will broadly impact the field of drug discovery because no investigations addressing the use of NChalc PLGA NPs combined with Dtxl PLGA NPs to enhance the anticancer activity of Dtxl have been reported. In addition, results from this project will increase our knowledge about the mechanism involved in the cancer cell resistance to Dtxl.