Synthesis Characterization and Biological evaluation of surface modified Pamam dendrimer with Gallic acid for anti proliferative effects in cancer cells

Abstract

Cancer is the second leading cause of death worldwide. Over the past decade, several strategies have been applied to reduce the toxicity and deleterious side effects of anti-cancer drugs. In clinical practices frequently used chemotherapeutic anti-cancer drugs are plant derivatives, but they have adverse cytotoxic effects and limited efficacy for drug resistance. Many natural derivatives have broad spectrum biological and anti-cancer activities, but due to limited bioavailability can t use at clinical level. Gallic acid (GA) is a natural polyphenol, which exhibits a broad spectrum of biological activities, but its therapeutic application was limited due to poor bioavailability. Since recent past to overcome the obstacle of anti-cancer therapy significant attention has been drawn to improve drug delivery system. The present study was aimed to improve drug delivery method using nano carrier PAMAM dendrimers. In the present study GA was conjugated with 4.0 G PAMAM dendrimer at outer surface. The conjugation of GA with PAMAM dendrimers has newlinebeen characterized by biophysical methods and further examined its bioavailability, anti-cancer activity and molecular mechanism of cell death in in vitro and in vivo model system of cancer. The results show that PAMAM-GA conjugate inhibits cell proliferation of different origin of cancer cells and induces mitochondria-dependent newlineapoptosis in HCT-116 cells. PAMAM-GA conjugate showed less cytotoxic response newlineas compared to the free Gallic acid to the normal cells. The results show that PAMAM-GA conjugate inhibits cell proliferation of different origin of cancer cells, improves cellular uptake of GA, inhibits colonogenic ability, restricts cancer cell migration by down regulating the expression of MMP-9, inhibits NF-kB activation and release of pro-inflammatory cytokines to manifest apoptotic cell death in HCT- 116 cells rather than necrosis. Interestingly, in vivo study shows that PAMAM-GA conjugate restricts tumor growth in DL lymphoma xenograft mouse model. newline