Pierson Rathinaraj1, Ganesan Muthusamy2, Nagarajan Rajendra Prasad2, Srithar Gunaseelan2, Boeun Kim3, Suhang Zhu4. 1. Centre for International Research and Internships, Waikato Institute of Technology, Hamilton, New Zealand. pierson.rathinaraj@wintec.ac.nz. 2. Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu, India. 3. Department of Chemical Engineering, Kyungpook National University, Daegu, Republic of Korea. 4. Department of Mechanical Engineering, Jinhua Polytechnic, Jinhua, People's Republic of China.
Abstract
BACKGROUND: Gold nanoparticles (GNPs) are receiving increasing attention as drug delivery carriers due to their high surface-to-volume ratio, hydrophilicity, and functionality. Drug delivery by nanocarriers has the potential to bypass P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) by altering the drug internalization mechanism and/or intracellular release pattern, inhibiting the activity of ABC-transporter efflux pumps, or downregulating the expression of genes responsible for the activity of efflux pumps. OBJECTIVE: We developed a folate-gold-bilirubin (FGB) nanoconjugate to reverse MDR in P-expressing KB-ChR-8-5 cells. METHODS: The P-gp overexpressing KB-ChR-8-5 cells were incubated with the FGB nanoconjugate, bilirubin, or GNPs. Various cellular endpoints, such as cytotoxicity, ROS generation, DNA damage, and apoptosis, were analyzed using analytical methods. Further, a KB-ChR-8-5 cell-bearing tumor xenograft was developed and the anticancer potential of the prepared FGB nanoparticles was compared to that of bilirubin or GNPs in this preclinical model. RESULTS: The FGB nanoconjugate was found to be a stronger inhibitor of the viability of multidrug-resistant KB-ChR-8-5 cells than bilirubin and GNPs treatment alone. The nanoconjugate induced reactive oxygen species (ROS) formation, DNA strand breaks, and apoptotic morphological changes in the P-gp-overexpressing drug-resistant cells to a greater degree than bilirubin treatment alone. Also, the FGB nanoparticles led to stronger suppression of tumor development in the KB-ChR-8-5 xenograft mouse model than achieved with bilirubin treatment alone. Thus, the present results suggest that the FGB nanoconjugate suppresses tumor growth in drug-resistant tumor cells by inducing apoptotic cell death. CONCLUSION: FGB nanoparticles significantly inhibit tumor growth, probably through the folate receptor, which is highly expressed in KB cells. Hence, folate-gold-bilirubin nanoparticles could be a promising agent for inducing apoptosis in P-gp-overexpressing drug-resistant cancer cells.
BACKGROUND: Gold nanoparticles (GNPs) are receiving increasing attention as drug delivery carriers due to their high surface-to-volume ratio, hydrophilicity, and functionality. Drug delivery by nanocarriers has the potential to bypass P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) by altering the drug internalization mechanism and/or intracellular release pattern, inhibiting the activity of ABC-transporter efflux pumps, or downregulating the expression of genes responsible for the activity of efflux pumps. OBJECTIVE: We developed a folate-gold-bilirubin (FGB) nanoconjugate to reverse MDR in P-expressing KB-ChR-8-5 cells. METHODS: The P-gp overexpressing KB-ChR-8-5 cells were incubated with the FGB nanoconjugate, bilirubin, or GNPs. Various cellular endpoints, such as cytotoxicity, ROS generation, DNA damage, and apoptosis, were analyzed using analytical methods. Further, a KB-ChR-8-5 cell-bearing tumor xenograft was developed and the anticancer potential of the prepared FGB nanoparticles was compared to that of bilirubin or GNPs in this preclinical model. RESULTS: The FGB nanoconjugate was found to be a stronger inhibitor of the viability of multidrug-resistant KB-ChR-8-5 cells than bilirubin and GNPs treatment alone. The nanoconjugate induced reactive oxygen species (ROS) formation, DNA strand breaks, and apoptotic morphological changes in the P-gp-overexpressing drug-resistant cells to a greater degree than bilirubin treatment alone. Also, the FGB nanoparticles led to stronger suppression of tumor development in the KB-ChR-8-5 xenograft mouse model than achieved with bilirubin treatment alone. Thus, the present results suggest that the FGB nanoconjugate suppresses tumor growth in drug-resistant tumor cells by inducing apoptotic cell death. CONCLUSION:FGB nanoparticles significantly inhibit tumor growth, probably through the folate receptor, which is highly expressed in KB cells. Hence, folate-gold-bilirubin nanoparticles could be a promising agent for inducing apoptosis in P-gp-overexpressing drug-resistant cancer cells.
Authors: Rui Hong; Gang Han; Joseph M Fernández; Byoung-jin Kim; Neil S Forbes; Vincent M Rotello Journal: J Am Chem Soc Date: 2006-02-01 Impact factor: 15.419
Authors: Shom Goel; Dan G Duda; Lei Xu; Lance L Munn; Yves Boucher; Dai Fukumura; Rakesh K Jain Journal: Physiol Rev Date: 2011-07 Impact factor: 37.312
Authors: Aleksandra Benko; David Medina-Cruz; Ada Vernet-Crua; Catherine P O'Connell; Małgorzata Świętek; Hamed Barabadi; Muthupandian Saravanan; Thomas J Webster Journal: Cancer Drug Resist Date: 2021-06-19