title: Intracellular delivery of redox cycler-doxorubicin to the mitochondria of cancer cell by folate receptor targeted mitocancerotropic liposomes.
abstract: Cancer cells reflect higher level of ROS in comparison to the normal cell, so they become more vulnerable to further oxidative stress induced by exogenous ROS-generating agents. Through this a novel therapeutic strategy has evolved, which involves the delivery of redox cycler-doxorubicin (DOX) to the mitochondria of cancer cell where it acts as a source of exogenous ROS production. The purpose of this study is to develop a liposomal preparation which exhibits a propensity to selectively target cancer cell along with the potential of delivering drug to mitochondria of cell. We have rendered liposomes mitocancerotropic (FA-MTLs) by their surface modification with dual ligands, folic acid (FA) for cancer cell targeting and triphenylphosphonium (TPP) cations for mitochondria targeting. The cytotoxicity, ROS production and cell uptake of doxorubicin loaded liposomes were evaluated in FR (+) KB cells and found to be increased considerably with FA-MTLs in comparison to folic acid appended, mitochondria targeted and non-targeted liposomes. As confirmed by confocal microscopy, the STPP appended liposomes delivered DOX to mitochondria of cancer cell and also showed higher ROS production and cytotoxicity in comparison to folic acid appended and non-targeted liposomes. Most importantly, mitocancerotropic liposomes showed superior activity over mitochondria targeted liposomes which confirm the synergistic effect imparted by the presence of dual ligands - folic acid and TPP on the enhancement of cellular and mitochondrial delivery of doxorubicin in KB cells.
authors.affiliation: Nano-Medicine Research Center, Department of Pharmaceutics, Indo-Soviet Friendship College of Pharmacy, Moga, Punjab, India.
authors.forename: Sarandeep Singh
authors.initials: SS
authors.lastname: Malhi
authors.forename: Abhishek
authors.initials: A
authors.lastname: Budhiraja
authors.forename: Sumit
authors.initials: S
authors.lastname: Arora
authors.forename: Kiran R
authors.initials: KR
authors.lastname: Chaudhari
authors.forename: Kunal
authors.initials: K
authors.lastname: Nepali
authors.forename: Raj
authors.initials: R
authors.lastname: Kumar
authors.forename: Harmik
authors.initials: H
authors.lastname: Sohi
authors.forename: Rayasa S R
authors.initials: RS
authors.lastname: Murthy
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage*; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism*; D005492:Folic Acid / Q000737:chemistry; D006801:Humans; D008081:Liposomes; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010084:Oxidation-Reduction; D011092:Polyethylene Glycols / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D058973:Folate Receptors, GPI-Anchored; D008081:Liposomes; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; D004317:Doxorubicin; D005492:Folic Acid; D002784:Cholesterol