title: Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery.
abstract: Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based chemotherapeutic agents which depend on enhanced permeability and retention for tumor penetration. Here, we evaluated the role of Clopidogrel, a well-known inhibitor of platelet aggregation, in potentiating the tumor cytotoxicity of cisplatin nano-formulation in a murine breast cancer model. In vivo studies in murine syngeneic 4T1 breast cancer model showed a significant greater penetration of macromolecular fluorescent nanoparticles after clopidogrel pretreatment. Compared to self-assembling cisplatin nanoparticles (SACNs), combination therapy with clopidogrel and SACN was associated with a 4 fold greater delivery of cisplatin to tumor tissue and a greater reduction in tumor growth as well as higher survival rate. Clopidogrel enhances therapeutic efficiency of novel cisplatin based nano-formulations agents by increasing tumor drug delivery and can be used as a potential targeting agent for novel nano-formulation based chemotherapeutics.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Ambarish
authors.initials: A
authors.lastname: Pandey
authors.forename: Sasmit
authors.initials: S
authors.lastname: Sarangi
authors.forename: Kelly
authors.initials: K
authors.lastname: Chien
authors.forename: Poulomi
authors.initials: P
authors.lastname: Sengupta
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Papa
authors.forename: Sudipta
authors.initials: S
authors.lastname: Basu
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000627:therapeutic use*; D000077144:Clopidogrel; D016503:Drug Delivery Systems / Q000379:methods*; D015674:Mammary Neoplasms, Animal / Q000098:blood supply / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D054118:Nanospheres / Q000737:chemistry / Q000627:therapeutic use*; D010539:Permeability; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine; D002945:Cisplatin