title: Efficient tumor regression by a single and low dose treatment with a novel and enhanced formulation of thermosensitive liposomal doxorubicin.
abstract: We have developed a novel and simplified thermosensitive liposomal formulation (HaT: Hyperthermia-activated cytoToxic) composed of DPPC lipid and Brij78 (96:4, molar ratio). The HaT nanoparticles were loaded with doxorubicin (DOX) with >95% efficiency when a pH gradient method and a drug/lipid ratio of 1/20 (w/w) were applied. Drug release from the HaT formulation was significantly faster at 40-41°C (100% release in 2-3min) with 3.4-fold increased membrane permeability compared to the LTSL (lyso-lipid temperature sensitive liposomes; DPPC: MSPC: DSPE-PEG(2000)=86:10:4, molar ratio), a formulation that is currently in clinical trials. Both formulations displayed similar stability at 37°C in serum (10-20% release in 30min), which corresponds to their comparable pharmacokinetics in the unheated mice. An approximately 1.4-fold increased drug delivery to the locally heated tumor (~43°C) was detected with HaT-DOX compared to LTSL-DOX. Moreover, when compared with free DOX, HaT enhanced drug uptake in the heated tumor by 5.2-fold and reduced drug delivery to the heart by 15-fold. A single i.v. treatment with HaT-DOX at 3mg DOX/kg in combination with localized hyperthermia demonstrated enhanced tumor regression compared to LTSL-DOX and free DOX, and exhibited little toxicity.
authors.affiliation: Drug Delivery and Formulation, Medicinal Chemistry Platform, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Tagami
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ernsting
authors.forename: Shyh-Dar
authors.initials: SD
authors.lastname: Li
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006979:Hyperthermia, Induced; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry*; D013696:Temperature
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D008081:Liposomes; D011092:Polyethylene Glycols; D004317:Doxorubicin; C043444:octadecyl polyoxyethylene ether