title: A thermosensitive liposome prepared with a Cu²⁺ gradient demonstrates improved pharmacokinetics, drug delivery and antitumor efficacy.
abstract: Here we report the development of an enhanced thermosensitive formulation composed of DPPC and Brij78, loaded with doxorubicin (DOX) using a Cu²⁺ gradient and post-inserted with an additional amount of Brij78. This optimal formulation (HaT-II: Hyperthermia-activated cytoToxic) displayed significantly improved stability in serum at 37 °C, and enhanced drug release rates at 41-42 °C, compared to LTSL (lyso-lipid temperature sensitive liposomes, DPPC/MSPC/DSPE-PEG₂₀₀₀=86/10/4, pH gradient drug loading). HaT-II released 100% DOX within 15-40s at 40-42 °C, with only 5% drug leakage at 37 °C after 30 min in serum, while LTSL lost 30% of its drug content at 37 °C and exhibited ~2-fold decreased release rate constants at 41-42 °C under the same conditions. The pharmacokinetics of DOX was significantly improved in non-heated HaT-II treated healthy mice with 2.5-fold increased area under the curve and 2-fold prolonged circulation half life compared to LTSL. This led to 2-fold improved drug delivery to the heated tumor by HaT-II (~20% injected dose/g tissue), relative to LTSL and significantly enhanced antitumor efficacy with complete inhibition of tumor growth after a single dose of HaT-II. Finally, HaT-II exhibited little toxicity in mice, inducing no body weight loss and no abnormality in the blood chemistry (10 mg DOX/kg).
authors.affiliation: Drug Delivery and Formulation, Medicinal Chemistry Platform, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Tagami
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: May
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ernsting
authors.forename: Shyh-Dar
authors.initials: SD
authors.lastname: Li
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003300:Copper / Q000737:chemistry / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006979:Hyperthermia, Induced; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D015060:1,2-Dipalmitoylphosphatidylcholine; D011092:Polyethylene Glycols; D003300:Copper; D004317:Doxorubicin; C043444:octadecyl polyoxyethylene ether