title: Formulation and optimization of idarubicin thermosensitive liposomes provides ultrafast triggered release at mild hyperthermia and improves tumor response.
abstract: Drug delivery through thermosensitive liposomes (TSL) in combination with hyperthermia (HT) has shown great potential. HT can be applied locally forcing TSL to release their content in the heated tumor resulting in high peak concentrations. To perform optimally the drug is ideally released fast (seconds) and taken up rapidly by tumor cells. The aim of this study was to develop a novel thermosensitive liposome formulation of the anthracycline idarubicin (IDA-TSL). The hydrophobicity of idarubicin may improve its release from liposomes and subsequently rapid cellular uptake when combined mild hyperthermia. Here, we investigated a series of parameters to optimize IDA-TSL formulation. The results show that the optimal formulation for IDA-TSL is DPPC/DSPC/DSPE-PEG (6/3.5/0.5 mol%), with ammonium EDTA of 6.5 pH as loading buffer and a size of ~85 nm. In vitro studies demonstrated minimal leakage of ~20% in FCS at 37 °C for 1h, while an ultrafast and complete triggered release of IDA was observed at 42 °C. On tumor cells IDA-TSL showed comparable cytotoxicity to free IDA at 42 °C, but low cytotoxicity at 37 °C. Intravital microscopy imaging demonstrated an efficient in vivo intravascular triggered drug release of IDA-TSL under mild hyperthermia, and a subsequent massive IDA uptake by tumor cells. In animal efficacy studies, IDA-TSL plus mild HT demonstrated prominent tumor growth inhibition and superior survival rate over free IDA with HT or a clinically used Doxil treatment. These results suggest beneficial potential of IDA-TSL combined with local mild HT.
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Wouter J M
authors.initials: WJM
authors.lastname: Lokerse
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Ann L B
authors.initials: ALB
authors.lastname: Seynhaeve
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Gerben A
authors.initials: GA
authors.lastname: Koning
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC, Rotterdam, The Netherlands. Electronic address: t.l.m.tenhagen@erasmusmc.nl.
authors.forename: Timo L M
authors.initials: TLM
authors.lastname: Ten Hagen
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D004339:Drug Compounding; D004355:Drug Stability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006979:Hyperthermia, Induced; D015255:Idarubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000008:administration & dosage; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012995:Solubility; D013696:Temperature; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D008055:Lipids; D008081:Liposomes; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D015255:Idarubicin
keywords: Cholesterol (PubChem CID: 5997); DPPC (PubChem CID: 160,339); DSPC (PubChem CID: 94,190); DSPE-PEG (PubChem CID: 86,278,269); Diammonium EDTA (PubChem CID: 13,847,684); Diammonium oxalate (PubChem CID: 14,213); Diammonium sulfate (PubChem CID: 6,097,028); HEPES (PubChem CID: 23,831); Idarubicin; Idarubicin hydrochloride (PubChem CID: 636,362); Mild hyperthermia; Sodium citrate (PubChem CID: 6224); Thermosensitive liposome; Triggered drug release