title: A gradient-loadable (64)Cu-chelator for quantifying tumor deposition kinetics of nanoliposomal therapeutics by positron emission tomography.
abstract: Effective drug delivery to tumors is a barrier to treatment with nanomedicines. Non-invasively tracking liposome biodistribution and tumor deposition in patients may provide insight into identifying patients that are well-suited for liposomal therapies. We describe a novel gradient-loadable chelator, 4-DEAP-ATSC, for incorporating (64)Cu into liposomal therapeutics for positron emission tomographic (PET). (64)Cu chelated to 4-DEAP-ATSC (>94%) was loaded into PEGylated liposomal doxorubicin (PLD) and HER2-targeted PLD (MM-302) with efficiencies >90%. (64)Cu-MM-302 was stable in human plasma for at least 48h. PET/CT imaging of xenografts injected with (64)Cu-MM-302 revealed biodistribution profiles that were quantitatively consistent with tissue-based analysis, and tumor (64)Cu positively correlated with liposomal drug deposition. This loading technique transforms liposomal therapeutics into theranostics and is currently being applied in a clinical trial (NCT01304797) to non-invasively quantify MM-302 tumor deposition, and evaluate its potential as a prognostic tool for predicting treatment outcome of nanomedicines.
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, MA, USA. Electronic address: hlee@merrimackpharma.com.
authors.forename: Helen
authors.initials: H
authors.lastname: Lee
authors.affiliation: STTARR Innovation Centre, Radiation Medicine Program, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada.
authors.forename: Jinzi
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaddy
authors.affiliation: inviCRO, LLC, Boston, MA, USA.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Orcutt
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Leonard
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Geretti
authors.affiliation: inviCRO, LLC, Boston, MA, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Hesterman
authors.affiliation: inviCRO, LLC, Boston, MA, USA.
authors.forename: Catey
authors.initials: C
authors.lastname: Harwell
authors.affiliation: inviCRO, LLC, Boston, MA, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Hoppin
authors.affiliation: STTARR Innovation Centre, Radiation Medicine Program, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Jaffray
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wickham
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Bart S
authors.initials: BS
authors.lastname: Hendriks
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Kirpotin
mesh_terms: D000818:Animals; D002247:Carbon Isotopes / Q000737:chemistry*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry*; D003300:Copper / Q000737:chemistry; D003301:Copper Radioisotopes / Q000737:chemistry; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry; D016503:Drug Delivery Systems; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry*; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000737:chemistry; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed
chemical_list: D002247:Carbon Isotopes; D002614:Chelating Agents; D003301:Copper Radioisotopes; D008081:Liposomes; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D003300:Copper; D004317:Doxorubicin
keywords: (64)Cu; Drug delivery; Liposome; PET imaging; Tumor deposition