title: Custom-designed Laser-based Heating Apparatus for Triggered Release of Cisplatin from Thermosensitive Liposomes with Magnetic Resonance Image Guidance.
abstract: Liposomes have been employed as drug delivery systems to target solid tumors through exploitation of the enhanced permeability and retention (EPR) effect resulting in significant reductions in systemic toxicity. Nonetheless, insufficient release of encapsulated drug from liposomes has limited their clinical efficacy. Temperature-sensitive liposomes have been engineered to provide site-specific release of drug in order to overcome the problem of limited tumor drug bioavailability. Our lab has designed and developed a heat-activated thermosensitive liposome formulation of cisplatin (CDDP), known as HTLC, to provide triggered release of CDDP at solid tumors. Heat-activated delivery in vivo was achieved in murine models using a custom-built laser-based heating apparatus that provides a conformal heating pattern at the tumor site as confirmed by MR thermometry (MRT). A fiber optic temperature monitoring device was used to measure the temperature in real-time during the entire heating period with online adjustment of heat delivery by alternating the laser power. Drug delivery was optimized under magnetic resonance (MR) image guidance by co-encapsulation of an MR contrast agent (i.e., gadoteridol) along with CDDP into the thermosensitive liposomes as a means to validate the heating protocol and to assess tumor accumulation. The heating protocol consisted of a preheating period of 5 min prior to administration of HTLC and 20 min heating post-injection. This heating protocol resulted in effective release of the encapsulated agents with the highest MR signal change observed in the heated tumor in comparison to the unheated tumor and muscle. This study demonstrated the successful application of the laser-based heating apparatus for preclinical thermosensitive liposome development and the importance of MR-guided validation of the heating protocol for optimization of drug delivery.
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto.
authors.forename: Yannan N
authors.initials: YN
authors.lastname: Dou
authors.affiliation: Department of Radiation Oncology, University of Toronto; Techna Institute and Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weersink
authors.affiliation: Techna Institute and Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network; STTARR Innovation Center, University Health Network.
authors.forename: Warren D
authors.initials: WD
authors.lastname: Foltz
authors.affiliation: Techna Institute and Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network; STTARR Innovation Center, University Health Network.
authors.forename: Jinzi
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Ontario Cancer Institute, University Health Network.
authors.forename: Naz
authors.initials: N
authors.lastname: Chaudary
authors.affiliation: Department of Radiation Oncology, University of Toronto; Medical Biophysics, University of Toronto; Institute of Biomaterials & Biomedical Engineering, University of Toronto; Techna Institute and Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network; STTARR Innovation Center, University Health Network.
authors.forename: David A
authors.initials: DA
authors.lastname: Jaffray
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto; cj.allen@utoronto.ca.
authors.forename: Christine
authors.initials: C
authors.lastname: Allen
mesh_terms: D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage* / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005682:Gadolinium / Q000008:administration & dosage / Q000737:chemistry; D006361:Heating; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000737:chemistry; D006358:Hot Temperature; D007834:Lasers; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D016513:Mice, SCID; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D006571:Heterocyclic Compounds; D008081:Liposomes; D009942:Organometallic Compounds; C062402:gadoteridol; D005682:Gadolinium; D002945:Cisplatin