title: Sequential HIFU heating and nanobubble encapsulation provide efficient drug penetration from stealth and temperature sensitive liposomes in colon cancer.
abstract: Mild hyperthermia generated using high intensity focused ultrasound (HIFU) and microbubbles (MBs) can improve tumor drug delivery from non-thermosensitive liposomes (NTSLs) and low temperature sensitive liposomes (LTSLs). However, MB and HIFU are limited by the half-life of the contrast agent and challenges in accurate control of large volume tumor hyperthermia for longer duration (>30min.). The objectives of this study were to: 1) synthesize and characterized long-circulating echogenic nanobubble encapsulated LTSLs (ELTSLs) and NTSLs (ENTSLs), 2) evaluate in vivo drug release following short duration (~20min each) HIFU treatments administered sequentially over an hour in a large volume of mouse xenograft colon tumor, and 3) determine the impact of the HIFU/nanobubble combination on intratumoral drug distribution. LTSLs and NTSLs containing doxorubicin (Dox) were co-loaded with a nanobubble contrast agent (perfluoropentane, PFP) using a one-step sonoporation method to create ELTSLs and ENTSLs, which then were characterized for size, release in a physiological buffer, and ability to encapsulate PFP. For the HIFU group, mild hyperthermia (40-42°C) was completed within 90min after liposome infusion administered sequentially in three regions of the tumor. Fluorescence microscopy and high performance liquid chromatography analysis were performed to determine the spatial distribution and concentration of Dox in the treated regions. PFP encapsulation within ELTSLs and ENTSLs did not impact size or caused premature drug release in physiological buffer. As time progressed, the delivery of Dox decreased in HIFU-treated tumors with ELTSLs, but this phenomenon was absent in the LTSL, NTSL, and ENTSL groups. Most importantly, PFP encapsulation improved Dox penetration in the tumor periphery and core and did not impact the distribution of Dox in non-tumor organs/tissues. Data from this study suggest that short duration and sequential HIFU treatment could have significant benefits and that its action can be potentiated by nanobubble agents to result in improved drug penetration.
authors.affiliation: Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: VanOsdol
authors.affiliation: Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, United States.
authors.forename: Kalyani
authors.initials: K
authors.lastname: Ektate
authors.affiliation: Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, United States.
authors.forename: Selvarani
authors.initials: S
authors.lastname: Ramasamy
authors.affiliation: Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, United States.
authors.forename: Danny
authors.initials: D
authors.lastname: Maples
authors.affiliation: Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, United States.
authors.forename: Willie
authors.initials: W
authors.lastname: Collins
authors.affiliation: Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, United States.
authors.forename: Jerry
authors.initials: J
authors.lastname: Malayer
authors.affiliation: Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, United States. Electronic address: ashish.ranjan@okstate.edu.
authors.forename: Ashish
authors.initials: A
authors.lastname: Ranjan
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003287:Contrast Media / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D005466:Fluorocarbons / Q000737:chemistry; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods; D008081:Liposomes / Q000737:chemistry*; D008819:Mice, Nude; D045423:Microbubbles; D013696:Temperature; D047368:Tumor Burden / Q000187:drug effects; D010420:Pentanes
chemical_list: D000903:Antibiotics, Antineoplastic; D003287:Contrast Media; D003692:Delayed-Action Preparations; D004317:Doxorubicin; D005466:Fluorocarbons; D008081:Liposomes; C008806:perfluoropentane; D010420:Pentanes
keywords: Drug penetration; Echogenic liposomes; HIFU; Solid tumor; Stealth liposomes; Temperature sensitive liposomes