title: Tumor vascular permeabilization using localized mild hyperthermia to improve macromolecule transport.
abstract: The abnormal tumor vasculature presents a major challenge to the adequate delivery of chemotherapeutics, often limiting efficacy. We developed a nanoparticle-based technique to deliver localized mild hyperthermia (MHT) used to transiently alter tumor vascular transport properties and enhance transport of macromolecules into tumor interstitium. The strategy involved administering and localizing accumulation of stealth gold nanorods (GNRs, 103 μg of GNRs/g of tumor), and irradiating tumor with a low-photon laser flux (1 W/cm(2)) to generate MHT. The treatment increased vascular permeability within 24 h after treatment, allowing enhanced transport of macromolecules up to 54 nm in size. A mathematical model is used to describe changes in tumor mass transport properties where the rate of macromolecular exchange between interstitial and vascular region (R) and maximum dye enhancement (Ymax) of 23-nm dextran dye is analytically solved. During enhanced permeability, R increased by 200% while Ymax increased by 30% relative to untreated group in pancreatic CAPAN-1 tumors. MHT treatment also enhanced transport of larger dextran dye (54 nm) as assessed by intravital microscopy, without causing occlusive cellular damage. Enhanced vascular transport was prolonged for up to 24 h after treatment, but reversible with transport parameters returning to basal levels after 36 h. This study indicates that localized mild hyperthermia treatment opens a transient time-window with which to enable and augment macromolecule transport and potentially improve therapeutic efficacy. From the clinical editor: In this study, local intra-tumor mild hyperthermia is induced using a nanoparticle-based approach utilizing stealth gold nanorods and irradiating the tumor with low-photon laser flux, resulting in locally increased vascular permeability enabling enhanced delivery of therapeutics, including macromolecules up to 54 nm in size. Similar approaches would be very helpful in addressing treatment-resistant malignancies in clinical practice.
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Dickson K
authors.initials: DK
authors.lastname: Kirui
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA; MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Koay
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA; Department of Breast Cancer Pathology and Research Laboratory, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, Tianjin, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Chemical and Nuclear Engineering, Center for Biomedical Engineering, The University of New Mexico, Albuquerque, NM, USA.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Cristini
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA; Weill Cornell Medical College, New York, NY, USA.
authors.forename: Haifa
authors.initials: H
authors.lastname: Shen
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address: mferrari@houstonmethodist.org.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
mesh_terms: D000818:Animals; D001692:Biological Transport; D001808:Blood Vessels / Q000378:metabolism*; D002199:Capillary Permeability; D006979:Hyperthermia, Induced; D051379:Mice; D008819:Mice, Nude; D043942:Nanotubes; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000628:therapy
keywords: Intravital microscopy; Macromolecular enhancement; Mild hyperthermia; Transport barriers; Vascular permeabilization