title: Overcoming limitations in nanoparticle drug delivery: triggered, intravascular release to improve drug penetration into tumors.
abstract: Traditionally, the goal of nanoparticle-based chemotherapy has been to decrease normal tissue toxicity by improving drug specificity to tumors. The enhanced permeability and retention effect can permit passive accumulation into tumor interstitium. However, suboptimal delivery is achieved with most nanoparticles because of heterogeneities of vascular permeability, which limits nanoparticle penetration. Furthermore, slow drug release limits bioavailability. We developed a fast drug-releasing liposome triggered by local heat that has already shown substantial antitumor efficacy and is in human trials. Here, we show that thermally sensitive liposomes (Dox-TSL) release doxorubicin inside the tumor vasculature. Real-time confocal imaging of doxorubicin delivery to murine tumors in window chambers and histologic analysis of flank tumors illustrates that intravascular drug release increases free drug in the interstitial space. This increases both the time that tumor cells are exposed to maximum drug levels and the drug penetration distance, compared with free drug or traditional pegylated liposomes. These improvements in drug bioavailability establish a new paradigm in drug delivery: rapidly triggered drug release in the tumor bloodstream.
authors.affiliation: Medical Physics Program, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Manzoor
authors.forename: Lars H
authors.initials: LH
authors.lastname: Lindner
authors.forename: Chelsea D
authors.initials: CD
authors.lastname: Landon
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Simnick
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Dreher
authors.forename: Shiva
authors.initials: S
authors.lastname: Das
authors.forename: Gabi
authors.initials: G
authors.lastname: Hanna
authors.forename: Won
authors.initials: W
authors.lastname: Park
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Chilkoti
authors.forename: Gerben A
authors.initials: GA
authors.lastname: Koning
authors.forename: Timo L M
authors.initials: TL
authors.lastname: ten Hagen
authors.forename: David
authors.initials: D
authors.lastname: Needham
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods*; D006358:Hot Temperature; D006801:Humans; D008081:Liposomes; D051379:Mice; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000627:therapeutic use*; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D004317:Doxorubicin