title: Spatial and temporal mapping of heterogeneity in liposome uptake and microvascular distribution in an orthotopic tumor xenograft model.
abstract: Existing paradigms in nano-based drug delivery are currently being challenged. Assessment of bulk tumor accumulation has been routinely considered an indicative measure of nanomedicine potency. However, it is now recognized that the intratumoral distribution of nanomedicines also impacts their therapeutic effect. At this time, our understanding of the relationship between the bulk (i.e., macro-) tumor accumulation of nanocarriers and their intratumoral (i.e., micro-) distribution remains limited. Liposome-based drug formulations, in particular, suffer from diminished efficacy in vivo as a result of transport-limiting properties, combined with the heterogeneous nature of the tumor microenvironment. In this report, we perform a quantitative image-based assessment of macro- and microdistribution of liposomes. Multi-scalar assessment of liposome distribution was enabled by a stable formulation which co-encapsulates an iodinated contrast agent and a near-infrared fluorescence probe, for computed tomography (CT) and optical microscopy, respectively. Spatio-temporal quantification of tumor uptake in orthotopic xenografts was performed using CT at the bulk tissue level, and within defined sub-volumes of the tumor (i.e., rim, periphery and core). Tumor penetration and relative distribution of liposomes were assessed by fluorescence microscopy of whole tumor sections. Microdistribution analysis of whole tumor images exposed a heterogeneous distribution of both liposomes and tumor vasculature. Highest levels of liposome uptake were achieved and maintained in the well-vascularized tumor rim over the study period, corresponding to a positive correlation between liposome and microvascular density. Tumor penetration of liposomes was found to be time-dependent in all regions of the tumor however independent of location in the tumor. Importantly, a multi-scalar comparison of liposome distribution reveals that macro-accumulation in tissues (e.g., blood, whole tumor) may not reflect micro-accumulation levels present within specific regions of the tumor as a function of time.
authors: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors: Sandra N
authors: SN
authors: Ekdawi
authors: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 3G9, Canada.
authors: James M P
authors: JM
authors: Stewart
authors: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors: Michael
authors: M
authors: Dunne
authors: Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors: Shawn
authors: S
authors: Stapleton
authors: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors: Nicholas
authors: N
authors: Mitsakakis
authors: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors: Yannan N
authors: YN
authors: Dou
authors: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 3G9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario M5S 3E2, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada; Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada; Techna Institute, University Health Network, Toronto, Ontario M5G 1P5, Canada.
authors: David A
authors: DA
authors: Jaffray
authors: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada. Electronic address: cj.allen@utoronto.ca.
authors: Christine
authors: C
authors: Allen
mesh_terms: D000818:Animals; D003287:Contrast Media / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D064593:Heterografts; D006801:Humans; D007472:Iohexol / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes; D016513:Mice, SCID; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D061848:Optical Imaging; D055420:Perfusion Imaging / Q000379:methods*; D012039:Regional Blood Flow; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed; D059016:Tumor Microenvironment; D002583:Uterine Cervical Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000378:metabolism
chemical_list: D003287:Contrast Media; D008055:Lipids; D008081:Liposomes; D007472:Iohexol
keywords: Computed tomography; Intratumoral distribution; Liposome; Nanomedicine; Optical microscopy; Tumor accumulation