title: The intra-tumoral relationship between microcirculation, interstitial fluid pressure and liposome accumulation.
abstract: The heterogeneous intra-tumoral accumulation of liposomes has been linked to both the chaotic tumor microcirculation and to elevated interstitial fluid pressure (IFP). Here, we explored the relationship between tumor microcirculation, IFP, and the intra-tumoral accumulation of liposomes. Measurements of the tumor microcirculation using perfusion imaging, IFP using a novel image-guided robotic needle positioning system, and the intra-tumoral distribution of liposomes using volumetric micro-CT imaging were performed in mice bearing subcutaneous and orthotopic MDA-MB-231 tumors. Intra-tumoral perfusion and IFP were substantially different between the two tumor implantation sites. Tumor perfusion and not vascular permeability was found to be the primary mediator of the intra-tumoral accumulation of CT-liposomes. A strong relationship was observed between the radial distribution of IFP, metrics of tumor perfusion, and the intra-tumoral accumulation of liposomes. Tumors with elevated central IFP that decreased at the periphery had low perfusion and low levels of CT-liposome accumulation that increased towards the periphery. Conversely, tumors with low and radially uniform IFP exhibited higher levels of tumor perfusion and CT-liposome accumulation. Both tumor perfusion and elevated IFP exhibit substantial intra-tumoral heterogeneity and both play an integral role in mediating the intra-tumoral accumulation of liposomes through a complex interactive effect. Measuring IFP in the clinical setting remains challenging and these results demonstrate that tumor perfusion imaging alone provides a robust non-invasive method to identify factors that contribute to poor liposome accumulation and may allow for pre-selection of patients that are more likely to respond to nanoparticle therapy.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, ON, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada. Electronic address: shawn.stapleton@rmp.uhn.on.ca.
authors.forename: Shawn
authors.initials: S
authors.lastname: Stapleton
authors.affiliation: STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, ON, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Tannock
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Allen
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, ON, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada; Techna Institute, University Health Network, Toronto, ON, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Jaffray
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D008081:Liposomes / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008833:Microcirculation / Q000502:physiology*; D011312:Pressure; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D008081:Liposomes
keywords: Blood flow; Drug delivery; Interstitial fluid pressure; Intra-tumoral heterogeneity; Liposomes; Nanomedicine; Transport