title: Investigation of Factors Determining the Enhanced Permeability and Retention Effect in Subcutaneous Xenografts.
abstract: Liposomal chemotherapy offers several advantages over conventional therapies, including high intratumoral drug delivery, reduced side effects, prolonged circulation time, and the possibility to dose higher. The efficient delivery of liposomal chemotherapeutics relies, however, on the enhanced permeability and retention (EPR) effect, which refers to the ability of macromolecules to extravasate leaky tumor vessels and accumulate in the tumor tissue. Using a panel of human xenograft tumors, we evaluated the influence of the EPR effect on liposomal distribution in vivo by injection of pegylated liposomes radiolabeled with (111)In. Liposomal accumulation in tumors and organs was followed over time by SPECT/CT imaging. We observed that fast-growing xenografts, which may be less representative of tumor development in patients, showed higher liposomal accumulation than slow-growing xenografts. Additionally, several other parameters known to influence the EPR effect were evaluated, such as blood and lymphatic vessel density, intratumoral hypoxia, and the presence of infiltrating macrophages. The investigation of various parameters showed a few correlations. Although hypoxia, proliferation, and macrophage presence were associated with tumor growth, no hard conclusions or predictions could be made regarding the EPR effect or liposomal uptake. However, liposomal uptake was significantly correlated with tumor growth, with fast-growing tumors showing a higher uptake, although no biological determinants could be elucidated to explain this correlation.
authors.affiliation: Laboratory of Experimental Surgical Oncology, Department of Surgery, Erasmus MC, Rotterdam, The Netherlands m.bolkestein@erasmusmc.nl.
authors.forename: Michiel
authors.initials: M
authors.lastname: Bolkestein
authors.affiliation: Departments of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: de Blois
authors.affiliation: Departments of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Koelewijn
authors.affiliation: Gustave Roussy Cancer Campus Grand Paris, Villejuif Paris, France; and.
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
authors.affiliation: Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Grosveld
authors.affiliation: Departments of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
authors.affiliation: Laboratory of Experimental Surgical Oncology, Department of Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Gerben A
authors.initials: GA
authors.lastname: Koning
mesh_terms: D000818:Animals; D001808:Blood Vessels; D049109:Cell Proliferation; D064593:Heterografts / Q000000981:diagnostic imaging*; D006801:Humans; D000860:Hypoxia / Q000000981:diagnostic imaging; D007205:Indium Radioisotopes; D008081:Liposomes; D042601:Lymphatic Vessels / Q000000981:diagnostic imaging; D008264:Macrophages / Q000000981:diagnostic imaging; D051379:Mice; D050997:Nanomedicine / Q000379:methods; D010539:Permeability; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics; D040521:Subcutaneous Tissue / Q000637:transplantation*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D023041:Xenograft Model Antitumor Assays
chemical_list: D007205:Indium Radioisotopes; D008081:Liposomes; D019275:Radiopharmaceuticals
keywords: EPR effect; SPECT; liposomes; nanomedicine