title: Tumor necrosis factor alpha mediates homogeneous distribution of liposomes in murine melanoma that contributes to a better tumor response.
abstract: Successful treatment of solid tumors with chemotherapeutics requires that adequate levels reach the tumor cells. Tumor vascular normalization has been proposed to enhance drug delivery and improve tumor response to chemotherapy. Differently, augmenting leakage of the tumor-associated vasculature, and as such enhance vascular abnormality, may improve tumor response as well. In the present study, we show that addition of low-dose tumor necrosis factor alpha (TNF) to systemic injections with pegylated long circulating liposomes augmented the tumor accumulation of these liposomes 5- to 6-fold, which strongly correlated with enhanced tumor response. Using intravital microscopy, we could study the liposomal distribution inside the tumor in more detail. Especially 100 nm liposomes effectively extravasate in the surrounding tumor tissue in the presence of TNF and this occurred without any effect on tumor vascular density, branching, and diameter. Next to that, we observed in living animals that tumor cells take up the liposomes intact, followed by intracellular degradation. To our knowledge, this is an unprecedented observation. Taken together, TNF renders more tumor vessels permeable, leading to a more homogeneous distribution of the liposomes throughout the tumor, which is crucial for an optimal tumor response. We conclude that delivery of nanoparticulate drug formulations to solid tumor benefits from augmenting the vascular leakage through vascular manipulation with vasoactive drugs like TNF.
authors.affiliation: Department of Surgical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands.
authors.forename: Ann L B
authors.initials: AL
authors.lastname: Seynhaeve
authors.forename: Saske
authors.initials: S
authors.lastname: Hoving
authors.forename: Debby
authors.initials: D
authors.lastname: Schipper
authors.forename: Cindy E
authors.initials: CE
authors.lastname: Vermeulen
authors.forename: Gisela aan
authors.initials: Ga
authors.lastname: de Wiel-Ambagtsheer
authors.forename: Sandra T
authors.initials: ST
authors.lastname: van Tiel
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: Timo L M
authors.initials: TL
authors.lastname: Ten Hagen
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D008081:Liposomes / Q000097:blood / Q000493:pharmacokinetics*; D008546:Melanoma, Experimental / Q000097:blood / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000097:blood / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin