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.
Highlights
Delivery of drugs in solid tumors is still a major problem faced in chemotherapy and frequently responsible for failure of initially promising agents
Anti–vascular endothelial growth factor therapy is thought to have its effect through inhibition of angiogenesis, the tumor vascular normalization inflicted by bevacizumab has been proposed as a major contribution to the observed clinical outcome [9, 10]
With respect to tumor necrosis factor a (TNF), we showed in previous studies that coadministration of liposomal doxorubicin (Doxil) and TNF resulted in a drug accumulation accompanied by pronounced tumor response in both rat and murine tumor models [15, 16]
Summary
Delivery of drugs in solid tumors is still a major problem faced in chemotherapy and frequently responsible for failure of initially promising agents. It is well recognized that the pathophysiology of the tumor vasculature and stromal compartment presents an important obstacle [1] This inadequate drug delivery leads to poor responses and regrowth of tumors. Administration of the anti–vascular endothelial growth factor compound bevacizumab improved tumor response and survival in patients with metastatic colorectal cancer when used in combination with 5-fluorouracil/leucovorin [7, 8]. Anti–vascular endothelial growth factor therapy is thought to have its effect through inhibition of angiogenesis, the tumor vascular normalization inflicted by bevacizumab has been proposed as a major contribution to the observed clinical outcome [9, 10]. TNF is likely to augment the leakiness of the vasculature by increasing the gaps in the endothelial lining, leading to improved extravasation of chemotherapeutic drugs into the tumor interstitium [18]
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