Targeting the invincible barrier for drug delivery in solid cancers: interstitial fluid pressure

The cover for issue 87 of Oncotarget features Figure 1, "The survival rate of genetically engineered mice with pancreatic ductal adenocarcinoma treated with a weekly injection of nano-albumin bound paclitaxel (NAB-paclitaxel) alone (orange line, n = 4), NAB-paclitaxel 3 hours after CYT-6091 treatment (green line, n = 4), and vehicle control (blue line, n = 3)," by Libutti, et al.

Although a number of new systemic therapeutic options in patients with advanced solid cancers have emerged due to the improved knowledge of molecular dysregulation in cancers, the durable, long-term, objective responses infrequently occur. While several mechanisms contributing to cancer drug resistance have been described, the common key barrier among solid cancers is the unique tumor microenvironment that causes the high interstitial fluid pressure (IFP). Elevated tumor IFP in the tumor microenvironment is believed to be from high cell density, increased intratumoral vascular permeability, abnormal extracellular matrix, and poor venous/lymphatic drainage.

Dr. Naris Nilubol from the Surgical Oncology Program, at NCI/NIH, in Bethesda, MD, USA said, "In the era of precision medicine for cancer, efforts have been made to identify agents that preferentially target expressed molecular pathways specific to the cancer cells. However, a major limitation of current systemically delivered cancer therapies is the failure of these drugs to effectively reach their target, the cancer cells."

Figure 1: The survival rate of genetically engineered mice with pancreatic ductal adenocarcinoma treated with a weekly injection of nano-albumin bound paclitaxel (NAB-paclitaxel) alone (orange line, n = 4), NAB-paclitaxel 3 hours after CYT-6091 treatment (green line, n = 4), and vehicle control (blue line, n = 3). The experiment was performed at the Rutgers Cancer Institute of New Jersey. The doses of paclitaxel and TNF were 40 mg/kg and 110 μg/kg, respectively. Arrows indicate the day of treatments.

The elevated tumor IFP markedly reduces drug delivery efficacy due to a drop of convection between the intra- and extra-vascular spaces, thus limiting drug distribution into the tumor microenvironment.

The Naris Nilubol research team concluded, "Preclinical studies of 1) systemically administered nanogold particles carrying tumor necrosis factor-alpha (TNF-alpha) followed by the systemic cytotoxic agent and 2) nanogold particles carrying both TNF-alpha and paclitaxel in genetically engineered mouse models that spontaneously develop solid tumors support this approach as the treatments induced tumor vascular leakage, reduced IFP, increased intratumoral cytotoxic drug accumulation, reduced tumor burden, and improved animal survival."

Full text - https://doi.org/10.18632/oncotarget.26267

Correspondence to - Naris Nilubol - niluboln@mail.nih.gov

Keywords - microenvironment, interstitial fluid pressure, drug delivery, tumor necrosis factor, nanomedicine