Using Simulated Microgravity to Enhance the Effectiveness of Nanodrug Chemotherapy in Breast Cancer
DOD BC084220
In this application, we propose to counteract increased interstitial fluid pressure (Pif) by increasing the capillary pressure (Pc) locally and improve drug delivery in the breast cancer tissue by increasing the streaming of flowing fluid. Increased Pif is a significant and unsolved problem that reduces drug delivery in breast cancer and its metastases. Brain and eye metastases are typically treated with radiotherapy or surgery for only palliative purposes.
In breast cancer the pressure of the fluid between the cancer cells, which is also known as interstitial fluid pressure (Pif), is higher than in normal tissues. This abnormality of breast cancer is also known as interstitial hypertension of breast cancer. The high fluid pressure prevents blood capillaries (Pc) from delivering (pushing) drug particles into the cancer by means of streaming of flowing fluid (convection). An increase of Pif reduces the transport of such drugs into the cancer by decreasing convection from blood into cancer tissues. Many anti-cancer drugs penetrate breast cancer mainly by streaming of flowing fluid. Elevated tumor Pif may lead to reduced drug delivery to the breast cancer and poor treatment outcome in breast cancer. Although lowering of tumor Pif directly is suggested to be a useful approach in improving anti-cancer drug efficacy, presently it is not possible to reduce Pif completely with the available technology.
We will make use of the research tools and knowledge acquired in microgravity/mechanobiology research to solve a significant problem (interstitial hypertension) in breast cancer therapy. As a proof of concept, we will use animal models of simulated microgravity and drug convection integrated into mouse models of breast cancer and its brain and eye metastasis models. If our hypothesis of this synergistic idea is proven true, it will be the first proof of concept to use simulated microgravity for the benefit of nanoparticle-based drug (large molecular weight drug) delivery in breast cancer.
The contribution to human health may ultimately be proven in patients with breast cancer and its metastases in eye and brain, from simulated microgravity as a short course (4-8 hours) of head-down tilt during and shortly after intravenous administration of monoclonal antibody-based antitumor therapeutics because of the unique regional change (increased Pc) that counteracts interstitial fluid pressure.
Funding
Principal Investigators: Leonardo Jose De Moura Carvalho, Ph.D. and John A. Frangos, Ph.D.
Agency: DOD