Does nicotine exposure inhibit convective drug delivery ?
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Lung cancer tumor remains the leading cause of cancer death in both men and women in California. Despite aggressive efforts, drug treatments are unsatisfactory and survival rates dismal. One of the causes of ineffectiveness of the chemotherapy results from the high pressure within the tumor which prevents the drugs in the tiny blood vessels to flow into the core of the tumor particularly into the fluid between the tumor cells which is called interstitial fluid. The healthy tissues have a negative interstitial fluid pressure (Pif) causing a relative vacuum. In lung cancer however, the interstitial fluid pressure is high because a cell type wrapping around the tiny vessels called pericytes exert force to the bulk of the tumor and increase the pressure within the tumor. This can be likened to a hand constantly squeezing a balloon filled with water. Many drugs used in lung cancer chemotherapy are transported through the tiny vessel walls to the core of the tumor by streaming of a flowing fluid. An increase in Pif causes inefficient transport of drugs by decreasing flow of drugs from the tiny blood vessels into the tissues. Our preliminary studies demonstrated that increased pressure in tissues with abundant new capillary vessels (similar to lung cancer) exposed to nicotine is far greater than the similar tissues not exposed to nicotine. This suggests that drug delivery into the lung cancer tumor from circulation may be significantly impeded in smokers, which could decrease the efficacy of their treatment. The ideas and experiments in this research plan are designed to identify the mechanism by which the pressure in the tumor increases in response to nicotine. The underlying hypothesis for this proposal is that nicotine, by increasing the compressive forces generated by pericyte cells, increases the interstitial fluid pressure by squeezing the tumor bulk constantly. We propose to unveil a novel adverse effect of nicotine exposure by which Pif is increased, which consequently reduces the flow of drugs into the lung cancer. Our goals are organized into three subdivisions for experimental testing of these hypotheses. Goal 1: We will isolate pericytes from around tiny vessels in lung cancer and expose them to nicotine to test whether nicotine-exposed pericytes generate more contractile force than pericytes not exposed to nicotine. We anticipate that nicotine increases squeezing force generation in lung cancer by stronger contraction of pericytes. Goal 2: We will characterize the flow of tagged-drugs from tiny vessels into the lung cancer by calculating the fraction of tagged drugs in the tumor to the concentration of the same drug in the blood circulation. We anticipate finding diminished flow of tagged-drugs into the lung cancer in nicotine-exposed mice compared to the control group not exposed to nicotine. Goal 3: We will block the receptors on pericytes that respond to nicotine to mitigate pericyte as an effective countermeasure against nicotine-driven Pif increase. Our proposed experiments are designed to understand the mechanism by which the pressure in lung cancer increases with nicotine exposure, and whether nicotine exposure reduces flow of drugs from tiny blood vessels into the lung cancer tumor. The proposed research is focused on a novel, potentially adverse effect of nicotine exposure in lung cancer; and is relevant to “Lung Cancer” primary research priority of TRDRP. The benefits of the proposed research will be two-fold: First, patients receiving any drug could benefit from improved drug delivery by avoiding continuous primary or second hand smoke exposure which contains nicotine. This newly discovered detrimental effect (reduction of drug delivery) caused by nicotine will be unveiled as an additional public health problem related to smoking. Second, we propose to stop nicotine-driven drug delivery problems by inhibiting pericytes in lung cancer tissues through their nicotinic acetylcholine receptors.