More than 50 million Americans are affected by neurological diseases each year, with a cost of more than $650 billion. Despite the high prevalence and substantial economic burden, the present outlook for patients suffering from many types of brain diseases remains poor due to the failure of conventional therapies. Treatment of brain diseases is challenging because invasive surgeries can damage healthy brain tissue, the blood-brain barrier (BBB) blocks most systemically administered drugs from entering the brain, and many therapeutic agents with beneficial effects in the brain have adverse side effects in other organs and tissues. The currently available techniques for brain drug delivery are invasive (e.g., convection-enhanced delivery), lack specific targeting to the diseased site (e.g., intranasal brain drug delivery), or are associated with systemic toxicity [e.g., focused ultrasound (FUS)-induced BBB disruption (FUS-BBBD) for the delivery of drugs injected into the systemic circulatory system]. The objective of this proposal is to develop f ocused ultrasound combined with microbubble-mediated intranasal delivery (FUSIN), which will achieve noninvasive and spatially targeted delivery of therapeutic agents to diseased brain sites without jeopardizing healthy regions of the brain and other organs. FUSIN utilizes the intranasal route for direct nose-to-brain drug administration, thereby bypassing the BBB and minimizing systemic exposure. It uses focused ultrasound to induce microbubble cavitation (expansion and contraction of microbubbles) within the focal zone of the FUS beam, leading to enhanced drug delivery at the FUS-targeted brain location. Our objective will be achieved by completing the following three specific aims using gold nanoparticles (AuNPs) as model agents and a mouse model of diffuse intrinsic pontine glioma, the deadliest cancer in children, as a model disease.
Aim 1 will identify the biophysical mechanisms of FUSIN-mediated agent transport using in vivo two-photon microscopy.
Aim 2 will systematically evaluate FUSIN delivery efficiency and effect on normal tissue to assess its potential as a platform technology for brain drug delivery.
Aim 3 will assess the feasibility and safety of real-time passive cavitation imaging-guided FUSIN to control AuNP delivery location and concentration through cavitation dose painting. The proposed research contains three main innovations: (1) the microbubble pump effect is proposed as a novel mechanism for microbubble-mediated drug delivery; (2) FUSIN is a novel spatially targeted brain drug delivery technique; and (3) cavitation dose painting is a novel approach for controlled drug delivery. This project is significant because FUSIN has the potential to impact the clinical management of a broad spectrum of brain disorders by significantly enhancing therapeutic agent delivery to diseased brain sites, substantially reducing toxicity to healthy brain regions and other organs, and eliminating the need for invasive surgery.
The proposed research is relevant for public health because it will develop a novel image-guided brain drug delivery platform (FUSIN) for improving the treatment of brain diseases, which are a major public health problem with few treatment options in the United States. The FUSIN technique can significantly improve the delivery efficiency of therapeutic agents specifically to diseased brain sites and substantially reduce adverse side-effects and toxicity to healthy brain regions and other organs. It is expected that this innovative platform has the potential to impact the treatment of a broad spectrum of brain diseases.
