Crossing the Blood-Brain Barrier: Directing Intracellular Sorting to Enhance Drug Delivery for Brain Cancer Treatment
Abstract
Topic: Brain Cancer Lay Abstract Career Goals Meilyn Sylvestre has fully dedicated herself to cancer research in her undergraduate and graduate research labs, and is developing translational cancer therapies for her PhD thesis. If awarded, the Horizon Award will advance her development as a cancer researcher by providing an opportunity to direct her own PhD thesis project, which will prepare her for a career as a leader in cancer therapies. The researcher development plan will support the Principal Investigator (PI) in achieving these goals by establishing key project milestones, outlining regular meetings with her collaborators, and defining what skills she needs to gain from her mentors. Background & Rationale The blood-brain barrier (BBB) is a physical barrier comprising the blood vessel cells of the brain, protecting the brain from bacteria and foreign molecules. In the context of brain cancer, the BBB excludes more than 99% of potential therapeutics from reaching the brain. For this reason, brain cancers are among the most difficult cancers to treat, as the BBB is the most formidable clinical challenge to developing successful brain therapies. One strategy to “trick” the BBB into transporting drugs into the brain is to use a “Trojan horse” strategy. By leveraging a protein in the blood called transferrin (Tf), which delivers iron necessary for cell metabolism, we can deliver anti-cancer carriers through the BBB and into the brain. We will decorate our drug carriers with the Tf protein to target the transferrin receptor (TfR), which is highly expressed by the BBB, increasing the likelihood of carrier interaction. When Tf is recognized by the transferrin receptor (TfR) (in a lock-and-key fashion), the TfR signals the cell to take in the Tf via an endosome, a small internal cellular vesicle, where it can undergo multiple fates: (i) destruction, (ii) crossing into the brain, or (iii) recycling back into the bloodstream. This process is mediated by several factors, such as the pH of the vesicle and the strength of the interaction between Tf and the TfR. If the pH of the vesicle is too acidic (low pH), or the interaction between Tf and the TfR is too strong, the carrier is sorted for destruction. To address these challenges, we propose a platform that increases a therapy’s ability to cross the BBB and to avoid destruction. The goal of this work is to develop nanoscale drug carriers that respond to and control the local pH within the endosome, in order to deliver anti-cancer drugs past the BBB and into the brain. We will accomplish this by designing nanoscale drug delivery systems that are decorated with Tf to mediate BBB uptake into the cell. Then, the carriers will be designed to (i) reduce the interaction strength between the Tf-decorated carrier and the TfR and (ii) prevent vesicle acidification to circumvent destruction. We anticipate that this system will enhance our carriers’ capacity to traverse the BBB and enter the brain. Clinical Applications The proposed work significantly expands treatment options for patients diagnosed with brain cancers or other neurological diseases. Service members in particular are at an increased risk for developing cancers that have a high risk of spreading to the brain. For example, lung, colorectal, breast cancers, and skin melanomas are among the most frequently diagnosed cancers by the US Department of Veterans Affairs. Significantly, 20%-40% of patients with lung, colorectal, or breast cancers, and 50% of melanoma patients, will develop secondary brain tumors. Our proposed platform advances cancer research by overcoming major obstacles in current brain therapies by enhancing drug delivery past the BBB. If successful, the proposed work shifts the paradigm of brain-therapies in the clinic, enabling the use of drugs and therapies that are normally unable to penetrate the brain. Furthermore, we use adaptable chemistries, making this technology customizable with other targ
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010782
Entities
People
- Meilyn Sylvestre
Organizations
- United States Army
- University of Washington