Acute lymphoblastic leukemia (ALL) accounts for more than 25% of all pediatric cancers. ALL cancer cells grow and multiply in the bone marrow crowding out normal blood cell production. To multiply, ALL cancer cells rely upon a constant supply of nutrients and amino acids – the building blocks of proteins. Specifically, asparagine that can be manufactured by normal cells to meet their normal growth and function, cannot be made by ALL cancer cells. The current therapeutic strategy is to eliminate access of ALL cancer cells to asparagine, is accomplished by injecting asparaginase, an enzyme that degrades asparagine, causing ALL cancer cells to die without harming normal cells. This therapy is u...

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Acute lymphoblastic leukemia (ALL) accounts for more than 25% of all pediatric cancers. ALL cancer cells grow and multiply in the bone marrow crowding out normal blood cell production. To multiply, ALL cancer cells rely upon a constant supply of nutrients and amino acids – the building blocks of proteins. Specifically, asparagine that can be manufactured by normal cells to meet their normal growth and function, cannot be made by ALL cancer cells. The current therapeutic strategy is to eliminate access of ALL cancer cells to asparagine, is accomplished by injecting asparaginase, an enzyme that degrades asparagine, causing ALL cancer cells to die without harming normal cells. This therapy is universally used as a first line treatment of ALL, but the enzyme – made by bacteria, is highly allergenic in 30% of children and sensitizes them to prohibit its future use. Unfortunately, there are currently no effective means to avoid such complications. We plan to address this unmet need by encapsulating asparaginase in silica nanoparticles. The silica shell is sufficiently porous to allow free access of asparagine to its interior to be degraded, but blocks larger molecules such as antibodies, effectively hiding the enzyme from the child’s immune system to prevent allergic reactions, sensitization, and enzyme neutralization. These nanoparticles can be made a 1000 times smaller than a red blood cell to ensure that they can reach all cancer cells to cut-off their asparagine supply. Because the enzyme is shielded, its function is protected and prolonged compared to the enzyme used clinically, providing additional therapeutic benefit. If our effort in this proposal that will be tested in mice and patient sera shows increased safety – no allergic reactions or sensitization, and increased efficacy – asparagine depletion and ALL cancer cell killing, it will justify translating our novel nanoparticles to the clinic to improve outcomes and extend the lives of affected children.

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