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Development of an oral formulation to increase adenosine 5'-triphosphate levels in erythrocytes for protection from ionizing radiation
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Development of an oral formulation to increase adenosine 5'-triphosphate levels in erythrocytes for protection from ionizing radiation

Anmol Rajesh Arora
Master of Science (M.S.), Drexel University
Dec 2019
DOI:
https://doi.org/10.17918/5x7w-g314
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Abstract

Drug development Drugs--Design Adenosine triphosphate Ionizing radiation Pharmacology
Adequate protection of healthy tissues against ionizing radiation (IR) from sources such as radiation therapy or nuclear devices is a significant unmet clinical need. Studies have shown that adenosine triphosphate (ATP) is a crucial signaling molecule mediating radiation-induced biological effects triggered to mitigate the deleterious consequences of [gamma] radiation on the human body. Oral delivery of unprotected ATP is not efficient as it highly likely to degrade prior to reaching the red blood cells (RBCs) due to the harsh digesting environment of the gastrointestinal (GI) tract. Moreover, the high electrostatic charge of the ATP makes it impermeable through the cellular barriers in the GI system and prevents it from efficient absorption and accumulation in the red blood cells (erythrocytes) - the primary source of stable ATP in the systemic circulation. In this project, we explored a method to encapsulate ATP in the form of liposomal (LPs) particles to protect the ATP from enzymatic degradation and enable it to pass through the GI system and efficiently accumulate in the erythrocytes. We encapsulated the ATP within liposome particles using a modified lipid thin-film hydration method with five rounds of freeze-thaw cycles and short sonications. We optimized the formulation in terms of the ATP encapsulation efficiency, liposome size distribution, and scale-up procedure. In vivo studies with daily oral ATP-LPs administration for seven days resulted in a significant 1.5-fold (p < 0.003 by paired t-test) increase in the ATP content in the red blood cells versus animals that received empty liposomes. Both ATP-containing and control formulations did not evoke measurable adverse effects in the tested animals based on behavioral and weight (less than 7.5% change) assessments. Our results indicate that oral administration of the ATP-LPs facilitates the absorption of ATP from the GI tract and leads to increased levels of ATP within red blood cells. Future studies will evaluate whether increased levels of ATP in the red blood cells afford protection from ionizing radiation in mice.

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