Polymerized Prodrugs of Bioenergy Molecules as Multifunctional Pharmaceutical Adjuvants in Drug Delivery and Cell-Survival Therapeutics

H. Cho, H. C. Kang
The Catholic University of Korea,
Korea

Keywords: bioenergy, endosomolysis, cell survival, energy-depletion, drug delivery

Summary:

In all living organisms, well-known bioenergy-generating nucleotides (e.g., adenosine triphosphate [ATP], guanosine triphosphate [GTP], cytidine triphosphate [CTP], and thymidine triphosphate [TTP]) are very significant molecules that generate bioenergy through phosphate release, are used as building blocks for constructing nucleic acids, and are involved in various biological processes, such as signaling, phosphorylation, intracellular trafficking, viability, and metabolism. Especially, the delivery of exogenous bioenergy molecules as tissue/cell-survival therapeutics has been shown to attenuate ischemia, liver injury, cytotoxic edema, infarction, renal failure, chronic pain, and so on because their intrinsic potentials could improve cell viability in various harsh environments such as low temperature, starvation, and oxidative stress. In addition, drug delivery technology has been explored as an option for the better treatment of various medical conditions, but often facing diverse barriers at a cellular level such as the plasma/nuclear membranes, the endo/lysosomes, and intracellular trafficking in particular when the pharmacological target is present inside cells. This compromises the efficacy of therapeutic molecules carried by a delivery system. However, these bioenergy molecules play a role as non-toxic endosomolytic agents because their secondary phosphate groups have pKa values of 6.1–6.5 which falls within the pH range of the early endosomes. Interestingly, some bioenergy molecules showed additional biofunctions for improved nuclear delivery and transcription activity (when pDNA is delivered). These bioenergy molecules could be applied as multifunctional pharmaceutical adjuvants for overcoming cellular and intracellular hurdles during drug delivery and tissue/cell-survival therapeutics for treating various diseases that involve energy depletion. Especially, polymerized prodrugs synthesized in non-toxic aqueous environments showed similar potentials like bioenergy molecules. Thus, the bioenergy polymers would be considered as pharmaceutical adjuvants and therapeutics.