Synthetic polynucleotides as endosomolytic agents and bioenergy sources.
Nucleotides (NTs), such as adenosine triphosphate (ATP) and guanosine triphosphate (GTP), are signaling and bioenergy molecules to mediate a range of cellular pathways. We recently reported their significant endosomolytic activity. To evaluate whether polymeric NTs keep endosomolytic and bioenergetic functions of NTs in drug delivery and cell survival, NTs were polymerized by a coupling reaction to form polynucleotides (pNTs: pATP and pGTP) with their molecular weights around 500kDa. The cellular toxicity, indicated by IC50, of pNT was as low as that of corresponding monomeric NT. pNTs were degraded by an intracellular enzyme, alkaline phosphatase. Introduction of pNTs in a polycation-gene complex (polyplex) enhanced the extent of gene expression in cancerous, non-cancerous, and stem cells, up to 1500-fold higher than that of pNT-free polyplex. In addition, cells stored in a pATP solution resulted in a significantly higher survival rate (e.g., up to 20% increase) when exposed to low temperatures than pATP-free solution. The presence of pNT in polyplexes prevented the reduction of transfection efficiency induced by a low temperature. The findings in this study suggest that endosomolytic and bioenergetic pNTs serve as a non-toxic gene carrier component and protect cells from a cold shock or energy depletion.
Department of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea.
Hana
H
Cho
Gwangju Center, Korean Basic Science Institute, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, Republic of Korea.
Young Ju
YJ
Lee
Department of Pharmaceutics and Pharmaceutical Chemistry, The University of Utah, 30S 2000 E, Rm 2972, Salt Lake City, UT 84112, USA; Utah-Inha Drug Delivery Systems (DDS) and Advanced Therapeutics Research Center, 7-50 Songdo-dong, Yeonsu-gu, Incheon 406-840, Republic of Korea. Electronic address: you.bae@utah.edu.
You Han
YH
Bae
Department of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea. Electronic address: hckang@catholic.ac.kr.
Han Chang
HC
Kang
D000255:Adenosine Triphosphate / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003080:Cold Temperature; D016503:Drug Delivery Systems; D011992:Endosomes / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008970:Molecular Weight; D011119:Polynucleotides / Q000737:chemistry / Q000494:pharmacology*; D013696:Temperature; D014162:Transfection
D011119:Polynucleotides; D000255:Adenosine Triphosphate; D000469:Alkaline Phosphatase
Adenosine triphosphate; Bioenergy; Drug delivery; Endosomolytic materials; Nucleotide polymers