Nucleotides as Nontoxic Endogenous Endosomolytic Agents in Drug Delivery

Cho, Hanna; Cho, Yong‐Yeon; Bae, You Han; Kang, Han Chang

doi:10.1002/adhm.201400008

Cited by 16 publications

(12 citation statements)

References 29 publications

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“…Another possible cause could be NTmediated cytotoxicity. High extracellular ATP levels (e.g., >1 mM) affected its negative biofunctions such as apoptosis, cell death, DNA fragmentation, and so on [3][4][5]14]. These results indicate that the extracellular ATP levels (<25 lM) of free ATP delivery could not make ATP-induced viability loss.…”

Section: Basementioning

confidence: 93%

“…Additionally, we recently reported endosomolytic function of NTs and their polymers. Their secondary phosphate groups, with pK a values ranging from 6.1 to 6.5 in a variety of endolysosomal pHs, buffered and retarded acidification in endolysosomes, which aided in the escape of nanosized drug delivery systems from endolysosomes and improved the therapeutic efficacy of the delivered payloads [14,15]. Among the various biological and therapeutic functions of NTs, we are interested in NTs as energy-carrying molecules because their bioenergy can promote cell survival and endow cellular tolerance against harsh energydepletion conditions, such as low temperature [16], serum depletion [17], starvation [17,18], and hypoxia [19].…”

Section: Introductionmentioning

confidence: 99%

“…Another strategy for loading NTs into nanocarriers is nanocomplexes (NCs) because cationic molecules or polymers (e.g., chitosan [25,26], poly(ethylene glycol)-b-poly(L-lysine) [27], branched polyethyleneimine (bPEI) [14,28], and poly(L-lysine) [14]) can electrostatically interact with the negatively-charged phosphate groups of NTs, resulting in simple formation of nanosized complexes. Instead of complex formation using cationic polymers, a small hydrophilic ion, Ca 2+ , has also been used because of its excellent biocompatibility and biodegradability [29,30].…”

Section: Introductionmentioning

confidence: 99%

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Enhanced cell survival of pH-sensitive bioenergetic nucleotide nanoparticles in energy/oxygen-depleted cells and their intranasal delivery for reduced brain infarction

et al. 2016

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Section: Basementioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enhanced cell survival of pH-sensitive bioenergetic nucleotide nanoparticles in energy/oxygen-depleted cells and their intranasal delivery for reduced brain infarction

et al. 2016

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“…Nucleotides, as one of the essential metabolites of organisms, are widely distributed in the human body and have a variety of biological functions, such as constituting nucleic acid, storeing energy, delivering drugs, and participating in metabolism and physiological regulation (Poijärvi-Virta, 2006;Cho et al, 2014a;Roy et al, 2016). As mentioned earlier, the lethality of bactericidal antibiotics in bacteria correlates with altered bacterial metabolism, including the increased abundance of carbon metabolites in the center of cells and the disruption of nucleotide pools.…”

Section: Nucleotide Supplementationmentioning

confidence: 97%

Combating Antibiotic Tolerance Through Activating Bacterial Metabolism

et al. 2020

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The emergence of antibiotic tolerance enables genetically susceptible bacteria to withstand the killing by clinically relevant antibiotics. As is reported, an increasing body of evidence sheds light on the critical and underappreciated role of antibiotic tolerance in the disease burden of bacterial infections. Considering this tense situation, new therapeutic strategies are urgently required for combating antibiotic tolerance. Herein, we provide an insightful illustration to distinguish between antibiotic resistance and tolerance, and highlight its clinical significance and complexities of drug-tolerant bacteria. Then, we discuss the close relationship between antibiotic tolerance and bacterial metabolism. As such, a bacterial metabolism-based approach was proposed to counter antibiotic tolerance. These exogenous metabolites including amino acids, tricarboxylic acid cycle (TCA cycle) metabolites, and nucleotides effectively activate bacterial metabolism and convert the tolerant cells to sensitive cells, and eventually restore antibiotic efficacy. A better understanding of molecular mechanisms of antibiotic tolerance particularly in vivo would substantially drive the development of novel strategies targeting bacterial metabolism.

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“…In this work, we desired to study the role of ATP's negative charge on triggering siRNA release. The pKa of ATP's primary and secondary phosphate groups are 1-2 and 6.5, respectively 16 , 17 and the cytosol pH in tumor cells is around 6.8-7.2 18 , 19 . Hence, the ATP is negatively charged in the biological environment (both intracellular and intracellular space).…”

Section: Introductionmentioning

confidence: 99%

ATP-activated decrosslinking and charge-reversal vectors for siRNA delivery and cancer therapy

Zhou

Zhang

et al. 2018

Theranostics

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Stimuli-responsive polycations have been developed for improved nucleic acid transfection and enhanced therapeutic efficacy. The most reported mechanisms for controlled release of siRNA are based on polyelectrolyte exchange reactions in the cytoplasm and the degradation of polycations initiated by specific triggers. However, the degradation strategy has not always been sufficient due to unsatisfactory kinetics and binding of cationic fragments to siRNA, which limits the gene silencing effect. In this study, a new strategy that combines degradation and charge reversal is proposed.Methods: We prepared a polycation (CrossPPA) by crosslinking of phenylboronic acid (PBA)-grafted 1.8k PEI with alginate. It was compared with 25k PEI, 1.8k PEI and 1.8k PEI-PBA on siRNA encapsulation, ATP-responsive behavior and mechanism, cytotoxicity, cell uptake, siRNA transfection, in vivo biodistribution and in vivo anti-tumor efficacy. The in vitro and in vivo experiments were performed on 4T1 murine breast cancer cells and 4T1 tumor model separately.Results: The crosslinking strategy obviously improve the siRNA loading ability of 1.8k PEI. We validated that intracellular levels of ATP could trigger CrossPPA disassembly and charge reversal, which resulted in efficient and rapid siRNA release due to electrostatic repulsion. Besides, CrossPPA/siRNA showed strong cell uptake in 4T1 cells compared with 1.8k PEI/siRNA. Notably, the cytotoxicity of CrossPPA was pretty low, which was owing to its biodegradability. Furthermore, the crosslinked polyplexes significantly enhanced siRNA transfection and improved tumor accumulation. The high gene silencing ability of CrossPPA polyplex led to strong anti-tumor efficacy when using Bcl2-targeted siRNA.Conclusion: These results indicated that the ATP-triggered disassembly and charge reversal strategy provided a new way for developing stimuli-responsive siRNA carriers and showed potential for nucleic acid delivery in the treatment of cancer.

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Nucleotides as Nontoxic Endogenous Endosomolytic Agents in Drug Delivery

Cited by 16 publications

References 29 publications

Enhanced cell survival of pH-sensitive bioenergetic nucleotide nanoparticles in energy/oxygen-depleted cells and their intranasal delivery for reduced brain infarction

Enhanced cell survival of pH-sensitive bioenergetic nucleotide nanoparticles in energy/oxygen-depleted cells and their intranasal delivery for reduced brain infarction

Combating Antibiotic Tolerance Through Activating Bacterial Metabolism

ATP-activated decrosslinking and charge-reversal vectors for siRNA delivery and cancer therapy

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