Drug-Induced Nanocarrier Assembly as a Strategy for the Cellular Delivery of Nucleotides and Nucleotide Analogues

• Published in: Biomacromolecules Vol. 14; no. 3; pp. 737 - 742
• Main Authors: Giacalone, Giovanna, Bochot, Amélie, Fattal, Elias, Hillaireau, Hervé
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 11-03-2013
• Subjects: Adenosine Triphosphate - chemistry; Adenosine Triphosphate - pharmacology; Animals; Applied sciences; Biological and medical sciences; Cell Survival; Chitosan - chemistry; Dideoxynucleotides - chemistry; Dideoxynucleotides - pharmacology; Drug Carriers - chemistry; Drug Delivery Systems - methods; Exact sciences and technology; General pharmacology; HIV Infections - drug therapy; Human immunodeficiency virus; Macrophages - metabolism; Medical sciences; Mice; Nanoparticles - chemistry; Natural polymers; Nucleotides - chemistry; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Physicochemistry of polymers; Starch and polysaccharides; Zidovudine - analogs & derivatives; Zidovudine - chemistry; Zidovudine - pharmacology; Biological properties; Particle size; Control release polymer; Gelation; Cytotoxicity; Drug carrier; Experimental study; In vitro; Nanoencapsulation; Structure processing relationship; Nanogel; Medium effect; Internalization; Nucleotide; Oside polymer; Antiviral; Electrokinetic potential; Chitosan; Kinetics; ATP; Zidovudine; Release; Macrophage
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/bm301832v

The natural nucleotide adenosine triphosphate (ATP) and nucleotide analogues such as azidothymidine triphosphate (AZT-TP) display important pharmacological activities for the treatment of ischemia and HIV infections, respectively. Their clinical use is, however, limited mostly due to their hydrophilicity, which highly restricts their diffusion into the target cells. Few nanocarriers have been proposed to address the challenge of ATP/AZT-TP cellular delivery, but the loading efficiency, preparation complexity, and efficient cellular delivery remain important barriers to their development. In this study, we propose an original, straightforward and versatile design of nucleotide and nucleotide analogue nanocarriers based on the natural polysaccharide chitosan (CS). We show that the drugs ATP and AZT-TP can induce ionotropic gelation of CS, leading to CS/ATP and CS/AZT-TP nanoparticles with high drug entrapment efficiency and loading rateup to 44%. Such nanocarriers release ATP and AZT-TP in physiological media and allow an efficient in vitro cellular delivery of these molecules down to the cell cytoplasm.