Formulations of biodegradable Nanogel carriers with 5'-triphosphates of nucleoside analogs that display a reduced cytotoxicity and enhanced drug activity.
Therapies including nucleoside analogs are associated with severe toxic side effects and acquirement of drug resistance. We have previously reported the drug delivery in the form of 5'-triphosphates (NTP) encapsulated in cross-linked cationic networks of polyethylenimine (PEI) and PEG/Pluronic polymers (Nanogels). In this study, Nanogels, containing biodegradable PEI that could easily dissociate in reducing cytosolic environment and form products with minimal toxicity, were synthesized and displayed low cytotoxicity. Toxicity of Nanogels was clearly dependent on the total positive charge of carriers and was 5-6 fold lower for carriers loaded with NTP. Though intracellular ATP level was immediately reduced by ca. 50% following the treatment with Nanogels, it was largely restored 24 h later. Effect of Nanogels on various respiratory components of cells was reversible too, and, therefore, resulted in low immediate cell death. Nanogel alone and formulations with AZT-TP demonstrated a much lower mitochondrial toxicity than AZT. As an example of potential antiviral applications of low-toxic Nanogel carriers, a 5'-triphosphorylated Ribavirin-Nanogel formulation was prepared that demonstrated a 30-fold decrease in effective drug concentration (EC(90)) and, totally, a 10-fold increase in selectivity index compared to the drug alone in MDCK cells infected with influenza A virus.
Kohli
Ekta
E
Center for Drug Delivery and Nanomedicine and Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-5830, United States.
Han
Huai-Yun
HY
Zeman
Arin D
AD
Vinogradov
Serguei V
SV
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D054306:Dideoxynucleotides; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D005562:Formazans / Q000378:metabolism; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008163:Luminescent Measurements; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000502:physiology; D000080385:Nanogels; D036103:Nanotechnology; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity*; D011094:Polyethyleneimine / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity*; D012235:Rhodamines / Q000378:metabolism; D012254:Ribavirin / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013778:Tetrazolium Salts / Q000378:metabolism; D013942:Thymine Nucleotides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
D000998:Antiviral Agents; D054306:Dideoxynucleotides; D004337:Drug Carriers; D005456:Fluorescent Dyes; D005562:Formazans; D000080385:Nanogels; D012235:Rhodamines; D013778:Tetrazolium Salts; D013942:Thymine Nucleotides; C413692:polyethylene glycol polyethyleneimine nanogel; C079782:MTT formazan; C022027:lissamine rhodamine B; D011092:Polyethylene Glycols; D012254:Ribavirin; D015215:Zidovudine; C052873:zidovudine triphosphate; D000255:Adenosine Triphosphate; D011094:Polyethyleneimine; D007770:L-Lactate Dehydrogenase