Tuning of Poly-S-Nitrosated Human Serum Albumin as Superior Antitumor Nanomedicine |
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| Affiliation: | 1. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan;2. Center for Clinical Pharmaceutical Science, Kumamoto University, Kumamoto 862-0973, Japan;3. Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan;4. Department of Biomedicine, University of Aarhus, Aarhus CDK-8000, Denmark;5. Pharmaceutical Research Laboratories, Kusatsu, Shiga 525-0055, Japan;6. Tohoku Nipro Pharmaceutical Corporation, Kagamiishimachi, Iwasegun, Fukushima 969-0401, Japan;7. Drug Delivery System Institute, Sojo University, Kumamoto 860-0082, Japan;1. Interdepartmental Laboratory for Electron Microscopy, Roma Tre University, I-00146 Roma, Italy;2. Department of Chemical Sciences and Technology, University of Roma "Tor Vergata", I-00133 Roma, Italy;3. Department of Clinical Sciences and Translational Medicine, University of Roma “Tor Vergata”, I-00133 Roma, Italy;4. Interuniversity Consortium for the Research on the Chemistry of Metals in Biological Systems, I-70126 Bari, Italy;5. D''Urso & Fanali S.r.l., I-21013 Gallarate, VA, Italy;6. Department of Science and High Technology, University of Insubria, I-21052 Busto Arsizio, VA, Italy;7. Neuroscience Research Center, University of Insubria, I-21052 Busto Arsizio, VA, Italy;1. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan;2. Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan;3. Center for Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan;4. DDS Research Institute, Sojo University, Kumamoto, Japan;1. School of Pharmacy, The University of Queensland, St. Lucia, Queensland 4072, Australia;2. Queensland Institute of Medical Research, Molecular Virology Laboratory, Brisbane, Queensland 4811, Australia |
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| Abstract: | ![]()
Macromolecules have been developed as carriers of low-molecular-weight drugs in drug delivery systems (DDS) to improve their pharmacokinetic profile or to promote their uptake in tumor tissue via enhanced permeability and retention (EPR) effects. We have previously demonstrated that poly-nitric oxide (NO) conjugated human serum albumin (Poly-SNO-HSA) has the potential to be a DDS carrier capable of accumulating NO in tumors. However, the stability of Poly-SNO-HSA in the circulation has to be improved, and its optimal molecular size for using the EPR effects has to be evaluated. In the present study, we performed two tuning methods for refining Poly-SNO-HSA, namely, pegylation and dimerization. We observed that pegylation enhanced the stability of Poly-SNO-HSA both in vitro and in vivo, and that dimerization of Poly-SNO-HSA enhanced the antitumor activity via more efficient delivery of NO in Colon 26 tumor-bearing mice. Intriguingly, dimerization resulted in a 10 times higher antitumor activity. These data suggest that pegylation and dimerization of Poly-SNO-HSA are very important tuners to optimize NO stability and accumulation, and thereby effect, in tumors. Thus, polyethylene glycol-Poly-SNO-HSA dimer seems to be a very appealing and safe NO carrier and thereby a strong candidate as an antitumor drug in future development of cancer therapeutics. |
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