S-Nitrosated human serum albumin dimer as novel nano-EPR enhancer applied to macromolecular anti-tumor drugs such as micelles and liposomes.

Abstract

The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid tumors, and it can serve as a basis for the development of macromolecular anticancer therapy. We have previously found that recombinant human serum albumin dimer, and especially its S-nitrosated form (SNO-HSA-Dimer), is an enhancer of the EPR effect. In this study, we investigated the influence of SNO-HSA-Dimer on the anti-tumor effect of two types of macromolecular anti-tumor drugs, namely N-(2-hydroxypropyl)methacrylamide polymer conjugated with zinc protoporphyrin, which forms micelles and can be used for fluorescence studies. The other was PEGylated liposomal doxorubicin (Doxil), a typical example of a stealth liposome approved for medical usage. In mice having C26 tumors with highly permeable vasculature, SNO-HSA-Dimer increases tumor accumulation of the drugs by a factor 3-4 and thereby their anti-tumor effects. Experiments with Evans blue revealed increased EPR effect in all parts of the tumor. Furthermore, SNO-HSA-Dimer improves the anti-metastatic effects of Doxil and reduces its minor uptake in non-tumorous organs such as liver and kidney. Tumor accumulation of Doxil in B16 tumors, which are characterized by a low permeable vasculature, increased even more (6-fold) in the presence of SNO-HSA-Dimer, and the improved accumulation lead to decreased tumor volume and increased survival of the animals. The administration of SNO-HSA-Dimer itself is safe, because it has no effect on blood pressure, heart rate or on several biochemical parameters. The present findings indicate that SNO-HSA-Dimer is promising for enhancing the EPR effect and consequently the specific, therapeutic effects of macromolecular anticancer drugs.

• Authors: Ryo Kinoshita, Yu Ishima, Mayumi Ikeda, Ulrich Kragh-Hansen, Jun Fang, Hideaki Nakamura, Victor T G Chuang, Ryota Tanaka, Hitoshi Maeda, Azusa Kodama, Hiroshi Watanabe, Hiroshi Maeda, Masaki Otagiri, Toru Maruyama
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 217 Pg. 1-9 (Nov 10 2015) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 26302904 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Acrylamides
• Antineoplastic Agents
• Liposomes
• Micelles
• Nitroso Compounds
• Protoporphyrins
• S-nitrosoalbumin, human
• Serum Albumin
• liposomal doxorubicin
• zinc protoporphyrin
• Polyethylene Glycols
• Doxorubicin
• N-(2-hydroxypropyl)methacrylamide
• Serum Albumin, Human

Topics

• Acrylamides (pharmacokinetics, therapeutic use)
• Animals
• Antineoplastic Agents (blood, pharmacokinetics, therapeutic use)
• Cell Line, Tumor
• Doxorubicin (analogs & derivatives, blood, pharmacokinetics, therapeutic use)
• Kidney (metabolism)
• Liposomes
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Micelles
• Neoplasms (drug therapy, metabolism, pathology)
• Nitroso Compounds (pharmacology, therapeutic use)
• Permeability
• Polyethylene Glycols (pharmacokinetics, therapeutic use)
• Protein Multimerization
• Protoporphyrins (pharmacokinetics, therapeutic use)
• Serum Albumin (pharmacology, therapeutic use)
• Serum Albumin, Human
• Tumor Burden (drug effects)