Masaki Otagiri
Sojo University, Japan
Title: S-nitrosated human serum albumin dimer with superior antitumor activity, long blood retention and excellent EPR effect
Biography
Biography: Masaki Otagiri
Abstract
Recombinant human serum albumin dimer (HSA-dimer) was produced by the yeast Pichia pastoris. HSA-dimer has a longer circulation, compared with HSA-monomer. Thus, HSA-dimer is expected to have an enhanced accumulation in solid tumor via the EPR mechanism due to its large molecular weight (130 kDa). In this conference, we will present a novel DDS system of NO, potential anticancer therapeutic, using HSA-dimer as a carrier, namely, SNO-HSA-dimer. SNO-HSAdimer treatment induced apoptosis of C26 tumor cells in vitro, depending on the concentration of NO. In in vivo experiments, SNO-HSA-dimer was found to specifically deliver large amounts of cytotoxic NO into tumor tissue but not into normal organs in C26 tumor-bearing mice. Interestingly, SNO-HSA-dimer caused a much higher concentration of NOx in the tumor than SNO-HSA-monomer. Moreover, especially, SNO-HSA-dimer has a high level of blood retention. The accumulation of SNO-HSA-dimer in tumor tissue is significantly high compared with SNO-HSA-monomer, suggesting that S-nitrosation of SNO-HSA-dimer further enhanced its EPR effect. Next, we examined whether SNO-HSA-dimer can enhance the activity of other macromolecular antitumor drugs via the augmented EPR effects. As antitumor drugs, we selected N-(2-hydroxypropyl) methacrylamide (HPMA)-zinc protoporphyrin (ZnPP) and doxil. HPMA-ZnPP (mean particle size: 80 nm) forms micelles and doxil has liposomal structure (mean particle size: 90 nm). The tumor growth was significantly inhibited when the two compounds were given simultaneously. The combination of SNO-HSA-dimer inhibited the tumor growth, compared with doxil or SNO-HSA-dimer alone. Furthermore, the combination of doxil and SNO-HSA-dimer significantly reduce the number of lung metastasis. Finally, possible side effects of SNO-HSA-dimer administration were evaluated by measuring blood pressure, heart rate and biochemical parameters. Fortunately, none of these above parameters were significantly affected by repeated administration of SNO-HSA-dimer. Thus, SNO-HSA-dimer strategy is a safe and effective therapeutic approach for improving the antitumor effects of macromolecular drugs.