Control of EPR effect by tumor-targeted NO donor via endogenous albumin transport system

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  • 内因性アルブミン輸送システムを利用した腫瘍選択的NO供与によるEPR効果の制御
  • ナイインセイ アルブミン ユソウ システム オ リヨウ シタ シュヨウ センタクテキ NO キョウヨ ニ ヨル EPR コウカ ノ セイギョ

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Abstract

A unique phenomenon in solid tumors, enhanced permeability and retention（EPR） effect, is very famous for the development of macromolecular anticancer therapy. However, cancers with low vascular permeability posed a challenge for these EPR based therapeutic systems. An intrinsic vascular modulator such as nitric oxide（NO） could augment the intrinsic EPR effect. We have demonstrated that S―nitrosated human serum albumin dimer（SNO―HSA Dimer） becomes an enhancer of the EPR effect in various tumor-bearing mice models. Here, we summarized the enhanced effect of SNO―HSA Dimer on the anticancer effect of two types of macromolecular anticancer drugs, namely PEGylated liposomal doxorubicin（Doxil®） and albumin bound paclitaxel nanoparticle（Abraxane®）. In C26―bearing mice with highly permeable vasculature, SNO―HSA Dimer could increase tumor accumulation of these anticancer drugs and thereby their anticancer effects. Interestingly, the tumor accumulation of Doxil® in B16―bearing mice, which are characterized by a low permeable vasculature, increased more 6―fold in the presence of SNO―HSA Dimer, and the improved accumulation of Doxil® led to increased survival and decreased tumor volume. On the other hand, SNO―HSA Dimer also augmented the tumor growth inhibition of Abraxane® in low vascular permeability B16―bearing mice. Furthermore, Abraxane® combined with SNO―HSA Dimer showed higher antitumor activity and improved survival rate of SUIT2 human pancreatic cancer orthotopic model. We also showed that the administration of SNO―HSA Dimer had no effect on blood pressure, heart rate and biochemical parameters, suggesting that SNO―HSA Dimer alone is very safe. Accordingly, we conclude that SNO―HSA Dimer is promising for regulating the EPR effect and enhanced therapeutic effects of many macromolecular anticancer drugs.

Journal

  • Drug Delivery System

    Drug Delivery System 33 (2), 130-138, 2018-03-25

    THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM

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