The development of ultra-long circulating nanodrug delivery systems have showed distinct advantage in maintaining the long-lasting tumor retention. Although the relationship between extended tumor retention and ultra-long plasma half-life was apparent, there was still a lack of experimental evidence to reveal the enhancement mechanism. Herein, we proposed a concept of "Sustained Irrigation" effect ("SI" effect) to elucidate that it was through sustained blood irrigation that the ultra-long circulating nanoparticles achieved long-lasting tumor retention. Besides, in order to intuitively verify the "SI" effect, we developed an "ON-OFF-ON" fluorescence switch technology. The ultra-long circulating delivery nanoparticle was constructed by encapsulating the protein with hydrophilic polymer shell. Nanoparticles with ultra-long plasma half-life (t1/2>40 h) fabricated by this method were employed as models for demonstrating the "SI" effect. The recovery of Cy5.5 fluorescence after the laser quenching meant the "fresh" Cy5.5-labeled nanoparticles were entering tumor, which confirmed the ultra-long circulating nanoparticles in blood could sustainedly irrigate to tumor. Our finding revealed the key mechanism by which ultra-long circulating NDDSs enhanced the tumor accumulation and retention, and provided experimental support for the development of ultra-long circulating delivery system in clinic.
Keywords: Blood circulation; Drug delivery; Tumor retention; “ON-OFF-ON” fluorescence switch; “Sustained irrigation” effect.
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