Seoul National University, South Korea
Activation of Chemo/Immunotherapy in Tumor Microenvironment
Nanostructures such as nanosheets, and nanoballs have been studied for delivery of chemical anticancer drugs and oligonucleotides. Graphene-based nanosheets were studied for tumor microenvironment-responsive anticancer drug delivery. The biofunctionalization of graphene-based nanosheets with melittin peptide derivatives of phospholipids selectively activated the release of melittin in tumor microenvironment. The activation of pore-forming melittin in tumor tissues increased delivery of anticancer drug-loaded GNS to tumor cells. Moreover, the overexpression of matrix metalloproteinase (MMP) in tumor microenvironment was used for responsive delivery systems. We designed graphene oxide (GO) nanotheranostics loaded with MMP-activable image probe derivative and therapeutic peptide. As an MMP-activable therapeutic model molecule, pore-forming bufforin IIb chimeric peptide with GO-anchoring peptide at the end was designed. GO loaded with imaging probe derivative and bufforin chimeric peptide did not show fluorescence due to the quenching of the probe by GO. However, in the presence of MMP-2, the surface-modified GO selectively recovered fluorescence by liberating PEG-Cy5.5 conjugate moiety to environment and killing of tumor cells. The surface-modified GO did not exert pore-forming activity in the absence of MMP. The MMP-sensitive de-shielding of PEG resulted in the exposure and sequential activation of therapeutic peptide on GO. In SCC7 tumor-bearing xenograft, the surface-modified GO showed the activated recovery of fluorescence at tumor tissues, and greater antitumor effect than other comparison groups. Moreover, we designed an adjuvant-entrapped nanoparticle which can activate in situ for activation of immune cells. The systemic administration of adjuvant-entrapped nanoparticles with light irradiation increased the activity of immune cell infiltration to the tumor cells, and inhibited tumor growth. These studies provide the potential of tumor microenvironment-responsive delivery of chemicals and adjuvants for next generation nanomedicine products.