In Situ Monitoring of MicroRNA Replacement Efficacy and Accurate Imaging-Guided Cancer Therapy through Light-Up Inter-Polyelectrolyte Nanocomplexes.

ABSTRACT: Replacement of downregulated tumor-suppressive microRNA (Ts-miRNA) is recognized as an alternative approach for tumor gene therapy. However, in situ monitoring of miRNA replacement efficacy in a real-time manner via noninvasive imaging is continually challenging. Here, glutathione (GSH)-activated light-up peptide-polysaccharide-inter-polyelectrolyte nanocomplexes are established through self-assembly of carboxymethyl dextran with disulfide-bridged ("S-S") oligoarginine peptide (S-Arg4), in which microRNA-34a (miR-34a) and indocyanine green (ICG) are simultaneously embedded and the nanocomplexes are subsequently stabilized by intermolecular cross-linking. Upon confinement within the robust nanocomplexes, the near-infrared fluorescence (NIRF) of ICG is considerably quenched ("off") due to the aggregation-caused quenching effect. However, after intracellular delivery, the disulfide bond in S-Arg4 can be cleaved by intracellular GSH, which leads to the dissociation of nanocomplexes and triggers the simultaneous release of miR-34a and ICG. The NIRF of ICG is concomitantly activated through dequenching of the aggregated ICG. Very interestingly, a good correlation between time-dependent increase in NIRF intensity and miR-34a replacement efficacy is found in nanocomplexes-treated tumor cells and tumor tissues through either intratumoral or intravenous injections. Systemic nanocomplexes-mediated miR-34a replacement significantly suppresses the growth of HepG-2- and MDA-MB-231-derived tumor xenografts, and provides a pronounced survival benefit in these animal models.

SUBMITTER: Deng X 

PROVIDER: S-EPMC5908377 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature