1 research outputs found
Codelivery of a miR-124 Mimic and Obatoclax by Cholesterol-Penetratin Micelles Simultaneously Induces Apoptosis and Inhibits Autophagic Flux in Breast Cancer in Vitro and in Vivo
Penetratin is a classical cell-penetrating
peptide with the potential
to assist in the transmembrane delivery of proteins or drugs. However,
the synthesis and application of cholesterol-penetratin (Chol-P) conjugates
as nonviral delivery systems for microRNAs or drugs have not previously
been reported. In this study, the amphiphilic Chol-P was shown to
self-assemble into micelles and efficiently deliver miR-124 and obatoclax.
The codelivered miR-124-M-Oba had a homogeneous particle size and
a positive zeta potential. Treatment with miR-124 mincreased cytotoxicity,
and cell proliferation, was promoted by miR-124 inhibitor-loaded micelles
in MCF-7 human breast cancer cells. Moreover, the inhibitory effects
on cell proliferation, colony formation, and cell migration were increased
in the miR-124-M-Oba group compared to the miR-124-M group. miR-124-M-Oba
induced higher levels of mitochondrial apoptosis via Bax and caspase-9
activation. In addition, we found that the cationic Chol-P and miR-124-M
could potently induce autophagy, and miR-124 was degraded in the corresponding
autophagolysosomes. The obatoclax encapsulated in miR-124-M-Oba could
inhibit the degradation of miR-124 and p62 in autophagolysosomes,
which consequently maintained the concentration of miR-124 in breast
cancer cells. Furthermore, miR-124-M-Oba potently inhibited tumor
growth in subcutaneous xenograft breast cancer models. In summary,
the miR-124-M-Oba prepared in this work showed improved apoptosis
induction and autophagic flux inhibitory effects in MCF-7 cells, and
miR-124-M-Oba may have potential applications in breast cancer therapy