A novel conjunction of folate-targeted carbon nanotubes containing protohemin and oridonin-liposome loaded microbubbles for cancer chemo-sonodynamic therapy

To facilitate targeting drug delivery and combined therapy, we constructed a novel drug carrier, in which oridonin-liposome containing microbubbles (LUMO) are covalently adhered to folic acid-conjugated multiwalled carbon nanotubes loaded with protohemin (FMTP) to form a novel conjugate (FMTP-LUMO). Oridonin (ORI) is used as a chemotherapeutic drug for chemotherapy (CHT), whereas protohemin (Ph) is applied in the field of sonodynamic therapy (SDT) as a sonosensitizer. In vitro release properties, cellular uptake and cytotoxicity in HepG-2 cells as well as in vivo antitumour effects in HepG-2 cell tumour-bearing mice submitted to chemo-sonodynamic therapy, SDT alone and CHT alone were evaluated upon ultrasound exposure. The results showed that the growth inhibition rates on FMTP-LUMO, FMTP, and LUMO were 95.4 ± 5.9%, 63.9 ± 7.4%, and 42.3 ± 2.9% in vitro, respectively. FMTP-LUMO exhibited strong binding to HepG-2 cells than MTP-LUMO. The chemo-sonodynamic therapy demonstrated a cooperative effect, resulting in significantly higher therapeutic efficacy for liver cancer. After treatment for 10 d, the tumour inhibition ratio for FMTP-LUMO exceeded to 90%, clearly higher than that of FMTP (42.8%) and LUMO (32.5%). Thus, FMTP-LUMO could serve as a highly effective drug carrier for chemo-sonodynamic therapy.