Mitochondria-targeting nanomedicine self-assembled from GSH-responsive paclitaxel-ss-berberine conjugate for synergetic cancer treatment with enhanced cytotoxicity

J Control Release. 2020 Feb;318:38-49. doi: 10.1016/j.jconrel.2019.12.011. Epub 2019 Dec 9.


Mitochondria play a fundamental role in plenty of cellular metabolic processes, and mitochondria-homing drug delivery is a promising and effective strategy for cancer treatment. Paclitaxel (PTX) is a broad-spectrum anticancer drug, but its therapeutic effect is highly limited due to the development of multidrug resistance. Berberine (BBR) can selectively accumulate in tumor cell mitochondria and inhibit the growth of cancer cells with different biological action mechanism from PTX. Here, these two "old" drug molecules, BBR and PTX were linked together by a disulfide bond rope to construct GSH-responsible drug-drug conjugate (PTX-ss-BBR). Molecular dynamics simulation results revealed that PTX-ss-BBR conjugate could be self-assembled in water to form nanoparticles (PTX-ss-BBR NPs) forced by π-π stacking and hydrophobic interactions and the average size of NPs was around 165 nm measured by DLS. The better in vitro potency of PTX-ss-BBR NPs against A549 cells might be ascribed to the simultaneous drug release and mitochondria-targeting delivery, which dissipated mitochondria membrane potential, upregulated ROS levels in cancer cells, arrested cells in phase G2/M, elicited apoptosis of cancer cells and inhibited the growth of tumors. Furthermore, PTX-ss-BBR NPs also exerted efficacy better than or comparable to BBR on S. aureus and E. coli, which were closely associated with the development of lung cancer. The synergistic effect of PTX and BBR enhanced the treatment effect of conventional chemotherapy drugs against A549 cells.

Keywords: Berberine; Mitochondria-targeting; Paclitaxel; Self-assembled nanomedicine.

Publication types

  • Research Support, Non-U.S. Gov't