Synergistically Enhanced Antimetastasis Effects by Honokiol-Loaded pH-Sensitive Polymer-Doxorubicin Conjugate Micelles.

In an effort to prevent metastasis of breast tumor cells at the same time of inhibiting tumor growth with less toxic side effects, honokiol (HNK) was encapsulated into pH-sensitive polymeric micelles based on the conjugate (PEOz-PLA-imi-DOX) of poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (PEOz-PLA) with doxorubicin (DOX). PEOz-PLA-imi-DOX was successfully synthesized by connecting DOX to the hydrophobic end of PEOz-PLA via acid cleavable benzoic imine linker. HNK-loaded conjugate micelles (HNK/PP-DOX-PM) with a size of 21 nm and homogeneous spherical shape exhibited high drug loading capacity. PEOz-PLA-imi-DOX and HNK/PP-DOX-PM displayed faster release of DOX at pH 5.0 than at pH 7.4. As anticipated, PEOz-PLA-imi-DOX maintained cytotoxicity of DOX against MDA-MB-231 cells. The synergistically enhanced in vitro antitumor effect of HNK/PP-DOX-PM was confirmed by their synergetic inhibition of MDA-MB-231 cell growth. Furthermore, the efficient prevention of tumor metastasis by HNK/PP-DOX-PM was testified by in vitro antiinvasion, wound healing and antimigration assessment in MDA-MB-231 cells, and in vivo bioluminescence imaging in nude mice. The suppression of growth and metastasis of tumor cells by HNK/PP-DOX-PM was attributed to synergistic effect of pH-triggered drug release and HNK-aroused inhibition of MMPs and EMT, respectively. In addition, HNK/PP-DOX-PM exhibited superior biosafety than physically encapsulated dual-drug micelles. Consequently, the fabricated HNK/PP-DOX-PM may have great potential for safe and effective suppression of tumor growth and metastasis.