Modifying positive surface charge and reducing bulk size of nanoparticles has been proven beneficial to
cancer cellular delivery, but meanwhile results in fast clearance and unspecific distribution in body after
intravenous injection. How to balance these problems is still a challenge to construct an ideal nano-scaled drug delivery system in
cancer treatment. Herein, we developed a multistage drug delivery system to enhance anticancer efficacy of
curcumin (CUR), which could intelligently alter its size and surface charge after long-circulation and extravasation from leaky blood vessels at
tumor sites. This micellar system was constructed by amphiphilic and pH-sensitive
methoxy poly(ethylene glycol)-poly(lactide)-poly(β-amino
ester) (
MPEG-PLA-PAE) copolymers. As compared with
MPEG-PLA micelles,
MPEG-PLA-PAE
micelles displayed several advantageous characteristics for
drug delivery and treatment. We found that CUR-loaded
MPEG-PLA-PAE
micelles remained stable in murine plasma at 37 °C even with high
drug loading. More interestingly, when the media pH decreased from 7.4 to 5.5, the
micelles shrank from 171.0 nm to 22.6 nm and their surface charge increased to 24.8 mV meanwhile, which resulted in the significantly improved cell uptake of CUR by human
breast cancer MCF-7 cells. Using
indocyanine green (ICG) as a fluorescence probe, it was observed that
MPEG-PLA-PAE
micelles experienced longer circulation than
MPEG-PLA micelles followed by accumulation at
tumors with stronger fluorescence intensity. Consequently,
MPEG-PLA-PAE
micelles achieved enhanced
cancer growth inhibition of 65.6% in vivo. All these findings demonstrated the potential of size/charge-changing
MPEG-PLA-PAE
micelles as a promising drug delivery system for
tumor-targeted
therapy.