We developed a novel linear pH-sensitive conjugate methoxy poly(ethylene glycol)-4β-aminopodophyllotoxin (
mPEG-NPOD-I) by a covalently linked 4β-aminopodophyllotoxin (NPOD) and PEG via
imine bond, which was amphiphilic and self-assembled to
micelles in an aqueous
solution. The
mPEG-NPOD-I
micelles simultaneously served as an anticancer
drug conjugate and as
drug carriers. As a
drug conjugate,
mPEG-NPOD-I showed a significantly faster NPOD release at a mildly acidic pH of 5.0 and 4.0 than a physiological pH of 7.4. Notably, it was confirmed that this
drug conjugate could efficiently deliver NPOD to the nuclei of the
tumor cells and led to much more cytotoxic effects to A549, Hela, and HepG2
cancer cells than the parent NPOD. The half maximal inhibitory concentration (IC₅₀) of
mPEG-NPOD-I was about one order magnitude lower than that of the NPOD. In vivo,
mPEG-NPOD-I reduced the size of the
tumors significantly, and the biodistribution studies indicated that this
drug conjugate could selectively accumulate in
tumor tissues. As
drug carriers, the
mPEG-NPOD-I
micelles encapsulated hydrophobic PTX with
drug-loading efficiencies of 57% and
drug-loading content of 16%. The loaded PTX also showed pH-triggered fast release behavior, and good additive cytotoxicity effect was observed for the PEG-NPOD-I/PTX. We are convinced that these multifunctional
drug conjugate
micelles have tremendous potential for targeted
cancer therapy.