Although PEGylation allows a drug delivery vehicle to have prolonged blood circulation time, it faces the problem of reduced cellular uptake. Removal of the
polyethylene glycol (PEG)-shell at the appropriate time through tumor-microenvironment triggers could be a feasible
solution to this problem. Here,
paclitaxel (PTX)-loaded mixed
micelles (PTX-mM) self-assembled from
stearate-modified
hyaluronic acid (SHA),
mPEG-b-poly(β-amino
ester) (
mPEG-b-PAE), and
ethylene acetyl-b-poly(β-amino
ester) (EA-b-PAE) were developed. In the preparation of PTX-mM, SHA
micelles were coated with EA-b-PAE followed by coloading of PTX and
mPEG-b-PAE. PTX-mM were capable of extracellular pH-triggered PEG-detachment and poly(β-amino
ester) (PAE)-mediated endosomal escape. When the pH was changed from pH 7.4 to pH 6.8, the particle size of PTX-mM significantly decreased from 97.5 ± 4.4 to 71.5 ± 2.3 nm. It also resulted in rapid and complete release of
mPEG-b-PAE from PTX-mM as monitored using
quartz crystal microbalance (QCM) technology. PTX-mM capable of PEG detachment provided significant enhancement of PTX accumulation in SKOV-3 cells compared to PEG nondetachable PTX-mM. Interestingly, intracellular transport studies using confocal
laser scanning microscopy (CLSM) showed that EA-b-PAE could promote the escape of
micelles from endolysosomes. The half-maximal inhibitory concentration (IC50) of PTX-mM against SKOV-3 cells was 5.7 μg/mL, and PTX-mM containing 20 μg/mL of PTX induced apoptosis in 53.0% of the cell population. PTX-mM exhibited a highly prolonged elimination half-life (t1/2, 2.83 ± 0.37 h) and improved area under the curve (AUC, 7724.82 ± 1190.75 ng/mL/h) than the PTX-loaded SHA
micelles (PTX-M). Furthermore, PTX-mM showed the highest
tumor inhibition rate (64.9%) and the longest survival time (53 days) against the SKOV-3
ovarian cancer xenograft models among all formulations. Taken together, the results suggested that PTX-mM have potential as an efficient anticancer formulation in treatment of
ovarian cancer.