Paclitaxel-Loaded Mixed Micelles Enhance Ovarian Cancer Therapy through Extracellular pH-Triggered PEG Detachment and Endosomal Escape.
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.
Department of Obstetrics and Gynecology, Zhongda Hospital, School of Medicine, Southeast University , Nanjing 210009, P. R. China.
Haijun
H
Zhao
Department of Engineering Physics, Tsinghua University , Beijing 100084, P. R. China.
Qian
Q
Li
Department of Obstetrics and Gynecology, Zhongda Hospital, School of Medicine, Southeast University , Nanjing 210009, P. R. China.|Department of Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Disease in Ministry of Education , Nanjing 210096, P. R. China.
Zehui
Z
Hong
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D011992:Endosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000737:chemistry* / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley
D008823:Micelles; D011092:Polyethylene Glycols; D017239:Paclitaxel
PEG detachment; endosomal escape; ovarian cancer therapy; pH-triggered mixed micelles; paclitaxel