Reduction-sensitive polymeric micelles as amplifying oxidative stress vehicles for enhanced antitumor therapy.
Chemotherapy-photodynamic therapy (PDT)-based combination therapy is a currently frequently used means in cancer treatment that photosensitizer was able to generate reactive oxygen species (ROS) for improving chemotherapy, owing to the high oxidative stress of the tumor microenvironment (TME). Whereas, cancer cells were accustomed to oxidative stress by overexpression of antioxidant such as glutathione (GSH), which would consume the damage of ROS, as well as it could result in ineffective treatment. Herein, amplification of oxidative stress preferentially in tumor cells by consuming GSH or generating ROS is a reasonable treatment strategy to develop anticancer drugs. To achieve excellent therapeutic effects, we designed a GSH-scavenging and ROS-generating polymeric micelle mPEG-S-S-PCL-Por (MSLP) for amplifying oxidative stress and enhanced anticancer therapy. The amphiphilic polymer of methoxy poly(ethylene glycol) (mPEG)-S-S-poly(ε-caprolactone) (PCL)-Protoporphyrin (Por) was self-assembled into polymeric micelles with the anticancer drug doxorubicin (DOX) for treatment and tracking via FRET. Spherical DOX/MSLP micelles with the average size of 88.76 ± 3.52 nm was procured with negatively charged surface, reduction sensitivity and high drug loading content (17.47 ± 1.53 %). The intracellular ROS detection showed that the MSLP could deplete glutathione and regenerate additional ROS. The cellular uptake of DOX/MSLP micelles was grabbed real-time monitoring by the Fluorescence resonance energy transfer (FRET) effect between DOX and MSLP. The reduction-sensitive polymeric micelles MSLP as amplifying oxidative stress vehicles combined chemotherapy and PDT exhibited significant antitumor activity both in vitro (IC50 = 0.041 μg/mL) and much better antitumor efficacy than that of mPEG-PCL-Por (MLP) micelles in vivo.
['Xia|Haoran|H|', 'Liang|Yan|Y|', 'Chen|Keqi|K|', 'Guo|Chunhua|C|', 'Wang|Mengdi|M|', 'Cao|Jie|J|', 'Han|Shangcong|S|', 'Ma|Qingming|Q|', 'Sun|Yong|Y|', 'He|Bin|B|']
D000970:Antineoplastic Agents D004317:Doxorubicin D008823:Micelles D018384:Oxidative Stress D011092:Polyethylene Glycols D011108:Polymers
Reduction-sensitive Oxidative stress Drug delivery FRET tracking Synergistic therapy