Abstract
BackgroundThe enhancement of tumor retention and cellular uptake of drugs are important factors in maximizing anticancer therapy and minimizing side effects of encapsulated drugs. Herein, a delivery nanoplatform, armed with a pH-triggered charge-reversal capability and self-amplifiable reactive oxygen species (ROS)-induced drug release, is constructed by encapsulating doxorubicin (DOX) in pH/ROS-responsive polymeric micelle.ResultsThe surface charge of this system was converted from negative to positive from pH 7.4 to pH 6.8, which facilitated the cellular uptake. In addition, methionine-based system was dissociated in a ROS-rich and acidic intracellular environment, resulting in the release of DOX and α-tocopheryl succinate (TOS). Then, the exposed TOS segments further induced the generation of ROS, leading to self-amplifiable disassembly of the micelles and drug release.ConclusionsWe confirms efficient DOX delivery into cancer cells, upregulation of tumoral ROS level and induction of the apoptotic capability in vitro. The system exhibits outstanding tumor inhibition capability in vivo, indicating that dual stimuli nano-system has great potential to function as an anticancer drug delivery platform.
Highlights
The enhancement of tumor retention and cellular uptake of drugs are important factors in maximizing anticancer therapy and minimizing side effects of encapsulated drugs
Fluorescence study indicated that the resulting poly(l-lysine)-graft-αtocopheryl succinate and methionine (PPT/D)(DMA) micelle had a relatively low critical micelle concentration (CMC) of 1.74 μg/mL (Fig. 1b)
In order to assess the charge-reversal property and stability of PPT/D(DMA)@DOX in pH 7.4, 6.8 and 5.5, we investigated the changes of zeta potential and size in Phosphate buffer saline (PBS) in 200 min
Summary
The enhancement of tumor retention and cellular uptake of drugs are important factors in maximizing anticancer therapy and minimizing side effects of encapsulated drugs. A delivery nanoplatform, armed with a pH-triggered charge-reversal capability and self-amplifiable reactive oxygen species (ROS)-induced drug release, is constructed by encapsulating doxorubicin (DOX) in pH/ROS-responsive polymeric micelle. Plenty of smart drug delivery systems have been proposed to improve the therapeutic efficacy and reduce undesirable side effects through achieving “on demand” drug release at tumor site under unique internal or external stimuli including pH gradient [1,2,3,4,5,6], intracellular reductive agents [7, 8], peculiar enzymes [9, 10], ROS [11, 12], and so on. Polymeric drug with ROS generation capability will be an effective approach to copying with insufficient ROS concentration for activating the complete drug release [13,14,15, 19].
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