The importance of mitochondrial delivery of an anticancer drug to cancer cells has been recognized to improve therapeutic efficacy. The introduction of lipophilic cations, such as triphenylphosphonium (TPP), onto the surface of nanocarriers was utilized to target mitochondria via strong electrostatic interactions between positively charged TPP and the negatively charged mitochondrial membrane. However, the highly positive charge nature of TPP leads to rapid clearance from the blood, decrease of circulation lifetime, and nonspecific targeting of mitochondria of cells. Here, we report a strategy for improving the anticancer efficacy of paclitaxel via redox triggered intracellular activation of mitochondria-targeting. The lipid-polymer hybrid nanoparticles (LPNPs) are composed of poly(d,l-lactide-co-glycolide) (PLGA), a TPP-containing amphiphilic polymer (C-PEG-TPP) and a reduction-responsive amphiphilic polymer (DLPE-S-S-mPEG). The charges of TPP in LPNPs were almost completely shielded by surface coating of a PEG layer, ensuring high tumor accumulation. After uptake by cancer cells, the surface charges of LPNPs were recovered due to the detachment of PEG under intracellular reductive conditions, resulting in rapid and precise localization in mitochondria. This kind of simple, easy and practicable mitochondria-targeting nanoplatform showed high anticancer activity, and the activatable strategy is valuable for developing a variety of nanocarriers for application in the delivery of other drugs.

Codelivery is a promising strategy to overcome the limitations of single chemotherapeutic agents in cancer treatment. Despite progress, codelivery of two or more different functional drugs to increase anticancer efficiency still remains a challenge. Here, reduction-sensitive lipid–polymer hybrid nanoparticles (LPNPs) drug delivery system composed of monomethoxy-poly(ethylene glycol)- S - S -hexadecyl (mPEG- S - S -C 16 ), soybean lecithin, and poly(D,L-lactide-co-glycolide) (PLGA) was used for codelivery of doxorubicin (DOX) and a Chinese herb extract triptolide (TPL). Hydrophobic DOX and TPL could be successfully loaded in LPNPs by self-assembly. More importantly, drug release and cellular uptake experiments demonstrated that the two drugs were reduction sensitive, released simultaneously from LPNPs, and taken up effectively by the tumor cells. DOX/TPL-coloaded LPNPs (DOX/TPL-LPNPs) exhibited a high level of synergistic activation with low combination index (CI) in vitro and in vivo. Moreover, the highest synergistic therapeutic effect was achieved at the ratio of 1:0.2 DOX/TPL. Further experiments showed that TPL enhanced the uptake of DOX by human oral cavity squamous cell carcinoma cells (KB cells). Overall, DOX/TPL-coencapsulated reduction-sensitive nanoparticles will be a promising strategy for cancer treatment.

An amphiphilic polymer DLPE-S-S-MPEG was synthesized and employed with PCL to prepare two-component reduction-sensitive lipid-polymer hybrid nanoparticles (SLPNPs) for in vitro and in vivo delivery of a hydrophobic anticancer drug (Doxorubicin, DOX). Insensitive lipid-polymer hybrid nanoparticles (ILPNPs) were prepared as a control. The mean sizes of the LPNPs ranged from 100 nm to 120 nm. The TEM observations showed that the LPNPs have spherical morphologies with homogeneous distribution. The disulfide bond of DLPE-S-S-MPEG was cleaved by dithiothreitol (DTT), which resulted in the disassembly of SLPNPs and triggered the release of encapsulated DOX. The in vitro cytotoxicities of DOX/LPNPs against HeLa cells, HepG2 cells and COS-7 cells were studied. It was demonstrated that DOX/SLPNPs showed higher cytotoxicity against HeLa cells and HepG2 cells than DOX/ILPNPs, but showed a slight difference in the case of COS-7 cells. CLSM observation and FCM measurement further confirmed that the introduction of S-S bonds caused fast intracellular release of DOX from SLPNPs. Moreover, compared with DOX/ILPNPs and free DOX, DOX/SLPNPs exhibited higher antitumor activity. Both DOX/SLPNPs and DOX/ILPNPs showed lower cardiac toxicity and kidney toxicity than free DOX, which were confirmed by histological and immunohistochemical analyses. The tissue distribution of DOX in mice exhibited that two kinds of DOX/LPNPs accumulated extensively in the liver and spleen, while free DOX accumulated mainly in the heart and kidney 12 h after injection. Two-component SLPNPs may be a promising drug delivery carrier for reduction-triggered delivery of DOX.

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