Probing the impact of sulfur/selenium/carbon linkages on prodrug nanoassemblies for cancer therapy

Tumor cells are characterized as redox-heterogeneous intracellular microenvironment due to the simultaneous overproduction of reactive oxygen species and glutathione. Rational design of redox-responsive drug delivery systems is a promising prospect for efficient cancer therapy. Herein, six paclitaxel-citronellol conjugates are synthesized using either thioether bond, disulfide bond, selenoether bond, diselenide bond, carbon bond or carbon-carbon bond as linkages. These prodrugs can self-assemble into uniform nanoparticles with ultrahigh drug-loading capacity. Interestingly, sulfur/selenium/carbon bonds significantly affect the efficiency of prodrug nanoassemblies. The bond angles/dihedral angles impact the self-assembly, stability and pharmacokinetics. The redox-responsivity of sulfur/selenium/carbon bonds has remarkable influence on drug release and cytotoxicity. Moreover, selenoether/diselenide bond possess unique ability to produce reactive oxygen species, which further improve the cytotoxicity of these prodrugs. Our findings give deep insight into the impact of chemical linkages on prodrug nanoassemblies and provide strategies to the rational design of redox-responsive drug delivery systems for cancer therapy.

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For in vitro study, sample size was three to satisfy statistical analysis. For in vivo study, sample size was five to eliminate the effect of individual difference.
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The methods in this study were mature and reliable, and have been widely used and verified in our previous study. These could insure the reproducibility of the results.
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We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response. KB cells are suspected contaminated by Hela cells, and are listed in the database of commonly misidentified cell lines by International Cell Line Authentication Committee (ICLAC). In this study, KB cells were just used to evaluated the in vitro cytotoxicity and in vivo antitumor efficiency of prodrug nanoassemblies. Hela cells are also widely used to evaluated the cytotoxicity and antitumor efficiency of chemotherapeutics drugs, and Hela cells are also very sensitive to PTX. Therefore, being used as an evaluation model instead of a disease model, the potential contamination of KB cells by Hela cells might not significantly influence the pharmacodynamic evaluation of prodrug nanoassemblies under the same experimental conditions. Moreover, the in vitro cytotoxicity of prodrug nanoassemblies were further validated using A549 cells and 4T1 cells, and the in vivo antitumor efficiency of prodrug nanoassemblies were further investigated using a 4T1 tumor bearing BALB/c mice.