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.

The current state of chemotherapy is far from satisfaction, restricted by the inefficient drug delivery and the off‐target toxicity. Prodrug nanoassemblies are emerging as efficient platforms for chemotherapy. Herein, three docetaxel dimeric prodrugs are designed using diselenide bond, disulfide bond, or dicarbide bond as linkages. Interestingly, diselenide bond‐bridged dimeric prodrug can self‐assemble into stable nanoparticles with impressive high drug loading (≈70%, w/w). Compared with disulfide bond and dicarbide bond, diselenide bond greatly facilitates the self‐assembly of dimeric prodrug, and then improves the colloidal stability, blood circulation time, and antitumor efficacy of prodrug nanoassemblies. Furthermore, the redox‐sensitive diselenide bond can specifically respond to the overexpressed reactive oxygen species and glutathione in tumor cells, leading to tumor‐specific drug release. Therefore, diselenide bond bridged prodrug nanoassemblies exhibit discriminating cytotoxicity between tumor cells and normal cells, significantly alleviating the systemic toxicity of docetaxel. The present work gains in‐depth insight into the impact of diselenide bond on the dimeric prodrug nanoassemblies, and provides promising strategies for the rational design of the high efficiency–low toxicity chemotherapeutical nanomedicines.

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OCTN2 (SLC22A5) is a Na -coupled absorption transporter for l-carnitine in small intestine. This study tests the potential of this transporter for oral delivery of therapeutic drugs encapsulated in l-carnitine-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (LC-PLGA NPs) and discloses the molecular mechanism for cellular endocytosis of transporter-targeting nanoparticles. Conjugation of l-carnitine to a surface of PLGA-NPs enhances the cellular uptake and intestinal absorption of encapsulated drug. In both cases, the uptake process is dependent on cotransporting ion Na . Computational OCTN2 docking analysis shows that the presence of Na is important for the formation of the energetically stable intermediate complex of transporter-Na -LC-PLGA NPs, which is also the first step in cellular endocytosis of nanoparticles. The transporter-mediated intestinal absorption of LC-PLGA NPs occurs via endocytosis/transcytosis rather than via the traditional transmembrane transport. The portal blood versus the lymphatic route is evaluated by the plasma appearance of the drug in the control and lymph duct-ligated rats. Absorption via the lymphatic system is the predominant route in the oral delivery of the NPs. In summary, LC-PLGA NPs can effectively target OCTN2 on the enterocytes for enhancing oral delivery of drugs and the critical role of cotransporting ions should be noticed in designing transporter-targeting nanoparticles.

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