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.

Rational design of nanoparticulate drug delivery systems (nano-DDS) for efficient cancer therapy is still a challenge, restricted by poor drug loading, poor stability, and poor tumor selectivity. Here, we report that simple insertion of a trisulfide bond can turn doxorubicin homodimeric prodrugs into self-assembled nanoparticles with three benefits: high drug loading (67.24%, w/w), high self-assembly stability, and high tumor selectivity. Compared with disulfide and thioether bonds, the trisulfide bond effectively promotes the self-assembly ability of doxorubicin homodimeric prodrugs, thereby improving the colloidal stability and in vivo fate of prodrug nanoassemblies. The trisulfide bond also shows higher glutathione sensitivity compared to the conventional disulfide bond, and this sensitivity enables efficient tumor-specific drug release. Therefore, trisulfide bond–bridged prodrug nanoassemblies exhibit high selective cytotoxicity on tumor cells compared with normal cells, notably reducing the systemic toxicity of doxorubicin. Our findings provide new insights into the design of advanced redox-sensitive nano-DDS 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.

Imaging-guided diagnosis and phototherapy has been emerging as promising theragnostic strategies for detection and treatment of cancer. 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) has been widely investigated for in vivo imaging and photothermal therapy (PTT). However, the tumor-homing ability and PTT efficiency of DiR is greatly limited by its extremely low water solubility and nonspecific distribution in off-target tissues. Herein, a facile nanoassembly of pure DiR is reported as a theragnostic nanocarrier platform for imaging-guided antitumor phototherapy. Self-assembly of DiR has almost no effect on its in vitro photothermal efficacy when compared with DiR solution. Interestingly, the PEGylated nanoassemblies of DiR showed distinct advantages over DiR solution and non-PEGylated nanoassemblies in terms of systemic circulation and tumor-homing capability in vivo. As a result, PEGylated DiR nanoassemblies demonstrate potent photothermal tumor therapy in BALB/c mice bearing 4T1 xenograft tumors. Such a pure photosensitizer-based nanoassembly holds great potential as a versatile platform for efficient imaging-guided cancer therapy.

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