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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 conjugate of paclitaxel (PTX) and docosahexaenoic acid has entered into clinical trials. However, the most recent clinical outcomes fell short of expectations, due to the extremely slow drug release from the hydrophobic conjugates. Herein, a novel prodrug-based nanoplatform self-assembled by the disulfide bond linked conjugates of PTX and oleic acid for rapid and differential release of PTX in tumor cells is reported. This redox-responsive prodrug-nanosystem demonstrates multiple therapeutic advantages, including one-step facile fabrication, high drug-loading efficiency (56%, w/w), on-demand drug release responding to redox stimuli, as well as favorable cellular uptake and biodistribution. These advantages result in significantly enhanced antitumor efficacy in vivo, with the tumor almost completely disappearing in mice. Such a uniquely engineered prodrug-nanosystem has great potential to be used as potent chemotherapeutic nanomedicine in clinical cancer therapy., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Spatiotemporal delivery of nanoparticles (NPs) at the "cellular level" is critical for nanomedicine, which is expected to deliver as much cytotoxic drug into cancer cells as possible when NPs accumulate in tumors. However, macrophages and cancer‐associated fibroblasts (CAFs) that are present within tumors limit the efficiency of spatiotemporal delivery. To overcome this limitation, glutathion pulse therapy is designed to promote reduction‐sensitive Larotaxel (LTX) prodrug NPs to escape the phagocytosis of macrophages and penetrate through the stromal barrier established by CAFs in the murine triple negative breast cancer model. This therapy improves the penetration of NPs in tumor tissues as well as the accumulation of LTX in cancer cells, and remodels the immunosuppressive microenvironment to synergize PD‐1 blockade therapy. More importantly, a method is established that can directly observe the biodistribution of NPs between different cells in vivo to accurately quantify the target drugs accumulated in these cells, thereby advancing the spatiotemporal delivery research of NPs at the "cellular level." [ABSTRACT FROM AUTHOR]

Carrier-free prodrug nanoassemblies have emerged as promising strategies to improve the therapeutic index of chemotherapeutics. Generally, prodrugs are composed of drug modules, response modules and modification modules. However, how to optimize the pharmacodynamics and tolerance of prodrug nanoassemblies by designing the structure of modification modules remains to be explored. Herein, four redox-cleavable prodrugs were synthesized by chemically coupling different branched-chain fatty alcohols with paclitaxel (PTX-SS-C16 NPs, PTX-SS-C18 NPs, PTX-SS-C20 NPs, PTX-SS-C24 NPs). Notably, the assembly ability of the prodrug nanoassemblies increased with the extension of the carbon chain of the modification modules. The redox-responsive rates of the prodrug nanoassemblies decreased with the extension of the carbon chain length. Among them, PTX-SS-C16 NPs and PTX-SS-C18 NPs displayed high redox responsiveness and antitumor efficacy. PTX-SS-C18 NPs and PTX-SS-C20 NPs possessed superior safety. However, PTX-SS-C24 NPs exhibited undesirable tumor selectivity and tolerance due to the excessive carbon chain length and inferior redox-responsive rate. This work demonstrated that tailoring the modification modules could simultaneously optimize the antitumor efficacy and tolerance of prodrug nanoassemblies for highly efficient therapeutics. [Display omitted] • The effect of the modification modules on the structure-activity relationship of the prodrug nanoassemblies was elucidated. • The major effects of minor differences in prodrug chemical structure on pharmacodynamics and tolerance were explored. • This tailoring nanomedicine strategy could screen the most promising prodrug nanoassemblies for clinical development. [ABSTRACT FROM AUTHOR]

Pure drug-assembled nanomedicines (PDANs) are currently under intensive investigation as promising nanoplatforms for cancer therapy. However, poor colloidal stability and less tumor-homing ability remain critical unresolved problems that impede their clinical translation. Herein, we report a core-matched nanoassembly of pyropheophorbide a (PPa) for photodynamic therapy (PDT). Pure PPa molecules are found to self-assemble into nanoparticles (NPs), and an amphiphilic PEG polymer (PPa-PEG 2K) is utilized to achieve core-matched PEGylating modification via the π‒π stacking effect and hydrophobic interaction between the PPa core and the PPa-PEG 2K shell. Compared to PCL-PEG 2K with similar molecular weight, PPa-PEG 2K significantly increases the stability, prolongs the systemic circulation and improves the tumor-homing ability and ROS generation efficiency of PPa-nanoassembly. As a result, PPa/PPa-PEG 2K NPs exert potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft model. Together, such a core-matched nanoassembly of pure photosensitizer provides a new strategy for the development of imaging-guided theragnostic nanomedicines. Pyropheophorbide a (PPa)-driven nanoassembly was formed by the core-matched modification of PPa-PEG 2K. Afterwards, PPa/PPa-PEG 2K NPs are endocytosed by tumor cells to exert effective photodynamic under laser irradiation. [Display omitted] [ABSTRACT FROM AUTHOR]

The potential toxicity of nanocarrier excipients and complicated preparation technologies have impeded the clinical application of nanomedicine. Recently, pure drug‐assembled nanosystems (PDANS) have been widely investigated, due to the unique self‐assembly characteristics of pure drug molecules. PDANS provides a facile nanoplatform for developing carrier‐free nanomedicine. Herein, the recent trends in PDANS for cancer therapy are outlined. First, the emerging strategies to develop single pure drug‐based nanoassemblies are discussed. Second, co‐assembly of two or more pure drugs for efficient combination therapy is overviewed. Then, the functional self‐assembly of non‐cytotoxic agents in tumor sites is presented. Finally, the rational design and self‐assembly mechanisms of these unique nanoplatforms are highlighted. [ABSTRACT FROM AUTHOR]

The clinical efficacy of existing cancer therapies is still far from satisfactory. There is an urgent need to integrate the emerging biomedical discovery and technological innovation with traditional therapies. Ferroptosis, a non-apoptotic programmed cell death modality, has attracted remarkable attention as an emerging therapeutic target for cancer treatment, especially with the burgeoning bionanotechnology. Given the rapid progression in ferroptosis-driven cancer nanotherapeutics, we intend to outline the latest advances in this field at the intersection of ferroptosis and bionanotechnology. First, the research background of ferroptosis and nanotherapeutics is briefly introduced to illustrate the feasibility of ferroptosis-driven nanotherapeutics for cancer therapy. Second, the emerging nanotherapeutics developed to facilitate ferroptosis of tumor cells are overviewed, including promotion of the Fenton reaction, inhibition of cellular glutathione peroxidase 4 (GPX-4), and exogenous regulation of lipid peroxidation. Moreover, ferroptosis-based combination therapeutics are discussed, including the emerging nanotherapeutics combining ferroptosis with tumor imaging, phototherapy, chemotherapy and immunomodulation. Finally, the future expectations and challenges of ferroptosis-driven nanotherapeutics in clinical cancer therapy are spotlighted. Unlabelled Image • Ferroptosis has emerged as a new therapeutic target for cancer treatment. • Ferroptosis-driven nanotherapeutics represents promising treatments for cancer. • Ferroptosis-based nano-DDS provide a versatile platform for combination therapy. [ABSTRACT FROM AUTHOR]

Cancer immunotherapies such as tumor vaccines, chimeric antigen receptor T cells and immune checkpoint blockades, have attracted tremendous attention. Among them, tumor vaccines prime immune response by delivering antigens and adjuvants to the antigen presenting cells (APCs), thus enhancing antitumor immunotherapy. Despite tumor vaccines have made considerable achievements in tumor immunotherapy, it remains challenging to efficiently deliver tumor vaccines to activate the dendritic cells (DCs) in lymph nodes (LNs). Rational design of nanovaccines on the basis of biomedical nanotechnology has emerged as one of the most promising strategies for boosting the outcomes of cancer immunotherapy. In recent years, great efforts have been made in exploiting various nanocarrier-based LNs-targeting tumor nanovaccines. In view of the rapid advances in this field, we here aim to summarize the latest progression in LNs-targeting nanovaccines for cancer immunotherapy, with special attention to various nano-vehicles developed for LNs-targeting delivery of tumor vaccines, including lipid-based nanoparticles, polymeric nanocarriers, inorganic nanocarriers and biomimetic nanosystems. Moreover, the recent trends in nanovaccines-based combination cancer immunotherapy are provided. Finally, the rationality, advantages and challenges of LNs-targeting nanovaccines for clinical translation and application are spotlighted. [Display omitted] • Nanocarriers have greatly facilitated the delivery of antigens/adjuvants/DNA/mRNA to LNs. • Nanocarriers-based vaccines represents a promising strategy for cancer immunotherapy. • Nanovaccines provide a versatile platform for combination immuno-therapy. [ABSTRACT FROM AUTHOR]

With the rapid development of conjugation chemistry and biomedical nanotechnology, prodrug-based nanosystems (PNS) have emerged as promising drug delivery nanoplatforms. Dimeric prodrug, as an emerging branch of prodrug, has been widely investigated by covalently conjugating two same or different drug molecules. In recent years, great progress has been made in dimeric prodrug-based nanosystems (DPNS) for cancer therapy. Many advantages offered by DPNS have significantly facilitated the delivery efficiency of anticancer drugs, such as high drug loading capacity, favorable pharmacokinetics, tumor stimuli-sensitive drug release and facile combination theranostics. Given the rapid developments in this field, we here outline the latest updates of DPNS in cancer treatment, focusing on dimeric prodrug-encapsulated nanosystems, dimeric prodrug-nanoassemblies and tumor stimuli-responsive DPNS. Moreover, the design principle, advantages and challenges of DPNS for clinical cancer therapy are also highlighted. Unlabelled Image • Conjugation chemistry and nanotechnology have greatly facilitated drug delivery. • PNS integrates the advantages of conjugation chemistry and nanotechnology. • DPNS has emerged as an emerging branch of PNS for efficient anticancer drug delivery. [ABSTRACT FROM AUTHOR]