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Drug-based supramolecular self-assembling delivery systems have enhanced the bioavailability of chemotherapeutic drugs and reduced systemic side effects; however, improving the delivery efficiency and responsive release ability of these systems remains challenging. This study focuses primarily on the utilization of per-6-thio-β-cyclodextrin (CD) to link a significant quantity of paclitaxel (PTX) via ROS-sensitive thioketal (TK) linkages (designated as CDTP), thereby allowing efficiently drug release when exposed to high levels of reactive oxygen species (ROS) in the tumor microenvironment. To construct these supramolecular nanoparticles (NPs) with CDTP, we introduced PEGylated ferrocene (Fc) through host-guest interactions. The intracellular hydrogen peroxide (H 2 O 2) is converted into hydroxyl radicals (•OH) through the Fc-catalyzed Fenton reaction. Additionally, the generated Fc+ consumes the antioxidant glutathione (GSH). In both in vivo and in vitro experiments, CDTP@Fc-PEG NPs were absorbed effectively by tumor cells, which increased levels of ROS and decreased levels of GSH, disrupting the redox balance of cancer cells and increasing their sensitivity to chemotherapy. Furthermore, CDTP@Fc-PEG NPs exhibited high tumor accumulation and cytotoxicity without causing significant toxicity to healthy organs. Collectively, our results suggest CDTP@Fc-PEG NPs as a promising supramolecular nano-delivery platform for high drug-loading of PTX and synergistic chemotherapy. [Display omitted] • The ROS-driven supramolecular NPs has been constructed successfully and corresponding characterizations have been conducted. • Supramolecular prodrug nano-delivery system that can respond to the TME, while also demonstrating a high drug-loading capacity and delivery efficiency. • The results show that the nanoparticle can deplete GSH and amplify ROS simultaneously, resulting in the disruption of redox homeostasis. And the chemosensitization due to redox imbalance has also verified. • The results of in vitro and in vivo experiments both confirmed the excellent antitumor capability and favorable biosafety of the nanoparticle. [ABSTRACT FROM AUTHOR]

The activation of key signaling pathways downstream of antigen receptor engagement is critically required for normal lymphocyte activation during the adaptive immune response. CARD11 is a multidomain signaling scaffold protein required for antigen receptor signaling to NF-kB, c-Jun N-terminal kinase, and mTOR. Germline mutations in the CARD11 gene result in at least four types of primary immunodeficiency, and somatic CARD11 gain-of-function mutations drive constitutive NF- B activity in diffuse large B cell lymphoma and other lymphoid cancers. In response to antigen receptor triggering, CARD11 transitions from a closed, inactive state to an open, active scaffold that recruits multiple signaling partners into a complex to relay downstream signaling. However, how this signal- induced CARD11 conversion occurs remains poorly understood. Here we investigate the role of Inducible Element 1 (IE1), a short regulatory element in the CARD11 Inhibitory Domain, in the CARD11 signaling cycle. We find that IE1 controls the signal-dependent Opening Step that makes CARD11 accessible to the binding of cofactors, including Bcl10, MALT1, and the HOIP catalytic subunit of the linear ubiquitin chain assembly complex. Surprisingly, we find that IE1 is also required at an independent step for the maximal activation of HOIP and MALT1 enzymatic activity after cofactor recruitment to CARD11. This role of IE1 reveals that there is an Enzymatic Activation Step in the CARD11 signaling cycle that is distinct from the Cofactor Association Step. Our results indicate that CARD11 has evolved to actively coordinate scaffold opening and the induction of enzymatic activity among recruited cofactors during antigen receptor signaling. [ABSTRACT FROM AUTHOR]

The use of cisplatin is restricted by systemic toxicity and drug resistance. Supramolecular nano-drug delivery systems involving drugs as building blocks circumvent these limitations promisingly. Herein, we describe a novel supramolecular system [Pt(IV)-SSNPs] based on poly(β-cyclodextrin), which was synthesized for efficient loading of adamantly-functionalized platinum(IV) prodrug [Pt(IV)-ADA 2 ] via the host-guest interaction between β-cyclodextrin and adamantyl. Pt(IV)-ADA 2 can be converted to active cisplatin in reducing environment in cancer cells, which further reduces systemic toxicity. The introduction of the adamantane group-tethered mPEG 2k endowed the Pt(IV)-SSNPs with a longer blood circulation time. In vitro assays exhibited that the Pt(IV)-SSNPs could be uptaken by CT26 cells, resulting in cell cycle arrest in the G2/M and S phases, together with apoptosis. Furthermore, the Pt(IV)-SSNPs showed effective tumor accumulation, better antitumor effect, and negligible cytotoxicity to major organs. These results indicate that supramolecular nanoparticles are a promising platform for efficient cisplatin delivery and cancer treatment. Composition and preparation of Pt(IV)-SSNPs and the possible mechanism of the in vivo drug release and anticancer treatment: accumulation in tumor cell; cell uptake; GSH-activated drug release; DNA binding inducing cell apoptosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Docetaxel (DTX)-based chemotherapy of prostate cancer is still confronted with significant challenges due to insufficient drug accumulation at the tumor sites and the systemic side effects on normal cells and organs. Tumor microenvironment-responsive nanosized drug delivery systems have shown enormous potential to improve the anticancer efficacy and minimize the systemic side effects of chemotherapeutics. However, most of the currently redox-responsive nanoparticles respond only to single stimuli, which compromise the treatment effect. Hence, inspired by the abundance of reactive oxygen species (ROS) and intracellular glutathione (GSH) in cancer cells, we proposed a unique ROS and GSH dual responsive nanocarrier (PCL-SS) for DTX delivery. The DTX-loaded PCL-SS nanoparticles (PCL-SS@DTX NPs) were not only stable in a normal physiological environment but also rapidly triggered DTX release in prostate cancer cells. In vitro experiments showed that PCL-SS@DTX NPs had robust prostate cancer cell cytotoxicity, induced cell apoptosis, inhibited cell migration and invasion and exhibited satisfactory biocompatibility. In mice bearing orthotopic prostate cancer, PCL-SS@DTX NPs could accumulate in orthotopic tumor sites and then significantly weaken tumor growth by inhibiting prostate cancer cell proliferation and inducing cell apoptosis, without obvious damages to major organs. Overall, this dual responsive nanosized drug delivery system may act as a promising therapeutic option for prostate cancer chemotherapy. The preparation of PCL-SS@DTX NPs and the ROS and GSH dual responsive drug release for orthotopic prostate cancer therapy. [Display omitted] • The reactive oxygen species and glutathione dual responsive nanoparticles (PCL-SS@DTX NPs) was prepared. • The PCL-SS@DTX NPs could rapidly and selectively trigger DTX release in tumor sites. • The PCL-SS@DTX NPs presented excellent biosecurity. • The PCL-SS@DTX NPs enhanced anti-tumor effect in vitro and in orthotopic prostate cancer mice. [ABSTRACT FROM AUTHOR]