Selenadiazole derivative-loaded metal azolate frameworks facilitate NK cell immunotherapy by sensitizing tumor cells and shaping immuno-suppressive microenvironments.

The low sensitivity of tumor cells and immunosuppressive microenvironments lead to unsatisfactory efficacy of natural killer (NK) cell immunotherapy. In this work, we developed a safe and effective combination treatment strategy by integrating a selenadiazole derivative (PSeD)-loaded metal azolate framework (PSeD@MAF-4(R)) with NK cells derived from cancer patients against a xenograft human breast tumor model. Intriguingly, it was found that only PSeD@MAF-4(R) pretreatment on tumor cells exhibited synergistic effects with NK cells in inhibiting tumor cell growth by up-regulating NKG2D and its ligands to maximize the interactions between NK and MCF-7 cells. Moreover, PSeD@MAF-4(R) pretreatment could significantly enhance the degranulation of NK cells and regulate their secretions of pro- or anti-inflammatory cytokines (e.g. IL-6, IL-10, and TGF-ß). Furthermore, PSeD@MAF-4(R) could significantly enhance the penetration capability of NK cells into tumor spheroids. The combination treatment mainly induced G1 phase arrest and activated multiple caspase-mediated apoptosis of tumor cells. In vivo evidence showed that PSeD@MAF-4(R) combined with NK cells could highly efficiently combat breast tumor progression via inducing and activating innate immune cell (DC and NK cell) infiltrations within tumor tissues while shaping the suppressive tumor microenvironment by down-regulating the expression of TGF-ß. This developed strategy may provide important information for developing NK cell-based combination cancer immunotherapy with high efficacy and good safety profiles.

Rational Design of Cancer-Targeted Selenadiazole Derivative as Efficient Radiosensitizer for Precise Cancer Therapy.

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovery of targeted therapies for personalized cancer medicine. Herein, cancer targeting RGD peptide has been covalently conjugated to selenadiazole derivative (RGD-SeD) to improve its cancer selectivity. The RGD decoration significantly enhances the anticancer efficacy of RGD-SeD in αVß3 integrin-overexpressing HepG2 liver cancer cells but not in normal liver cells. Cellular uptake assay and fluorescent imaging confirmed the selectivity of RGD-SeD to integrin-overexpressing cancer cells. RGD-SeD strongly sensitizes HepG2 cells to clinically used X-ray radiotherapy through ROS overproduction, which triggers DNA damage-mediated apoptosis and G2/M cell cycle arrest. This X-ray-responsive DNA damage activates p53 signaling pathways by phosphorylation of ATM/ATR and γ-H2A.X. Furthermore, in a HepG2 nude mice xenograft model, the combined treatment of RGD-SeD and X-ray demonstrates potent in vivo antitumor efficacy via induction of apoptotic cell death but shows no toxicity on the functions of major organs. In summary, this study provides a strategy to design a selenium-based cancer targeting radiosensitizer for precise cancer therapy.

Selenadiazole Derivatives Inhibit Angiogenesis-Mediated Human Breast Tumor Growth by Suppressing the VEGFR2-Mediated ERK and AKT Signaling Pathways.

Selenadiazole derivatives (SeDs) have been found to show promise in chemo-/radiotherapy applications by activating various downstream signaling pathways. However, the functional role of SeDs on angiogenesis, which is pivotal for tumor progression and metastasis, has not yet been elucidated. In the present study, we have examined the antiangiogenic activities of SeDs and elucidated their underlying mechanisms. The results showed that the as-synthesized SeDs not only enhanced their anticancer activities against several human cancer cells but also showed more potent inhibition on human umbilical vein endothelial cells (HUVECs). The in vitro results suggested that SeDs, especially 1 a, dose-dependently inhibited the vascular endothelial growth factor (VEGF)-induced cell migration, invasion, and capillary-like structure formation of HUVECs. Compound 1 a also significantly suppressed VEGF-induced angiogenesis in a Matrigel plug assay as part of a C57/BL6 mice assay by means of down regulation of VEGF. Furthermore, we found that 1 a significantly inhibited MCF-7 human breast tumor growth in nude mice without severe systematic cytotoxicity. Compound 1 a was more effective in inhibiting cell proliferation and induced a much more pronounced apoptosis effect in endothelial cells than MCF-7 cells, which implies that endothelial cells might be the primary target of 1 a. Further mechanistic studies on tumor growth inhibition effects and neovessel formation suppression demonstrated that 1 a inhibited cell viability of MCF-7 and HUVECs by induction of cell apoptosis, accompanied by poly(adenosine diphosphate ribose)polymerase (PARP) cleavage and caspase activation. Additionally, the 1 a-induced antiangiogenesis effect was achieved by abolishing the VEGF-VEGFR2-ERK/AKT (ERK=extracellular signal-regulated kinases; AKT=protein kinease B) signal axis and enhanced the apoptosis effect by triggering reactive oxygen species (ROS)-mediated DNA damage. Taken together, these results clearly demonstrate the antiangiogenic potency of SeDs and the underlying molecular mechanisms.

Therapeutic nanosystems co-deliver anticancer drugs and oncogene SiRNA to achieve synergetic precise cancer chemo-gene therapy.

Co-delivering a chemotherapeutic agent and cancer-specific small interfering RNA (siRNA) as a new therapeutic modality provides a promising strategy for cancer treatment. In this study, we designed and described a cancer-target and pH-sensitivity nanosystem (RGD-SeNPs/siRNA) which has a DOX-loaded SeNPs core and c-myc siRNA-delivered PAMAM-RGD decoration for combination therapy against glioblastoma. The nanosystem exhibited high stability in water and FBS solutions for a long time. PAMAM-RGD surface decoration significantly enhanced the cellular uptake of RGD-SeNPs/siRNA and increased the selectivity between normal and cancer cells. More importantly, the nanosystem expanded to petaloid particles under pH 5.3 circumstance, which prolonged the duration of drugs after ingestion and reduced undesirable side effects. In addition, a blood-brain barrier (BBB) model we established in vitro revealed the nanosystem effectively penetrated BBB and enhanced antitumor activity. Moreover, the nanosystem also exhibited excellent advantages in penetrating ability and inhibitory effects on U251 tumor spheroids, demonstrating its in vivo anticancer potential. Therefore, this study provides a strategy for the design of cancer-targeted nanoplatforms as carriers of oncogene siRNA and chemotherapeutics to achieve synergistic cancer therapy.