An AIEgen and Iodine Double-Ornamented Platinum(II) Complex for Bimodal Imaging-Guided Chemo-Photodynamic Combination Therapy.

Real-time biodistribution monitoring and enhancing the therapeutic efficacy of platinum(II)-based anticancer drugs are urgently required to elevate their clinical performance. Herein, a tetraphenylethene derivative (TP) with aggregation-induced emission (AIE) properties and an iodine atom are selected as ligands to endow platinum (II) complex TP-Pt-I with real-time in vivo self-tracking ability by fluorescence (FL) and computerized tomography (CT) imaging, and improved anticancer efficacy by the combination of chemotherapy and photodynamic therapy. Especially, benefiting from the formation of a donor-acceptor-donor structure between the AIE photosensitizer TP and Pt-I moiety, the heavy atom effects of Pt and I, and the presence of I, TP-Pt-I displayed red-shifted absorption and emission wavelengths, enhanced ROS generation efficiency, and improved CT imaging capacity compared with the pristine TP and the control agent TP-Pt-Cl. As a result, the enhanced intratumoral accumulation of TP-Pt-I loaded nanoparticles is readily revealed by dual-modal FL and CT imaging with high contrast. Meanwhile, the TP-Pt-I nanoparticles show significantly improved tumor growth-inhibiting effects on an MCF-7 xenograft murine model by combining the chemotherapeutic effects of platinum(II) and the photodynamic effects of TP. This self-tracking therapeutic complex thus provides a new strategy for improving the therapeutic outcomes of platinum(II)-based anticancer drugs.

A Nanoscale Trans-Platinum(II)-Based Supramolecular Coordination Self-Assembly with a Distinct Anticancer Mechanism.

Drug resistance significantly hampers the clinical application of existing platinum-based anticancer drugs. New platinum medications that possess distinct mechanisms of action are highly desired for the treatment of Pt-resistant cancers. Herein, a nanoscale trans-platinum(II)-based supramolecular coordination self-assembly (Pt-TCPP-BA) is prepared via using trans-[PtCl2(pyridine)(NH3)] (transpyroplatin), tetracarboxylporphyrin (TCPP), and benzoic acid (BA) as building blocks to combat drug resistance in platinum-based chemotherapy. Mechanistic studies indicate that Pt-TCPP-BA shows a hydrogen-peroxide-responsive dissociation behavior along with the generation of bioactive trans-Pt(II) and TCPP-Pt species. Different from cisplatin, these degradation products interact with DNA via interstrand cross-links and small groove binding, and induce significant upregulation of cell-death-related proteins such as p53, cleaved caspase 3, p21, and phosphorylated H2A histone family member X in cisplatin-resistant cancer cells. As a result, Pt-TCPP-BA exhibits potent killing effects against Pt-resistant tumors both in vitro and in vivo. Overall, this work not only provides a new platinum drug for combating drug-resistant cancer but also offers a new paradigm for the development of platinum-based supramolecular anticancer drugs.

Iodine Conjugated Pt(IV) Nanoparticles for Precise Chemotherapy with Iodine-Pt Guided Computed Tomography Imaging and Biotin-Mediated Tumor-Targeting.

Theranostics of platinum (Pt)-based chemotherapy are able to self-track the biodistribution and pharmacokinetics while performing therapeutic effects. Pt-based CT imaging is expected to visualize and monitor the tumor throughout the entire tumor inhibition stage. However, a sufficient Pt concentration is necessary for CT imaging, which may bring about severe nephrotoxicity. A Bio-Pt-I compound is designed and synthesized by conjugation of iodine and biotin to the structure of Pt and further self-assembles into nanoparticles. The introduction of iodine not only enhances the CT imaging signal with a much lower dose of Pt but also overcomes the resistance of tumor cells to Pt-containing nanomedicine by inhibiting the expression of Bcl-2. Furthermore, biotin-mediated tumor targeting increases drug accumulation in tumors. This work combines CT imaging based self-track with efficient cisplatin-resistance reversion ability, which may promote the clinical transformation of Pt-containing nanomedicine.

Synergistic enhancement of immunological responses triggered by hyperthermia sensitive Pt NPs via NIR laser to inhibit cancer relapse and metastasis.

The combination of tumor ablation and immunotherapy is a promising strategy against tumor relapse and metastasis. Photothermal therapy (PTT) triggers the release of tumor-specific antigens and damage associated molecular patterns (DAMPs) in-situ. However, the immunosuppressive tumor microenvironment restrains the activity of the effector immune cells. Therefore, systematic immunomodulation is critical to stimulate the tumor microenvironment and augment the anti-tumor therapeutic effect. To this end, polyethylene glycol (PEG)-stabilized platinum (Pt) nanoparticles (Pt NPs) conjugated with a PD-L1 inhibitor (BMS-1) through a thermo-sensitive linkage were constructed. Upon near-infrared (NIR) exposure, BMS-1 was released and maleimide (Mal) was exposed on the surface of Pt NPs, which captured the antigens released from the ablated tumor cells, resulting in the enhanced antigen internalization and presentation. In addition, the Pt NPs acted as immune adjuvants by stimulating dendritic cells (DCs) maturation. Furthermore, BMS-1 relieved T cell exhaustion and induced the infiltration of effector T cells into the tumor tissues. Thus, Pt NPs can ablate tumors through PTT, and augment the anti-tumor immune response through enhanced antigen presentation and T cells infiltration, thereby preventing tumor relapse and metastasis.

Correction: Combining PD-L1 inhibitors with immunogenic cell death triggered by chemo-photothermal therapy via a thermosensitive liposome system to stimulate tumor-specific immunological response.

Correction for 'Combining PD-L1 inhibitors with immunogenic cell death triggered by chemo-photothermal therapy via a thermosensitive liposome system to stimulate tumor-specific immunological response' by Jie Yu et al., Nanoscale, 2021, DOI: .

Combining PD-L1 inhibitors with immunogenic cell death triggered by chemo-photothermal therapy via a thermosensitive liposome system to stimulate tumor-specific immunological response.

Immune checkpoint blockade (ICB) therapy in combination with immunogenic death (ICD) triggered by photothermal therapy (PTT) and oxaliplatin (OXA) treatment was expected to elicit both innate and adaptive immune responses for tumor control and metastasis prevention. In this study, a photothermal agent (IR780), a folic acid (FA) linked oxaliplatin (OXA) prodrug, and PD-L1 inhibitors (BMS-1) were integrated into a liposomal system. The FA tumor-targeting and enhanced permeability and retention (EPR) effect of the liposomal system prolonged circulating times and increased accumulation in tumors, resulting in an enhanced photothermal effect and less systemic toxicity. In addition, PTT and OXA had a considerable synergistic effect in the induction of a combined ICD. The PD-1/PD-L1 checkpoint, which is a negative immune regulatory mechanism, could be blocked by the thermosensitive released BMS-1. Finally, ICD was harnessed to synergize with a small molecule PD-L1 inhibitor for activation of the immune system in the treatment of tumor relapse and metastasis.

Combination of starvation therapy and Pt-NP based chemotherapy for synergistic cancer treatment.

Platinum nanoparticles (Pt-NPs) have been developed for enhanced toxicity against tumor cells. However, the therapeutic effect of Pt-NPs was severely limited by the lack of cellular uptake of Pt-NPs and an oxidative environment. The combination of starvation therapy with Pt-NP based chemotherapy in a well-designed nano-system is expected to eliminate tumors. Therefore, GOx and Pt-NPs were coated with PLGA to obtain a functional nano-system (GOx-Pt-NS), which increased the cellular uptake of Pt-NPs. The accumulation of GOx-Pt-NS in tumors increased significantly via the enhanced permeability and retention (EPR) effect of nanoparticles. In addition, protection of the GOx-Pt-NS overcame several drawbacks of GOx such as poor stability, short in vivo half-life, immunogenicity, and systemic toxicity. Glucose oxidase (GOx) elevated the gluconic acid ROS levels in tumor cells, resulting in an acidic and oxidative environment. The acidic and oxidative environment enhanced the conversion of Pt2+via Pt NPs as well as DNA-binding ability. Finally, combining GOx based starvation therapy with Pt-NP based chemotherapy was expected to eliminate tumors more efficiently through a synergistic strategy.

Piperine inhibits colorectal cancer migration and invasion by regulating STAT3/Snail-mediated epithelial-mesenchymal transition.

Cancer metastasis is the primary cause of death in patients diagnosed with colorectal cancer. Piperine, an active nontoxic ingredient in pepper, has potent anti-inflammatory and anti-cancer properties. However, little is known about the anti-migratory and anti-invasive effects of piperine on colorectal cancer. We demonstrated piperine inhibited the migration and invasion of colorectal cancer cells. Then, we found piperine reversed the biomarker expression of epithelial-to-mesenchymal transition (EMT), and suppressed the EMT regulator Snail. Furthermore, signal transducers and activators of transcription 3 (STAT3) was downregulated by piperine. Finally, STAT3 inhibitors were applied to observe the role of STAT3 in colorectal cancer migration, invasion and EMT. Collectively, piperine inhibits colorectal cancer migratory and invasive capacities through STAT3/Snail mediated EMT. Therefore, piperine could be applied as a possible therapeutic regimen for the prevention of colorectal cancer metastasis.

Diagnostic Value of Interferon-Gamma Release Assays Combined with Multiple Indicators for Tuberculous Peritonitis.

OBJECTIVE: To investigate the diagnostic value of interferon-gamma release assays combined with multiple indicators for tuberculous peritonitis. METHODS: Patients who were admitted to the hospital due to suspected tuberculous peritonitis were prospectively included during the 30-month study period. Moreover, healthy individuals were recruited and included in the control group. All the study participants were assessed using various indexes, such as interferon-gamma release assays. RESULTS: A total of 180 patients with suspected tuberculous peritonitis were enrolled, and 24 were excluded. 73 patients with a confirmed diagnosis of tuberculous peritonitis were included in the tuberculous peritonitis group, 83 patients with other diseases in the other-disease control group, and 52 healthy individuals in the control group. Moreover, 83 patients in the other-disease control group and 52 participants in the control group were identified as 135 nontuberculous peritonitis patients. The area under the receiver operating characteristics curve for the QuantiFERON-TB test was 0.851 (95% confidence interval: 0.799-0.903), and the optimal cutoff value was 0.55 IU/mL, which corresponds to a sensitivity and specificity of 86.30% and 80.00%, respectively. The receiver operating characteristic curves for the combination of the QuantiFERON-TB test and the use of erythrocyte sedimentation rate, serum adenosine deaminase level, serum cancer antigen 125 level, and hypersensitive C-reactive protein level had an area under the curve of 0.859 (95% confidence interval: 0.809-0.909), with a sensitivity and specificity of 97.26% and 62.96%, respectively. CONCLUSIONS: The combined use of the QuantiFERON-TB test and multiple indexes can significantly improve the accuracy of diagnosing tuberculous peritonitis.