Magnetically modified-mitoxantrone mesoporous organosilica drugs: an emergent multimodal nanochemotherapy for breast cancer.

BACKGROUND: Chemotherapy, the mainstay treatment for metastatic cancer, presents serious side effects due to off-target exposure. In addition to the negative impact on patients' quality of life, side effects limit the dose that can be administered and thus the efficacy of the drug. Encapsulation of chemotherapeutic drugs in nanocarriers is a promising strategy to mitigate these issues. However, avoiding premature drug release from the nanocarriers and selectively targeting the tumour remains a challenge. RESULTS: In this study, we present a pioneering method for drug integration into nanoparticles known as mesoporous organosilica drugs (MODs), a distinctive variant of periodic mesoporous organosilica nanoparticles (PMOs) in which the drug is an inherent component of the silica nanoparticle structure. This groundbreaking approach involves the chemical modification of drugs to produce bis-organosilane prodrugs, which act as silica precursors for MOD synthesis. Mitoxantrone (MTO), a drug used to treat metastatic breast cancer, was selected for the development of MTO@MOD nanomedicines, which demonstrated a significant reduction in breast cancer cell viability. Several MODs with different amounts of MTO were synthesised and found to be efficient nanoplatforms for the sustained delivery of MTO after biodegradation. In addition, Fe3O4 NPs were incorporated into the MODs to generate magnetic MODs to actively target the tumour and further enhance drug efficacy. Importantly, magnetic MTO@MODs underwent a Fenton reaction, which increased cancer cell death twofold compared to non-magnetic MODs. CONCLUSIONS: A new PMO-based material, MOD nanomedicines, was synthesised using the chemotherapeutic drug MTO as a silica precursor. MTO@MOD nanomedicines demonstrated their efficacy in significantly reducing the viability of breast cancer cells. In addition, we incorporated Fe3O4 into MODs to generate magnetic MODs for active tumour targeting and enhanced drug efficacy by ROS generation. These findings pave the way for the designing of silica-based multitherapeutic nanomedicines for cancer treatment with improved drug delivery, reduced side effects and enhanced efficacy.

Monitoring of singlet oxygen generation of a novel Schiff-base substituted silicon phthalocyanines by sono-photochemical studies and in vitro activities on prostate cancer cell.

This study demonstrates the potential of sono-photodynamic therapy as an effective approach for enhancing singlet oxygen generation using the synthesized Schiff-base diaxially substituted silicon phthalocyanines. In photochemical studies, the singlet oxygen quantum yields (Φ∆) were determined as 0.43 for Si1a, 0.94 for Q-Si1a, 0.58 for S-Si1a, and 0.49 for B-Sia1. In sono-photochemical studies, the Φ∆ values were reached to 0.67 for Si1a, 1.06 for Q-Si1a, 0.65 for S-Si1a, and 0.67 for B-Sia1. In addition, this study demonstrates the therapeutic efficacy of phthalocyanines synthesized as sensitizers on the PC3 prostate cancer cell line through in vitro experiments. The application of these treatment modalities exhibited notable outcomes, leading to a substantial decrease in cell viability within the PC3 prostate cancer cell line. These findings highlight the potential of utilizing these synthesized phthalocyanines as promising therapeutic agents for prostate cancer treatment.

Asymmetric silicon phthalocyanine based nanoparticle with spatiotemporally targeting of mitochondria for synergistic apoptosis-ferroptosis antitumor treatment.

A promising therapeutic strategy in cancer treatment merges photodynamic therapy (PDT) induced apoptosis with ferroptosis, a form of programmed cell death governed by iron-dependent lipid peroxidation. Given the pivotal role of mitochondria in ferroptosis, the development of photosensitizers that specifically provoke mitochondrial dysfunction and consequentially trigger ferroptosis via PDT is of significant interest. To this end, we have designed and synthesized a novel nanoparticle, termed FECTPN, tailored to address this requisite. FECTPN harnesses a trifecta of critical attributes: precision mitochondria targeting, photoactivation capability, pH-responsive drug release, and synergistic apoptosis-ferroptosis antitumor treatment. This nanoparticle was formulated by conjugating an asymmetric silicon phthalocyanine, Chol-SiPc-TPP, with the ferroptosis inducer Erastin onto a ferritin. The Chol-SiPc-TPP is a chemically crafted entity featuring cholesteryl (Chol) and triphenylphosphine (TPP) functionalities bonded axially to the silicon phthalocyanine, enhancing mitochondrial affinity and leading to effective PDT and subsequent apoptosis of cells. Upon cellular uptake, FECTPN preferentially localizes to mitochondria, facilitated by Chol-SiPc-TPP's targeting mechanics. Photoactivation induces the synchronized release of Chol-SiPc-TPP and Erastin in the mitochondria's alkaline domain, driving the escalation of both ROSs and lipid peroxidation. These processes culminate in elevated antitumor activity compared to the singular application of Chol-SiPc-TPP-mediated PDT. A notable observation is the pronounced enhancement in glutathione peroxidase-4 (GPX4) expression within MCF-7 cells treated with FECTPN and subjected to light exposure, reflecting intensified oxidative stress. This study offers compelling evidence that FECTPN can effectively induce ferroptosis and reinforces the paradigm of a synergistic apoptosis-ferroptosis pathway in cancer therapy, proposing a novel route for augmented antitumor treatments.

Prevention of the Lachnum polysaccharide and its selenium derivatives on cisplatin-induced acute kidney injury in mice.

To investigate the renal protective effects of the polysaccharide LEP-1a and derivatives of selenium (SeLEP-1a) from Lachnum YM38, cisplatin (CP) was used to establish an acute kidney model. LEP-1a and SeLEP-1a could effectively reverse the decrease in renal index and improved renal oxidative stress. LEP-1a and SeLEP-1a significantly reduced the contents of the inflammatory cytokines. They could inhibit the release of cyclooxygenase 2 (COX-2) and nitric oxide synthase (iNOS) and increase the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1). At the same time, the PCR results indicated that SeLEP-1a could significantly inhibit the mRNA expression levels of toll-like receptor 4 (TLR4), nuclear factor-kB (NF-κB) p65 and inhibitor of kappa B-alpha (IκBα). Western blot analysis showed that LEP-1a and SeLEP-1a significantly downregulated the expression levels of Bcl-2-associated X protein (Bax) and cleaved caspase-3 and upregulated phosphatidylinositol 3-kinase (p-PI3K), protein kinase B (p-Akt) and B-cell lymphoma 2 (Bcl-2) protein expression levels in the kidney. LEP-1a and SeLEP-1a could improve CP-induced acute kidney injury by regulating the oxidative stress response, NF-κB-mediated inflammation and the PI3K/Akt-mediated apoptosis signalling pathway.

Effect of Axial Ligand Length on Biological and Anticancer Properties of Axially Disubstituted Silicon Phthalocyanines.

In this study, three new axially disubstituted silicon phthalocyanines (SiPc1-3) and their quaternized phthalocyanine derivatives (QSiPc1-3) were prepared and characterized. The biological properties (antioxidant, antimicrobial, antibiofilm, and microbial cell viability activities) of the water-soluble silicon phthalocyanines were examined, as well. A 1 % DMSO diluted with pure water was used as a solvent in biological activity studies. All the compounds exhibited high antioxidant activity. They displayed efficient antimicrobial and antimicrobial photodynamic therapeutic properties against various microorganisms, especially Gram (+) bacteria. Additionally, they demonstrated high antibiofilm activities against S. aureus and P. aeruginosa. In addition, 100 % bacterial reduction was obtained for all the studied phthalocyanines against E. coli viable cells. Besides, the DNA cleavage and binding features of compounds (QSiPc1-3) were studied using pBR322 DNA and CT-DNA, respectively. Furthermore, the human topoisomerase I enzyme inhibition activities of compounds QSiPc1-3 were studied. Anticancer properties of the water-soluble compounds were investigated using cell proliferation MTT assay. They exhibited anticarcinogenic activity against the human colon cancer cell line (DLD-1). Compounds QSiPc1 and QSiPc3 displayed a high anticarcinogenic effect on the DLD-1 cell line. The obtained results indicated that all the studied compounds may be effective biological agents and anticancer drugs after further investigations.

Threshold of Toxicological Concern: Extending the chemical space by inclusion of a highly curated dataset for organosilicon compounds.

The Threshold of Toxicological Concern (TTC) for non-genotoxic substances, a risk assessment tool to establish safe exposure levels for chemicals with insufficient toxicological data, is based on the 5th percentile of cumulated distributions of Point of Departures in a high amount of repeat-dose, developmental and reproductive toxicity studies, grouped by Cramer Classes. The lack of organosilicon compounds in this dataset has resulted in regulatory concerns over the applicability of the TTC concept for this chemistry. We collected publicly available, scientifically robust oral repeat-dose and DART studies for 71 organosilicon substances for inclusion in the existing TTC dataset, using criteria for evaluation of studies and derivation of points of departure analogous to the Munro and COSMOS TTC publications. The resulting 5th percentile of this dataset was 13-fold higher than the 5th percentile for Cramer Class III compounds reported by Munro (which is the default for silicon-containing substances). Both the existing TTC for Cramer Class III compounds from Munro (1.5 µg/kg bw/day) and the COSMOS TTC (2.3 µg/kg bw/day), recommended by the SCCS for cosmetics-related substances, provide a conservative and sufficiently protective approach for this class of chemistry.

Overcoming prostate cancer drug resistance with a novel organosilicon small molecule.

A major challenge to the treatment of advanced prostate cancer (PCa) is the development of resistance to androgen-deprivation therapy (ADT) and chemotherapy. It is imperative to discover effective therapies to overcome drug resistance and improve clinical outcomes. We have developed a novel class of silicon-containing compounds and evaluated the anticancer activities and mechanism of action using cellular and animal models of drug-resistant PCa. Five organosilicon compounds were evaluated for their anticancer activities in the NCI-60 panel and established drug-resistant PCa cell lines. GH1504 exhibited potent in vitro cytotoxicity in a broad spectrum of human cancer cells, including PCa cells refractory to ADT and chemotherapy. Molecular studies identified several potential targets of GH1504, most notably androgen receptor (AR), AR variant 7 (AR-v7) and survivin. Mechanistically, GH1504 may promote the protein turnover of AR, AR-v7 and survivin, thereby inducing apoptosis in ADT-resistant and chemoresistant PCa cells. Animal studies demonstrated that GH1504 effectively inhibited the in vivo growth of ADT-resistant CWR22Rv1 and chemoresistant C4-2B-TaxR xenografts in subcutaneous and intraosseous models. These preclinical results indicated that GH1504 is a promising lead that can be further developed as a novel therapy for drug-resistant PCa.

Super-Assembled Periodic Mesoporous Organosilica Frameworks for Real-Time Hypoxia-Triggered Drug Release and Monitoring.

Hypoxia, induced by inadequate oxygen supply, is a key indication of various major illnesses, which necessitates the need to develop new nanoprobes capable of sensing hypoxia environments for the targeted system monitoring and drug delivery. Herein, we report a hypoxia-responsive, periodic mesoporous organosilica (PMO) nanocarrier for repairing hypoxia damage. ß-cyclodextrin (ß-CD) capped azobenzene functionalization on the PMO surface could be effectively cleaved by azoreductase under a hypoxia environment. Moreover, the nanosystem is equipped with fluorescence resonance energy transfer (FRET) pair (tetrastyrene derivative (TPE) covalently attached to the PMO framework as the donor and Rhodamine B (RhB) in the mesopores as the receptor) for intracellular visualization and tracking of drug release in real-time. The design of intelligent nanocarriers capable of simultaneous reporting and treating of hypoxia conditions highlights a great potential in the biomedical domain.

Photosensitizer IR700DX-6T- and IR700DX-mbc94-mediated photodynamic therapy markedly elicits anticancer immune responses during treatment of pancreatic cancer.

BACKGROUND/AIMS: IR700DX-6T and IR700DX-mbc94 are two chemically synthesized photosensitizers (PSs) that target the translocator protein (TSPO) and type 2 cannabinoid receptor (CB2R), respectively, for photodynamic therapy (PDT) of cancer. Recently, we found that IR700DX-6T and IR700DX-mbc94 exhibited high selectivity and efficiency in PDT for breast cancer and malignant astrocytoma. Yet, the phototherapeutic effects of the PSs on pancreatic cancer and underlying mechanisms remain unknown. This study investigated the effect of IR700DX-6T- or IR700DX-mbc94-PDT on pancreatic cancer and whether the treatment involves eliciting anticancer immune responses in support of superior therapeutic efficacy. METHODS: Four pancreatic cancer cell lines were used for in vitro studies. C57BL/6 mice bearing pancreatic cancer cell-derived xenografts were generated for in vivo studies regarding the therapeutic effects of IR700DX-6T-PDT and IR700DX-mbc94-PDT on pancreatic cancer. The immunostimulatory or immunosuppressive effects of IR700DX-6T-PDT and IR700DX-mbc94-PDT were examined by detecting CD8+ T cells, regulatory T cells (Tregs), and dendritic cells (DCs) using flow cytometry and immunohistochemistry (IHC). RESULTS: TSPO and CB2R were markedly upregulated in pancreatic cancer cells and tissues. Both IR700DX-6T-PDT and IR700DX-mbc94-PDT significantly inhibited pancreatic cancer cell growth in a dose- and time-dependent manner. Notably, assessment of anticancer immune responses revealed that both IR700DX-6T-PDT and IR700DX-mbc94-PDT significantly induced CD8+ T cells, promoted maturation of DCs, and suppressed Tregs, with stronger effects exerted by IR700DX-6T-PDT compared to IR700DX-mbc94-PDT. CONCLUSIONS: IR700DX-6T-PDT and IR700DX-mbc94-PDT involves eliciting anticancer immune responses. Our study has also implicated that PDT in combination with immunotherapy holds promise to improve therapeutic efficacy for patients with pancreatic cancer.

G2-S16 Polyanionic Carbosilane Dendrimer Can Reduce HIV-1 Reservoir Formation by Inhibiting Macrophage Cell to Cell Transmission.

Human immunodeficiency virus (HIV-1) is still a major problem, not only in developing countries but is also re-emerging in several developed countries, thus the development of new compounds able to inhibit the virus, either for prophylaxis or treatment, is still needed. Nanotechnology has provided the science community with several new tools for biomedical applications. G2-S16 is a polyanionic carbosilane dendrimer capable of inhibiting HIV-1 in vitro and in vivo by interacting directly with viral particles. One of the main barriers for HIV-1 eradication is the reservoirs created in primoinfection. These reservoirs, mainly in T cells, are untargetable by actual drugs or immune system. Thus, one approach is inhibiting HIV-1 from reaching these reservoir cells. In this context, macrophages play a main role as they can deliver viral particles to T cells establishing reservoirs. We showed that G2-S16 dendrimer is capable of inhibiting the infection from infected macrophages to healthy T CD4/CD8 lymphocytes by eliminating HIV-1 infectivity inside macrophages, so they are not able to carry infectious particles to other body locations, thus preventing the reservoirs from forming.

Immunoproteasome and Non-Covalent Inhibition: Exploration by Advanced Molecular Dynamics and Docking Methods.

The selective inhibition of immunoproteasome is a valuable strategy to treat autoimmune, inflammatory diseases, and hematologic malignancies. Recently, a new series of amide derivatives as non-covalent inhibitors of the ß1i subunit with Ki values in the low/submicromolar ranges have been identified. Here, we investigated the binding mechanism of the most potent and selective inhibitor, N-benzyl-2-(2-oxopyridin-1(2H)-yl)propanamide (1), to elucidate the steps from the ligand entrance into the binding pocket to the ligand-induced conformational changes. We carried out a total of 400 ns of MD-binding analyses, followed by 200 ns of plain MD. The trajectories clustering allowed identifying three representative poses evidencing new key interactions with Phe31 and Lys33 together in a flipped orientation of a representative pose. Further, Binding Pose MetaDynamics (BPMD) studies were performed to evaluate the binding stability, comparing 1 with four other inhibitors of the ß1i subunit: N-benzyl-2-(2-oxopyridin-1(2H)-yl)acetamide (2), N-cyclohexyl-3-(2-oxopyridin-1(2H)-yl)propenamide (3), N-butyl-3-(2-oxopyridin-1(2H)-yl)propanamide (4), and (S)-2-(2-oxopyridin-1(2H)-yl)-N,4-diphenylbutanamide (5). The obtained results in terms of free binding energy were consistent with the experimental values of inhibition, confirming 1 as a lead compound of this series. The adopted methods provided a full dynamic description of the binding events, and the information obtained could be exploited for the rational design of new and more active inhibitors.

Endoscopic near-infrared photoimmunotherapy in an orthotopic head and neck cancer model.

Near-infrared photoimmunotherapy (NIR-PIT) is a cell selective cancer therapy that uses an antibody-photoabsorber (IRDye700DX, IR700) conjugate (APC) and NIR light. NIR-PIT targeting epidermal growth factor receptor (EGFR) in head and neck cancer (HNC) was conditionally approved in Japan in 2020. APC-bound tumors can be detected using endoscopic fluorescence imaging, whereas NIR light can be delivered using endoscopic fiber optics. The aims of this study were: (1) to assess the feasibility of endoscopic NIR-PIT in an orthotopic HNC model using a CD44-expressing MOC2-luc cell line; and (2) to evaluate quantitative fluorescence endoscopic imaging prior to and during NIR-PIT. The results were compared in 3 experimental groups: (1) untreated controls, (2) APC injection without light exposure (APC-IV), and (3) APC injection followed by NIR light exposure (NIR-PIT). APC injected groups showed significantly higher fluorescence signals for IR700 compared with the control group prior to therapeutic NIR light exposure, and the fluorescence signal significantly decreased in the NIR-PIT group after light exposure. After treatment, the NIR-PIT group showed significantly attenuated bioluminescence compared with the control and the APC-IV groups. Histology demonstrated diffuse necrotic death of the cancer cells in the NIR-PIT group alone. In conclusion, endoscopically delivered light combined with quantitative fluorescence imaging can be used to "see and treat" HNC. This method could also be applied to other types of cancer approachable with endoscopy.

Elimination of cells deviated from human induced pluripotent stem cells with a photoactivatable IR700-labelled antibody.

Human induced pluripotent stem cells (hiPSCs) are important starting materials for cell therapy products (CTPs) used for transplantation. During cell culture, hiPSCs often spontaneously undergo morphological changes and lose pluripotency. Such cells are called 'deviated cells', which are deviated from the undifferentiated state of hiPSCs, lack the expression of hiPSC markers and become positive for the early differentiation marker SSEA1 (stage-specific embryonic antigen 1, Lewis X glycan). Previously, we identified fibronectin (FN) as a predominant carrier protein of SSEA1 secreted from deviated cells, but not hiPSCs. A sandwich assay using antibodies (Abs) against FN and SSEA1 was developed for non-destructive quantitative evaluation of deviated cells present in hiPSC cultures. In this study, a novel technology was developed to specifically eliminate deviated cells using an anti-FN Ab along with a near-infrared (NIR) photoabsorber, IRDye700DX N-hydroxysuccinimide ester (IR700), which has been used for cancer photoimmunotherapy. The anti-FN Ab conjugated with the IR700 dye (IR700-αFN) bound to and induced the death of deviated cells upon NIR irradiation. In contrast, IR700-αFN failed to stain the hiPSCs, and IR700-αFN/NIR had little or no effect on survival. Finally, IR700-αFN/NIR irradiation induced selective removal of deviated cells from a mixed culture with hiPSCs, demonstrating that the proposed method is suitable for the removal of unwanted deviated cells present in hiPSC culture for the production of CTPs.

Designer Anticancer Nanoprodrugs with Self-Toxification Activity Realized by Acid-triggered Biodegradation and In†Situ Fragment Complexation.

Prodrugs that allow in situ chemical conversion of less toxic precursors into active drugs in response to certain stimuli are promising anticancer candidates. Herein, we present a novel design of nanoprodrugs with a "degradation-mediated self-toxification" strategy, which realizes intracellular synthesis of anticancer agents using the nanoparticles' own degradation fragments as the precursors. To fulfill this concept, a metal complexing dicyclohexylphosphine (DCP) organosilane is carefully screened out from various ligands to conjugate onto Pd(OH)2 nanodots confined hollow silica nanospheres (PD-HSN). This constructed nanoprodrug shows acid-triggered degradation in lysosomes and neutralizes protons to induce lysosomes rupturing, generating predesigned less toxic fragments (Pd2+ and DCP-silicates) that complex into DCP/Pd complex in situ for inducing DNA damage, leading to enhanced anticancer activity against various cancer cell lines as well as in a xenograft tumour model.

Tumor-selective new piperazine-fragmented silicon phthalocyanines initiate cell death in breast cancer cell lines.

A new silicon phthalocyanine with piperazine-furan ring and its quaternized form were synthesized. All compounds were analyzed by spectroscopic techniques (FT-IR, 1H-NMR, MS, and UV-vis), and the absorbance characteristics of silicon phthalocyanines were evaluated with the expected strong typical absorption bands in the far-red spectrum. The cytotoxic effects of these phthalocyanines induced by photodynamic therapy (PDT) were determined in a dose-dependent manner. Following cytotoxicity analysis, flow cytometric research of cell death was performed. The formation of reactive oxygen species (ROS) was determined by confocal microscopy. High levels of cytotoxicity and decreased viable cell population have been detected in cancer cells after treatment. In addition, ROS formation was observed in PDT treated cancer cells. However, low levels of cell death and ROS formation were observed in non-tumorigenic cells. According to western blot data, PDT-mediated treatment was found to provide different expression patterns of the cleaved PARP1 protein. The presented study demonstrates that PDT-mediated treatment of newly synthesized phthalocyanines has significant anti-cancer effects on breast cancer cells and may induce different cell death pathways.

Synthesis and photodynamic activities of novel silicon(iv) phthalocyanines axially substituted with water soluble groups against HeLa cancer cell line.

In this study, compounds 1 and 2, and their silicon(iv) phthalocyanine (SiPc) derivatives 3 and 4, which bear these ligands as substituents on the axial positions were synthesized. These SiPcs (3 and 4) were also converted to their water soluble derivatives (3a and 4a). All these novel compounds were fully characterized by a combination of spectroscopic data such as FT-IR, 1H-NMR, 13C-NMR and UV-vis as well as mass spectroscopy. The photophysicochemical properties (fluorescence quantum yields and lifetimes, singlet oxygen, and photodegradation quantum yields) were investigated in DMSO for all the studied SiPcs (3 and 4) and in both DMSO and aqueous solutions for the water soluble SiPcs (3a and 4a). Effects of quaternization of these phthalocyanines on photophysicochemical properties were also determined. The photodynamic therapy activities of the water soluble SiPcs (3a and 4a) were tested against to the HeLa cancer cell lines and these phthalocyanines exhibited cytotoxicity against these cell lines.

Design, synthesis and biological evaluation of water soluble and non-aggregated silicon phthalocyanines, naphthalocyanines against A549, SNU-398, SK-MEL128, DU-145, BT-20 and HFC cell lines as potential anticancer agents.

Cancer has become an important public problem in worldwide since cancer incidence and mortality are growing rapidly. In this study, water soluble and non-aggregated silicon (IV) phthalocyanines and naphthalocyanines containing (3,5-bis{3-[3-(diethylamino)phenoxy]propoxy}phenyl)methoxy groups have been synthesized and characterized to investigate their anticancer potential. Their DNA binding/nuclease, topoisomerases inhibition were investigated using UV-Vis absorption, thermal denaturation and agarose gel electrophoresis. The in vitro cytotoxic properties of the compounds on human lung (A549), breast (BT-20), liver (SNU-398), prostate (DU-145), melanoma (SK-Mel 128) carcinoma and human fibroblast (HFC) normal cell lines were evaluated by using MTT assay. In order to determine the mechanism of cancer cell growth suppression, cell cycle analysis was carried out using flow cytometer on A549 cell line. The Kb values of SiPc1a and SiNc2a were 6.85 ± (0.35) × 106 and 1.72 ± (0.16) × 104 M-1 and Tm values of ct-DNA were calculated as 82.02 °C and 78.07 °C, respectively in the presence of both compounds. The ΔTm values of SiPc1a and SiNc2a were calculated as 6.45 and 2.50 °C, respectively. The nuclease effects of SiPc1a and SiNc2a with supercoiled plasmid pBR322 DNA demonstrated that both compounds did not trigger any DNA nuclease effects at the lowest concentrations without irradiation whereas both compounds in the presence of activating agent (H2O2) showed significant plasmid DNA nuclease actions under irradiation (22.5 J/cm2). SiPc1a and SiNc2a inhibited to topoisomerase I on increasing concentrations whilst they had lower inhibition action toward topoisomerase II that of topoisomerase I. The in vitro cytotoxicity studies displayed that SiPc1a had the highest cytotoxic effects among the tested compounds against A549, SNU-398, SK-MEL128, DU-145, BT-20 and HFC cell lines with CC50 values ranged from 0.49 to 2.99 µM. Furthermore, SiPc1a inhibited cell proliferation by cell cycle arrest in G0/G1 phase. All of these results suggested that SiPc1a is a promising candidate as an anticancer agent.

Opioid System Contributes to the Trifluoromethyl-Substituted Diselenide Effectiveness in a Lifestyle-Induced Depression Mouse Model.

Energy-dense foods and ethanol consumption are associated with mood disorders. m-Trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] has been a prominent pharmacological target due to its antidepressant-like effects. This study investigated if the modulation of opioid and glucocorticoid receptors and its well-known antioxidant property contribute to the (m-CF3-PhSe)2 antidepressant-like effect in young mice subjected to an energy-dense diet and ethanol intake. Swiss male mice [postnatal day (PND) 25] were exposed to an energy-dense diet (containing 20% fat and 20% carbohydrate) or standard chow until the PND 67. Mice received ethanol (2 g/kg) or water administration (3 times a week, intragastrically [i.g.]) from PND 45 to PND 60. After that, mice received (m-CF3-PhSe)2 (5 mg/kg/day; i.g) or vegetal oil administration from PND 60 to 66. Mice performed the behavioral tests to evaluate the depressive-like phenotype. The results showed that individually neither an energy-dense diet nor ethanol group induced a depressive-like phenotype, but the association of both induced this phenotype in young mice. Oxidative stress was characterized by the increase of malondialdehyde, the decrease in the superoxide dismutase activity, and non-protein sulfhydryl levels in the cerebral cortex of depressive-like mice. Depressive-like mice showed an increase in the protein levels of opioid receptors and depletion in those of glucocorticoid. (m-CF3-PhSe)2 abolished depressive-like phenotype and oxidative stress as well as modulated the levels of glucocorticoid and opioid receptors. In conclusion, the modulation of opioid and glucocorticoid receptors and the antioxidant property contributed to the (m-CF3-PhSe)2 antidepressant-like effect in young mice exposed to an energy-dense diet and ethanol intake.

Immunogenic necroptosis in the anti-tumor photodynamic action of BAM-SiPc, a silicon(IV) phthalocyanine-based photosensitizer.

Photodynamic therapy (PDT) is an anti-tumor modality which employs three individually non-toxic substances, including photosensitizer, light and oxygen, to produce a toxic effect. Besides causing damage to blood vessels that supply oxygen and nutrients to the tumor and killing the tumor by a direct cytotoxic effect, PDT has also been known to trigger an anti-tumor immune response. For instance, our previous study showed that PDT with BAM-SiPc, a silicon(IV) phthalocyanine based-photosensitizer, can not only eradicate the mouse CT26 tumor cells in a Balb/c mouse model, but also protect the mice against further re-challenge of the tumor cells through an immunomodulatory mechanism. To understand more about the immune effect, the biochemical actions of BAM-SiPc-PDT on CT26 cells were studied in the in vitro system. It was confirmed that the PDT treatment could induce immunogenic necroptosis in the tumor cells. Upon treatment, different damage-associated molecular patterns were exposed onto the cell surface or released from the cells. Among them, calreticulin was found to translocate to the cell membrane through a pathway similar to that in chemotherapy. The activation of immune response was also demonstrated by an increase in the expression of different chemokines.

A multifunctional oxygen-producing MnO2-based nanoplatform for tumor microenvironment-activated imaging and combination therapy in vitro.

The current trend of cancer therapy has changed from monotherapy to synergistic or combination therapies. Among the treatment strategies, photodynamic therapy (PDT) and starvation therapy are widely employed together. However, the therapeutic effect of these treatments could lead to strong resistance and poor prognosis due to tumor hypoxia. Therefore, a smart nanoplatform (MONs-GOx@MnO2-Ce6) has been constructed herein by the assembly of glucose oxidase (GOx)-coated mesoporous organosilica nanoparticles (MONs) and MnO2 nanosheets-chlorin e6 (Ce6), which form a nanosystem. Once MONs-GOx@MnO2-Ce6 enter tumor cells, it catalyzes the oxidation of glucose using oxygen (O2) and generates hydrogen peroxide (H2O2) and gluconic acid, the former of which may accelerate the decomposition of MnO2 nanosheets. The released MnO2 nanosheets would regenerate O2 in the presence of H2O2. In this case, MnO2 nanosheets serve as (i) a nanocarrier and fluorescence quencher for the photosensitizer Ce6, (ii) a degradable material that is activated by the tumor microenvironment (TME) for fluorescence recovery, and (iii) an O2-producing carrier that reacts with H2O2 for relieving hypoxia in the tumor, which contributes to the combined starvation/photodynamic cancer therapy since these treatment strategies need O2. MONs-GOx@MnO2-Ce6 could not only realize cancer cell imaging, but also reduce intracellular glucose uptake and Glut1 expression, inhibiting the metabolism of cancer cells. This strategy shows great potential for clinical applications.