Targeted pH-responsive biomimetic nanoparticle-mediated starvation-enhanced chemodynamic therapy combined with chemotherapy for ovarian cancer treatment.

In recent years, the use of arsenic trioxide (ATO) in the context of ovarian cancer chemotherapy has attracted significant attention. However, ATO's limited biocompatibility and the occurrence of severe toxic side effects hinder its clinical application. A nanoparticle (NP) drug delivery system using ATO as a therapeutic agent is reported in this study. Achieving a synergistic effect by combining starvation therapy, chemodynamic therapy, and chemotherapy for the treatment of ovarian cancer was the ultimate goal of this system. This nanotechnology-based drug delivery system (NDDS) introduced arsenic-manganese complexes into cancer cells, leading to the subsequent release of lethal arsenic ions (As3+) and manganese ions (Mn2+). The acidic microenvironment of the tumor facilitated this process, and MR imaging offered real-time monitoring of the ATO dose distribution. Simultaneously, to produce reactive oxygen species that induced cell death through a Fenton-like reaction, Mn2+ exploited the surplus of hydrogen peroxide (H2O2) within tumor cells. Glucose oxidase-based starvation therapy further supported this mechanism, which restored H2O2 and lowered the cellular acidity. Consequently, this approach achieved self-enhanced chemodynamic therapy. Homologous targeting of the NPs was facilitated through the use of SKOV3 cell membranes that encapsulated the NPs. Hence, the use of a multimodal NDDS that integrated ATO delivery, therapy, and monitoring exhibited superior efficacy and biocompatibility compared with the nonspecific administration of ATO. This approach presents a novel concept for the diagnosis and treatment of ovarian cancer.

Green-synthesized copper oxide nanoparticles induce apoptosis and up-regulate HOTAIR and HOTTIP in pancreatic cancer cells.

Aim: Cu2O nanoparticles were synthesized using an extract from S. latifolium algae (SLCu2O NPs). Their effect on PANC-1 cells and the expression of two drug resistance-related lncRNAs were evaluated in comparison with Arsenic trioxide.Materials & methods: SLCu2O NPs were characterized using XRD, SEM, and TEM microscopies. The effects of SLCu2O NPs on cell cytotoxicity, cell cycle, and apoptosis, and expression of two drug resistance-related lncRNAs were examined using MTT assay, flow cytometry, and real-time PCR, respectively.Results: SLCu2O NPs demonstrated anti-cancer properties against PANC-1 cells comparable to Arsenic trioxide, and the expression of lncRNAs increased upon treatment with them.Conclusion: SLCu2O NPs demonstrate anti-cancer properties against PANC-1 cells; however, using gene silencing strategies along with SLCu2O NPs is suggested.

[Box: see text].

Maximizing arsenic trioxide's anticancer potential: Targeted nanocarriers for solid tumor therapy.

Arsenic trioxide (ATO) has gained significant attention due to its promising therapeutic effects in treating different diseases, particularly acute promyelocytic leukemia (APL). Its potent anticancer mechanisms have been extensively studied. Despite the great efficacy ATO shows in fighting cancers, drawbacks in the clinical use are obvious, especially for solid tumors, which include rapid renal clearance and short half-life, severe adverse effects, and high toxicity to normal cells. Recently, the emergence of nanomedicine offers a potential solution to these limitations. The enhanced biocompatibility, excellent targeting capability, and desirable effectiveness have attracted much interest. Therefore, we summarized various nanocarriers for targeted delivery of ATO to solid tumors. We also provided detailed anticancer mechanisms of ATO in treating cancers, its clinical trials and shortcomings as well as the combination therapy of ATO and other chemotherapeutic agents for reduced drug resistance and synergistic effects. Finally, the future study direction and prospects were also presented.

Thiolated chitosan nanoparticles for stable delivery and smart release of As2O3 for liver cancer through dual actions.

In this work, multifunctional thiolated chitosan derivatives (DCA-CS-PEG-FA-NAC) were synthesized, and arsenic trioxide (ATO) was loaded onto the derivatives through glutathione (GSH)-sensitive AsIII-S bonds, and stable CS-ATO nanodrugs were prepared by simple self-assembly method. By adjusting the thiol substitution degree of CS, the drug loading capacity of the nanodrugs was significantly improved, which could reach 20 ATO per CS molecule (DCA10.7-CS-PEG3.1-FA-NAC20.2-ATO). In vitro release studies obviously showed the low leakage of ATO under physiological conditions while over 95 % ATO was released after 24 h under GSH. In vitro and in vivo investigations demonstrated that the DCA10.7-CS-PEG3.1-FA-NAC20.2-ATO nanodrug could significantly enhance the tumor intracellular accumulation of ATO, reduce the toxic and side effects of ATO on healthy organs, and improve the therapeutic effect of ATO on the HepG2 mice tumor model (tumor inhibition rate was as high as 86.4 %), indicating the potential application of ATO in clinical treatment of liver cancer.

Arsenic trioxide activates yes-associated protein by lysophosphatidic acid metabolism to selectively induce apoptosis of vascular smooth muscle cells.

Inhibition of vascular smooth muscle cells (VSMCs) proliferation without dysregulating endothelial cells (ECs) may provide an ideal therapy for in-stent restenosis. Due to its anti-proliferation effect on VSMCs and pro-endothelium effect, arsenic trioxide (ATO) has been used in a drug-eluting stent in a recent clinical trial. However, the underlying mechanism by which ATO achieves this effect has not been determined. In the present work, we showed that ATO induced apoptosis in VSMCs but not in ECs. Mechanistically, ATO achieved this through modulation of cellular metabolism to increase lysophosphatidic acid (LPA) in VSMCs, while LPA concentration was stable in ECs. The elevated LPA facilitated the nuclear accumulation and initiated the transcriptional function of Yes-associated protein (YAP) in VSMCs. YAP regulated the transcription of N6-Methyladenosine (m6A) modulators (Mettl14 and Wtap) to increase the m6A methylation levels of apoptosis-related genes to induce their high expression and exacerbate VSMCs apoptosis. On the other hand, YAP nuclear accumulation in ECs was not observed. Collectively, our data exhibited the molecular process involved in selective apoptosis of VSMCs induced by ATO.

Antibacterial, antifungal and enzymatic activities of azithromycin-heavy metal complexes: Newly synthesized and characterized.

As part of our continuous research to understand the interaction mechanism of drug and metallo-elements, heavy metal complexes of azithromycin (AZI) were synthesized with arsenic oxide, lead carbonate and silver chloride salts in molar ratio of 2: 1 (L: M). Synthesized heavy metal complexes have shown good percent yield and characterized through spectroscopic parameters including UV-Visible, TLC, FT-IR, NMR and elemental analysis (CHN). Spectroscopic characterization reveals the binding of ligand AZI with heavy metals in bi-dentate manner involving the hydroxide and 9a-NCH3 group of the aglycone ring of AZI. These newly synthesized heavy metal complexes were evaluated for their antimicrobial response against selected gram positive and gram negative organisms and antifungal species. It was noted that all newly synthesized complexes exhibits increased activity against B.subtilus whereas, AZI itself didn't show any activity, while synthesized complexes have low to moderate response against all the studied organisms. Complex A-M12 possess greater enzymatic response against both urease and alpha chymotrypsin among all the studied complexes. Results obtained were then statistically analyzed through one way ANOVA and Dunnett's test by using SPSS version 20.0 suggesting the significant response of complexes against selected organisms.

Iodide Analogs of Arsenoplatins-Potential Drug Candidates for Triple Negative Breast Cancers.

Patients with triple negative breast cancers (TNBCs)-highly aggressive tumors that do not express estrogen, progesterone, and human epidermal growth factor 2 receptors-have limited treatment options. Fewer than 30% of women with metastatic TNBC survive five years after their diagnosis, with a mortality rate within three months after a recurrence of 75%. Although TNBCs show a higher response to platinum therapy compared to other breast cancers, drug resistance remains a major obstacle; thus, platinum drugs with novel mechanisms are urgently needed. Arsenoplatins (APs) represent a novel class of anticancer agents designed to contain the pharmacophores of the two FDA approved drugs cisplatin and arsenic trioxide (As2O3) as one molecular entity. Here, we present the syntheses, crystal structures, DFT calculations, and antiproliferative activity of iodide analogs of AP-1 and AP-2, i.e., AP-5 and AP-4, respectively. Antiproliferative studies in TNBC cell lines reveal that all AP family members are more potent than cisplatin and As2O3 alone. DFT calculations demonstrate there is a low energy barrier for hydrolysis of the platinum-halide bonds in arsenoplatins, possibly contributing to their higher cytotoxicities compared to cisplatin.

Formulation Comprising Arsenic Trioxide and Dimercaprol Enhances Radiosensitivity of Pancreatic Cancer Xenografts.

OBJECTIVE: To investigate the efficacy of a formula comprising arsenic trioxide and dimercaprol (BAL-ATO) as a radiosensitizing agent in model mice with pancreatic cancer xenografts. METHODS: Female BALB/c nude mice bearing SW1990 human pancreatic cancer xenografts were divided into four treatment arms, including control, radiotherapy (RT), BAL-ATO, and RT + BAL-ATO groups. Survival and tumor volume were analyzed. We also assessed apoptosis in tumor samples by live imaging and detected hypoxia by confocal laser microscope observation. We further investigated the mechanisms of BAL-ATO action in RT by detecting affected proteins by western blot and immunohistochemistry assays. RESULTS: Median survival was significantly longer in the RT + BAL-ATO group (64.5 days) compared with the control (49.5 days), RT (39 days), and BAL-ATO (48 days) groups (P < 0.001). RT + BAL-ATO inhibited the growth of tumors in mice by 73% compared with the control group, which was significantly higher than the rate of inhibition following RT alone (59%) (P < 0.01). Further analysis showed an improved microenvironment in terms of hypoxia in tumors treated with BAL-ATO alone or RT + BAL-ATO. Expression of signaling molecules associated with pancreatic cancer stem cells, including CD24, CD44, ALDH1A1, Gli-1, and Nestin, was detected in tumors treated with BAL-ATO alone or in combination with RT. CONCLUSION: These data suggest that BAL-ATO function as a radiosensitizer in mice with pancreatic cancer xenografts, via mechanisms involving hypoxia reduction and inhibition of signaling pathways associated with pancreatic cancer stem cells. BAL-ATO may thus be a promising radiosensitizing agent in patients with pancreatic cancer.

Investigation of the Physical Properties and Clinical Application of Embosphere Microspheres.

BACKGROUND: The aim of this study was to understand physical characteristics of Embosphere microspheres for the clinical use of microsphere chemotherapy embolization of liver cancer. METHODS: The morphology of Embosphere microspheres in different states, including static, oscillating, and in a magnetic field was observed with the naked eye. Ninety-five patients diagnosed with primary hepatocellular carcinoma (HCC) were separated into 3 groups based on the types of embolic material as follows: 32 cases of sole microspheres, 34 cases of iodinated oil (17 cases with additional application of gelatin sponge particle), and 29 cases of iodinated oil + Embosphere microspheres. RESULTS: The diameter of the microspheres ranged from 100 to 300 µm, with a sedimentation rate υ = 0.0375 cm/s in physiological saline. The diameter of microspheres ranged from 300 to 500 µm, with a sedimentation rate υ = 0.1875 cm/s. The swelling rate of microspheres was 90%. Microspheres showed nondirectional movement in a 1.5- or 3.0-T magnetic field during magnetic resonance imaging. A volumetric ratio of 1:1.4-1:1.5 between microspheres and contrast agent resulted in optimal suspension properties. Microspheres appeared circular with a smooth surface upon water adsorption. Microsphere embolism was observable in blood vessels of pathological sections. The surface of microspheres can adsorb 5-fluorouracil and arsenic trioxide. There are statistically significant differences in local-regional tumor control conditions among patients treated with sole microspheres, iodinated oil, and iodinated oil + microspheres during transarterial chemoembolization. CONCLUSIONS: Embosphere microspheres can be used to embolize patients with rupture and hemorrhage of HCC. Embosphere microsphere embolization is superior to iodinated oil and iodinated oil + microsphere for HCC.

Arsenic trioxide-loaded CalliSpheres: In vitro study of drug release and antitumor activity, and in vivo study of pharmacokinetics, treatment efficacy and safety in liver cancer.

The aim of the present study was to investigate the arsenic trioxide (ATO) loading/releasing efficiency of CalliSphere beads (CBs), as well as the in vitro anticancer activity, in vivo pharmacokinetics, treatment efficacy and safety of ATO-eluting CBs in liver cancer. The ATO loading and releasing efficiencies in CBs were evaluated. Furthermore, cell viability, invasion, apoptosis, VEGF expression and MMP9 expression were determined in liver cancer cells treated with ATO-eluting CBs or ATO solution. Rabbit liver models were established and underwent TACE with ATO-eluting CBs or ATO/lipiodol emulsion. Subsequently, their ATO pharmacokinetics were determined and macroscopic/microscopic examinations were conducted. In vitro, CB-loaded ATO increased during 40 min with an optimal loading efficiency of 23.0±2.5%, and released ATO rapidly within the first 30 min (31.40±10.0%) then slowed down within the latter 48 h (47.20±4.70%). ATO-eluting CBs exhibited decreased cell viability to some extent and similar invasive cell count, apoptosis rate, VEGF and MMP9 levels compared with ATO solution at various concentrations and time-points. In vivo, ATO concentration was lower in plasma, but higher in tumor tissues, and necrosis was more complete in tumor tissue while milder in normal liver parenchyma after rabbit liver was embolized with ATO-eluting CBs compared with ATO/lipiodol emulsion. ATO-eluting CBs may be a novel and promising therapeutic option in treating liver cancer.

Angiopep-2-modified calcium arsenite-loaded liposomes for targeted and pH-responsive delivery for anti-glioma therapy.

The blood-brain barrier (BBB) is the most critical obstacle in the treatment of central nervous system disorders, such as glioma, the most typical type of brain tumor. To overcome the BBB and enhance drug-penetration abilities, we used angiopep-2-modified liposomes to deliver arsenic trioxide (ATO) across the BBB, targeting the glioma. Angiopep-2-modified calcium arsenite-loaded liposomes (A2-PEG-LP@CaAs), with uniformly distributed hydrodynamic diameter (96.75 ± 0.57 nm), were prepared using the acetate gradient method with high drug-loading capacity (7.13 ± 0.72%) and entrapment efficiency (54.30 ± 9.81%). In the acid tumor microenvironment, arsenic was responsively released, thereby exerting an anti-glioma effect. The anti-glioma effect of A2-PEG-LP@CaAs was investigated both in vitro and in vivo. As a result, A2-PEG-LP@CaAs exhibited a potent, targeted anti-glioma effect mediated by the lipoprotein receptor-related (LRP) receptor, which is overexpressed in both the BBB and glioma. Therefore, A2-PEG-LP@CaAs could dramatically promote the anti-glioma effect of ATO, as a promising strategy for glioma therapy.

Arsenoplatin-Ferritin Nanocage: Structure and Cytotoxicity.

Arsenoplatin-1 (AP-1), the prototype of a novel class of metallodrugs containing a PtAs(OH)2 core, was encapsulated within the apoferritin (AFt) nanocage. UV-Vis absorption spectroscopy and inductively coupled plasma-atomic emission spectroscopy measurements confirmed metallodrug encapsulation and allowed us to determine the average amount of AP-1 trapped inside the cage. The X-ray structure of AP-1-encapsulated AFt was solved at 1.50 Å. Diffraction data revealed that an AP-1 fragment coordinates the side chain of a His residue. The biological activity of AP-1-loaded AFt was comparatively tested on a few representative cancer and non-cancer cell lines. Even though the presence of the cage reduces the overall cytotoxicity of AP-1, it improves its selectivity towards cancer cells.

The first step of arsenoplatin-1 aggregation in solution unveiled by solving the crystal structure of its protein adduct.

Arsenoplatin-1 (AP-1) is an innovative dual-action anticancer agent that contains a platinum(ii) center coordinated to an arsenous acid moiety. We found that AP-1 spontaneously aggregates in aqueous solutions generating oligomeric species of increasing length. Afterward, we succeeded in solving the crystal structure of the adduct formed between the model protein lysozyme and an early AP-1 oligomer that turned out to be a trimer. Remarkably, this crystal structure traps an early stage of AP-1 aggregation offering detailed insight into the molecular process of the oligomer's growth.

Arsenic trioxide-eluting electrospun nanofiber-covered self-expandable metallic stent reduces granulation tissue hyperplasia in rabbit trachea.

Stent-related granulation tissue hyperplasia is a major complication that limits the application of stents in airways. In this study, an arsenic trioxide-eluting electrospun nanofiber-covered self-expandable metallic stent (ATO-NFCS) was developed. Poly-L-lactide-caprolactone (PLCL) was selected as the drug-carrying polymer. Stents with two different ATO contents (0.4% ATO/PLCL and 1.2% ATO/PLCL) were fabricated. The in vitro release in simulated airway fluid suggested that the total ATO release time was 1 d. The growth of human embryonic pulmonary fibroblasts (CCC-HPF-1), normal human bronchial epithelial cells and airway smooth muscle cells was inhibited by ATO. When embedded in paravertebral muscle, the nanofiber membrane showed good short-term and long-term biological effects. In an animal study, placement of the ATO-NFCS in the trachea through a delivery system under fluoroscopy was feasible. The changes in liver and kidney function 1 and 7 d after ATO-NFCS placement were within the normal range. On pathological examination, the heart, liver, spleen, lungs and kidneys were normal. The effectiveness of the ATO-NFCS in reducing granulation tissue hyperplasia and collagen deposition was demonstrated in the rabbit airway (n = 18) at 4 weeks. The present study preliminarily investigated the efficacy of the ATO-NFCS in reducing granulation tissue formation in the trachea of rabbits. The results suggest that the ATO-NFCS is safe in vivo, easy to place, and effective for the suppression of granulation tissue formation.

Nanosized drug-eluting bead for transcatheter arterial chemoembolization (ND-TACE).

Commercially available drug-eluting embolization beads (100-500 µm) reduced the occurrence of adverse events related to an anticancer drug, but were unascertained to remarkably benefit the transcatheter arterial chemoembolization (TACE) treatment of intermediate-stage liver cancer. Dextran-coated arsenite nanoparticles with the size ranging from 400 to 600 nm were developed as a nanosized drug-eluting bead (NDEB) for chemoembolization therapy of the rabbit VX2 liver tumor. We fully characterized their relevant physicochemistry and drug release properties. Their hemolysis was investigated before vessel embolization. The introduction of the NDEB allowed continuous embolization of tumor feeding vessels and sustained release of arsenic trioxide, thereby causing severe tumor necrosis and reduced vascularity. Sonography including B mode ultrasound, color Doppler flow imaging (CDFI) and dynamic contrast-enhanced ultrasound (CEUS) were performed to evaluate the tumor vascularity and viability. Additionally, its hepatotoxicity was tolerable at a medium dose. NDEB-TACE might be an effective therapeutic strategy for interventional therapy.

Construction of arsenic-metal complexes loaded nanodrugs for solid tumor therapy: A mini review.

Arsenic trioxide (As2O3), a front-line therapeutic agent against acute promyelocytic leukemia, has a broad spectrum against malignancies. Unfortunately, the clinical application of As2O3 in treating hematological cancers has not been transformed to solid tumors, for its dose-limited toxicity and undesirable pharmacokinetics. The ordinary As2O3 loaded nanodrugs (such as liposomes, polymer micelles, albumin-based nanodrugs, and silica-based nanodrugs, etc.) still could not fuel up pharmaceuticals and eradicate toxicity for low delivery efficiency caused by the instability and severe drug leakage of formulations during circulation. Recently, the approach of forming and delivering arsenic-metal complexes which will dissociate in the tumoral environment caught our mind. This is the most effective strategy to reduce drug leakage in circulation and accumulate arsenite ions in tumor sites, therefore promote the anti-tumor effect and lighten the toxicity of the drug. This review aims to explain the formation mechanism of arsenic-metal nanocomposites and summarize the constructing strategies of the arsenic-metal nanocomplexes (arsenic-nickel, arsenic-manganese, arsenic-platinum, arsenic-gadolinium, arsenic-zinc, and arsenic-iron nanobins) loaded nanodrugs for solid tumor therapy. Furthermore, the expectations and challenges of arsenic-metal complexes containing nanodrugs for cancer therapy in the future were discussed.

Dual oligopeptides modification mediates arsenic trioxide containing nanoparticles to eliminate primitive chronic myeloid leukemia cells inside bone marrow niches.

Chronic myeloid leukemia (CML) is one type of hematopoietic stem cell diseases. Although BCR-ABL1 tyrosine kinase inhibitors are remarkably effective in inducing remission in chronic phase patients, they are not curative in a majority of patients due to their failure to eradicate residual CML stem/progenitor cells, which reside in bone marrow niches. Here, we presented novel dual oligopeptides-conjugated nanoparticles and demonstrated their effective delivery of arsenic trioxide in bone marrow niches for the elimination of primitive CML cells. We encapsulated As-Ni transitional metal compounds into polymeric nanoparticles based on the reverse micelle rationale. The loading density and stability of arsenic trioxide in nanoparticles were improved. In vitro experiments demonstrated that dual oligopeptides conjugated nanoparticles could deliver arsenic trioxide into bone marrow niches including endosteal niches and vascular niches. The colony-forming activity of CML cells was remarkably restrained in the presence of metaphyseal bone fragments pre-incubated with bone marrow niche targeted arsenic nanoparticles. The in vitro vascular niche model suggested that CML cell proliferation was also successfully inhibited through a tight contact with HUVECs, which were pre-treated using niche-targeted arsenic nanoparticles. This bone marrow niche targeted delivery strategy has a potential usage for the treatment of CML and other malignant hematologic disorders originated from the bone marrow.

The Effect of Arsenic Trioxide on All-trans Retinoic Acid Binding to Human Serum Albumin.

Tretinoin or All-trans retinoic acid (ATRA) is an efficient medication in leukemia treatment. Arsenic trioxide (ATO) significantly improves the effectiveness of ATRA. In this study, the effect of ATO on ATRA binding to human serum albumin (HSA) was investigated. Fluorescence and UV-Vis spectroscopy and equilibrium dialysis technique were used to determine ATRA binding to HSA in the presence and absence of ATO and of two compounds, warfarin and ibuprofen, specific for binding to HSA sites I and II, respectively ("site markers"). The association constants for ATRA binding and the number of binding sites as well as the thermodynamic parameters of complex formation, were obtained at different temperatures. Fluorescence results showed a static quenching mechanism for ATRA binding to HSA. The calculated thermodynamic parameters revealed that the binding reaction is a spontaneous and exothermic process and also that hydrogen bonds and van der Waals forces have a central role in the binding of ATRA to HSA. Competitive experiments showed that none of markers seriously prevents ATRA binding to HSA. Interestingly, the fluorescence and equilibrium dialysis data showed that ATO increases the binding of ATRA to HSA, and converts the binding mode of ATRA from mainly hydrogen bonding to include hydrophobic interactions as well. These results suggest that ATO can prevent the metabolism of ATRA and keep it in the blood for longer by increasing the binding of ATRA to HSA.

Effects of Proanthocyanidins on Arsenic Methylation Metabolism and Efflux in Human Hepatocytes L-02.

This study investigated the effects of proanthocyanidins (PC) on arsenic methylation metabolism and efflux in human hepatocytes (L-02), as well as the relationships between PC and GSH, MRP1 and other molecules. Cells were randomly divided into blank control group, arsenic trioxide exposure group (ATO, As2O3, 25µmol/L), and PC-treated arsenic exposure group (10, 25, 50mg/L). After 24/48h, the contents of different forms of arsenic were determined, and the methylation indexes were calculated. Intracellular S-adenosyl methionine (SAM), arsenic (+3 oxidation state) methyltransferase (AS3MT), multidrug resistance-associated protein 1 (MRP1), and reduced glutathione (GSH) were ascertained. Changing trends were observed and the correlation between arsenic metabolism and efflux related factors and arsenic metabolites was analyzed. We observed that cells showed increased levels of content/constituent ratio of methyl arsenic, primary/secondary methylation index, methylation growth efficiency/rate, and the difference of methyl arsenic content in cells and culture medium (P<0.05, resp.). Compared with ATO exposure group, the intracellular SAM content in PC-treated group decreased, and the contents of GSH, AS3MT, and MRP1 increased (P<0.05, resp.). There was a positive correlation between the content of intracellular GSH/AS3MT and methyl arsenic. The content of MRP1 was positively correlated with the difference of methyl arsenic content in cell and culture medium; conversely, the SAM content was negatively correlated with intracellular methyl arsenic content (P<0.05, resp.). Taken together, these results prove that PC can promote arsenic methylation metabolism and efflux in L-02 cells, which may be related to the upregulation of GSH, MRP1, and AS3MT levels by PC.