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International Journal of Molecular... Mar 2021We investigate dissociative electron attachment to tirapazamine through a crossed electron-molecule beam experiment and quantum chemical calculations. After the electron...
We investigate dissociative electron attachment to tirapazamine through a crossed electron-molecule beam experiment and quantum chemical calculations. After the electron is attached and the resulting anion reaches the first excited state, D, we suggest a fast transition into the ground electronic state through a conical intersection with a distorted triazine ring that almost coincides with the minimum in the D state. Through analysis of all observed dissociative pathways producing heavier ions (90-161 u), we consider the predissociation of an OH radical with possible roaming mechanism to be the common first step. This destabilizes the triazine ring and leads to dissociation of highly stable nitrogen-containing species. The benzene ring is not altered during the process. Dissociation of small anionic fragments (NO, CN, CN, NH, O) cannot be conclusively linked to the OH predissociation mechanism; however, they again do not require dissociation of the benzene ring.
Topics: Algorithms; Anions; Electrons; Models, Chemical; Radiation-Sensitizing Agents; Tirapazamine
PubMed: 33808887
DOI: 10.3390/ijms22063159 -
Biofabrication Apr 2021Replication of physiological oxygen levels is fundamental for modeling human physiology and pathology inmodels. Environmental oxygen levels, applied in mostmodels,...
Replication of physiological oxygen levels is fundamental for modeling human physiology and pathology inmodels. Environmental oxygen levels, applied in mostmodels, poorly imitate the oxygen conditions cells experience, where oxygen levels average ∼5%. Most solid tumors exhibit regions of hypoxic levels, promoting tumor progression and resistance to therapy. Though this phenomenon offers a specific target for cancer therapy, appropriateplatforms are still lacking. Microfluidic models offer advanced spatio-temporal control of physico-chemical parameters. However, most of the systems described to date control a single oxygen level per chip, thus offering limited experimental throughput. Here, we developed a multi-layer microfluidic device coupling the high throughput generation of 3D tumor spheroids with a linear gradient of five oxygen levels, thus enabling multiple conditions and hundreds of replicates on a single chip. We showed how the applied oxygen gradient affects the generation of reactive oxygen species (ROS) and the cytotoxicity of Doxorubicin and Tirapazamine in breast tumor spheroids. Our results aligned with previous reports of increased ROS production under hypoxia and provide new insights on drug cytotoxicity levels that are closer to previously reportedfindings, demonstrating the predictive potential of our system.
Topics: Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Female; Humans; Hypoxia; Microfluidics; Oxygen; Spheroids, Cellular
PubMed: 33440359
DOI: 10.1088/1758-5090/abdb88 -
Advanced Healthcare Materials May 2021Hepatocellular carcinoma (HCC) is one of the most common and deadliest malignancy cancers, which remains a major global health problem. At present, over 50% of patients...
Hepatocellular carcinoma (HCC) is one of the most common and deadliest malignancy cancers, which remains a major global health problem. At present, over 50% of patients with HCC have implemented systemic therapies, such as interventional therapy or local chemotherapy that are scarcely effective and induce serious side effects to the remaining normal liver, further limiting their clinical outcomes. Herein, a tumor microenvironment triggered cascade-activation nanoplatform (A-NP ) is prepared based on β-lapachone (β-Lap) and tirapazamine (TPZ) for the synergistic therapy of HCC. The A-NP exerts its targeting effect by binding to the receptor of tumor cells with an external aptamer. In the tumor microenvironment, the nanoplatform can realize H O -triggered disassembly to release β-Lap and TPZ. The released β-Lap generates ROS to induce tumor cell apoptosis under the catalysis of the tumor cell over-expressed NAD(P)H-quinone oxidoreductase-1 (NQO1) enzyme. In this process, oxygen is consumed to intensify tumor hypoxia, and eventually cascade activates TPZ to exert the anti-tumor effect. The studies in vitro and in vivo consistently demonstrate that the as-prepared A-NP nanoplatform possesses an excellent synergistic anti-tumor effect. This design of nanoplatform with cascade activation effect provides a promising strategy for HCC treatment.
Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Humans; Liver Neoplasms; Tirapazamine; Tumor Hypoxia; Tumor Microenvironment
PubMed: 33644987
DOI: 10.1002/adhm.202002036 -
Acta Biomaterialia Jan 2022Disturbance in redox homeostasis always leads to oxidative damages to cellular components, which inhibits cancer cell proliferation and causes tumor regression....
Disturbance in redox homeostasis always leads to oxidative damages to cellular components, which inhibits cancer cell proliferation and causes tumor regression. Therefore, synergistic effects arising from cellular redox imbalance together with other treatment modalities are worth further investigation. Herein, a metal-organic framework nanosystem (NMOF) based on coordination between Fe (III) and 4,4,4,4-(porphine-5,10,15,20-tetrayl) tetrakis (benzoic acid) (TCPP) was synthesized through a one-pot method. After surface capping of silk fibroin (SF) to form NMOF@SF nanoparticles (NPs), this nanoplatform can serve as an eligible nanocarrier to deliver tirapazamine (TPZ), a hypoxia-activated precursor. As-developed NS@TPZ (NST) NPs remained inactive in the normal tissue, whereas became highly active upon endocytosis by tumor cells via glutathione (GSH)-mediated reduction of Fe (III) into Fe (II), further enabling Fe (II)-mediated chemodynamic therapy (CDT). Upon optical laser irradiation, TCPP-mediated photodynamic therapy (PDT) coordinated with CDT to aggravate intracellular oxidative stress. Thus, such reactive oxygen species accumulation and GSH deprivation contributed to a deleterious redox dyshomeostasis. On the other hand, local deoxygenation caused by PDT can increase the cytotoxicity of released TPZ, which significantly improved the integral therapeutic effectiveness relying on the combined redox balance disruption and bioreductive chemotherapy. More importantly, severe immunogenic cell death can be triggered by the combinatorial treatment modalities and the presence of SF, which facilitated an almost complete tumor eradication in vivo. Taken together, this paradigm provides an insightful strategy for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy, which can remarkably enhance antitumor efficacy with negligible adverse effects. STATEMENT OF SIGNIFICANCE: Recently, silk fibroin (SF) has been demonstrated to be effective in activating antitumor immune system through polarization tumor-associated macrophages into M1 subtype. However, engineering SF into multifunctional nanocomposites is seldom reported for combination tumor therapy. In another aspect, disruption of redox homeostasis becomes increasingly attractive for tumor suppression with high clinical-relevance. Herein, we established a newfashioned NMOF nanosystem, named as NST, for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy. This platform takes advantages of Fe/Fe coupled Fenton-like reaction and GSH depletion, as well as TCPP-mediated photosensitization for admirable redox unbalancing, which further initiates hypoxia-relevant toxin of TPZ for chemotherapy. Finally, combinatorial treatments and the presence of SF could trigger ICD for rendering a complete tumor eradication in vivo.
Topics: Antineoplastic Agents; Cell Line, Tumor; Fibroins; Humans; Metal-Organic Frameworks; Nanoparticles; Neoplasms; Oxidation-Reduction; Photochemotherapy; Tirapazamine
PubMed: 34775125
DOI: 10.1016/j.actbio.2021.11.009 -
Science Advances Mar 2021Various cancers treated with cisplatin almost invariably develop drug resistance that is frequently caused by substantial DNA repair. We searched for acquired...
Various cancers treated with cisplatin almost invariably develop drug resistance that is frequently caused by substantial DNA repair. We searched for acquired vulnerabilities of cisplatin-resistant cancers to identify undiscovered therapy. We herein found that cisplatin resistance of cancer cells comes at a fitness cost of increased intracellular hypoxia. Then, we conceived an inspired strategy to combat the tumor drug resistance by exploiting the increased intracellular hypoxia that occurs as the cells develop drug resistance. Here, we constructed a hypoxia-amplifying DNA repair-inhibiting liposomal nanomedicine (denoted as HYDRI NM), which is formulated from a platinum(IV) prodrug as a building block and payloads of glucose oxidase (GOx) and hypoxia-activatable tirapazamine (TPZ). In studies on clinically relevant models, including patient-derived organoids and patient-derived xenograft tumors, the HYDRI NM is able to effectively suppress the growth of cisplatin-resistant tumors. Thus, this study provides clinical proof of concept for the therapy identified here.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cisplatin; DNA Repair; Humans; Hypoxia; Nanomedicine; Neoplasms; Tirapazamine
PubMed: 33771859
DOI: 10.1126/sciadv.abc5267 -
Frontiers in Bioengineering and... 2023Cancer selectivity, including targeted internalization and accelerated drug release in tumor cells, remains a major challenge for designing novel stimuli-responsive...
Cancer selectivity, including targeted internalization and accelerated drug release in tumor cells, remains a major challenge for designing novel stimuli-responsive nanocarriers to promote therapeutic efficacy. The hypoxic microenvironment created by photodynamic therapy (PDT) is believed to play a critical role in chemoresistance. We construct dual-responsive carriers (NP) that encapsulate the photosensitizer chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) to enable efficient PDT and PDT-boosted hypoxia-activated chemotherapy. Due to TAT masking, NP prolonged payload circulation in the bloodstream, and selective tumor cell uptake occurred via acidity-triggered TAT presentation. PDT was performed with a spatially controlled 660-nm laser to enable precise cell killing and exacerbate hypoxia. Hypoxia-responsive conversion of the hydrophobic NI moiety led to the disassembly of NP, facilitating TPZ release. TPZ was reduced to cytotoxic radicals under hypoxic conditions, contributing to the chemotherapeutic cascade. This work offers a sophisticated strategy for programmed chemo-PDT.
PubMed: 37362218
DOI: 10.3389/fbioe.2023.1197404 -
Biomaterials Science Aug 2019Tumor hypoxia, which is indispensable to tumor propagation and therapy resistance, has been one of the most important factors influencing clinical outcomes. To modulate...
Tumor hypoxia, which is indispensable to tumor propagation and therapy resistance, has been one of the most important factors influencing clinical outcomes. To modulate the hypoxia microenvironment, we herein developed reactive oxygen species (ROS)-sensitive arylboronic ester-based biomimetic nanocarriers co-encapsulated with a photosensitizer chlorin e6 (Ce6) and a hypoxia-activated prodrug tirapazamine (TPZp) for tumor-specific release and synergistic photodynamic chemotherapy. In order to bypass macrophage uptake and improve tumor penetration, the nanocarriers were further modified with the red blood cell membrane and iRGD peptide (denoted as NPs@i-RBMCe6+TPZp). After administration, NPs@i-RBMCe6+TPZp exhibited prolonged blood circulation, selective tumor accumulation and excellent penetration into the tumor interior. Upon light irradiation, ROS were generated by Ce6 for photodynamic therapy (PDT), which subsequently caused dissociation of the ROS-responsive nanocarriers. An enhanced therapeutic effect was further achieved through the activation of TPZp in the aggravated local hypoxia microenvironment. The synergistic cancer therapy based on NPs@i-RBMCe6+TPZp significantly suppressed tumor growth with negligible side effects. The biomimetic nanocarriers have great potential to overcome hypoxia-limited PDT, and significantly improve the anticancer efficacy by synergistic tumor-targeted PDT and hypoxia-activated chemotherapy.
Topics: Animals; Antineoplastic Agents; Biomimetic Materials; Breast Neoplasms; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Carriers; Drug Screening Assays, Antitumor; Female; Mice; Molecular Structure; Nanoparticles; Photochemotherapy; Photosensitizing Agents; Prodrugs; Reactive Oxygen Species; Structure-Activity Relationship; Tirapazamine
PubMed: 31187794
DOI: 10.1039/c9bm00634f -
Journal of Materials Chemistry. B Nov 2021Multimodal synergistic therapy has gained increasing attention in cancer treatment to overcome the limitations of monotherapy and achieve high anticancer efficacy. In...
A triple-stimulus responsive melanin-based nanoplatform with an aggregation-induced emission-active photosensitiser for imaging-guided targeted synergistic phototherapy/hypoxia-activated chemotherapy.
Multimodal synergistic therapy has gained increasing attention in cancer treatment to overcome the limitations of monotherapy and achieve high anticancer efficacy. In this study, a synergistic phototherapy and hypoxia-activated chemotherapy nanoplatform based on natural melanin nanoparticles (MPs) loaded with the bioreduction prodrug tirapazamine (TPZ) and decorated with hyaluronic acid (HA) was developed. A self-reporting aggregation-induced emission (AIE)-active photosensitizer (PS) (BATTMN) was linked to the prepared nanoparticles by boronate ester bonds. The MPs and BATTMN-HA played roles as quenchers for PS and cancer targeting/photodynamic moieties, respectively. As a pH sensitive bond, the borate ester bonds between HA and BATTMN are hydrolysed in the acidic cancer environment, thereby separating BATTMN from the nanoparticles and leading to the induction of fluorescence for imaging-guided synergistic phototherapy/hypoxia-activated chemotherapy under dual irradiation. TPZ can be released upon activation by pH, near-infrared (NIR) and hyaluronidase (Hyal). Particularly, the hypoxia-dependent cytotoxicity of TPZ was amplified by oxygen consumption in the tumor intracellular environment induced by the AIE-active PS in photodynamic therapy (PDT). The nanoparticles developed in our research showed favorable photothermal conversion efficiency ( = 37%), desired cytocompatibility, and excellent synergistic therapeutic efficacy. The proposed nanoplatform not only extends the application scope of melanin materials with AIE-active PSs, but also offers useful insights into developing multistimulus as well as multimodal synergistic tumor treatment.
Topics: Animals; Antineoplastic Agents; Boronic Acids; Combined Modality Therapy; Drug Carriers; Drug Therapy; Female; Humans; MCF-7 Cells; Melanins; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Photosensitizing Agents; Photothermal Therapy; Prodrugs; Tirapazamine; Tumor Hypoxia; Xenograft Model Antitumor Assays; Mice
PubMed: 34693960
DOI: 10.1039/d1tb01657a -
Advanced Healthcare Materials Jan 2020Sonodynamic therapy (SDT) shows tremendous potential to induce immunogenic cell death (ICD) and activate antitumor immunity. However, it can aggravate hypoxia and...
Sonodynamic therapy (SDT) shows tremendous potential to induce immunogenic cell death (ICD) and activate antitumor immunity. However, it can aggravate hypoxia and release platelet (PLT)-associated danger-associated molecular patterns (DAMPs), which impede therapeutic efficacy and promote tumor metastasis. In order to solve these problems, a biomimetic decoy (designated as Lipo-Ce6/TPZ@M ) is constructed to reverse the drawbacks of SDT by loading sonosensitizer chlorin e6 (Ce6) and hypoxia-activated tirapazamine (TPZ) in the red blood cells-PLTs hybrid membrane (M )-camouflaged pH-sensitive liposome. After administration, the decoy exhibits enhanced cancer accumulation and retention abilities due to the immune escape and specific targeting behaviors by biomimetic surface coating. Upon local ultrasound, Ce6 produces toxic reactive oxygen species for SDT, and the resulting hypoxia microenvironment activates TPZ, which can realize a high-effective synergistic therapy. Meanwhile, DAMPs-mediated tumor metastasis is significantly inhibited, because the decoy retains platelet binding functions but is incapable of platelet-mediated metastasis. In addition, ICD-mediated strong antitumor immunities further prevent the growth and metastasis of the residual tumors left behind after synergistic treatment. Taken together, this study highlights the potential of using this cascade therapeutic therapy plus biomemitic decoy in one nanosystem to both eliminate melanoma in situ and suppress lung metastasis.
Topics: Animals; Antineoplastic Agents; Apoptosis; Biomimetic Materials; Cell Hypoxia; Cell Line, Tumor; Chlorophyllides; Humans; Liposomes; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Porphyrins; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Tirapazamine; Tissue Distribution; Ultrasonic Therapy; Xenograft Model Antitumor Assays
PubMed: 31762228
DOI: 10.1002/adhm.201901335 -
Small (Weinheim An Der Bergstrasse,... Aug 2020Fenton reaction-mediated chemodynamic therapy (CDT) can kill cancer cells via the conversion of H O to highly toxic HO•. However, problems such as insufficient H O...
Fenton reaction-mediated chemodynamic therapy (CDT) can kill cancer cells via the conversion of H O to highly toxic HO•. However, problems such as insufficient H O levels in the tumor tissue and low Fenton reaction efficiency severely limit the performance of CDT. Here, the prodrug tirapazamine (TPZ)-loaded human serum albumin (HSA)-glucose oxidase (GOx) mixture is prepared and modified with a metal-polyphenol network composed of ferric ions (Fe ) and tannic acid (TA), to obtain a self-amplified nanoreactor termed HSA-GOx-TPZ-Fe -TA (HGTFT) for sustainable and cascade cancer therapy with exogenous H O production and TA-accelerated Fe /Fe conversion. The HGTFT nanoreactor can efficiently convert oxygen into HO• for CDT, consume glucose for starvation therapy, and provide a hypoxic environment for TPZ radical-mediated chemotherapy. Besides, it is revealed that the nanoreactor can significantly elevate the intracellular reactive oxygen species content and hypoxia level, decrease the intracellular glutathione content, and release metal ions in the tumors for metal ion interference therapy (also termed "ion-interference therapy" or "metal ion therapy"). Further, the nanoreactor can also increase the tumor's hypoxia level and efficiently inhibit tumor growth. It is believed that this tumor microenvironment-regulable nanoreactor with sustainable and cascade anticancer performance and excellent biosafety represents an advance in nanomedicine.
Topics: Glucose; Glucose Oxidase; Humans; Hypoxia; Nanomedicine; Neoplasms; Oxygen; Tumor Microenvironment
PubMed: 32537936
DOI: 10.1002/smll.202000897