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Journal of Vascular and Interventional... Aug 2022To investigate the safety of replacing doxorubicin with tirapazamine in conventional transarterial chemoembolization (TACE) in an Asian population with hepatocellular...
PURPOSE
To investigate the safety of replacing doxorubicin with tirapazamine in conventional transarterial chemoembolization (TACE) in an Asian population with hepatocellular carcinoma (HCC), and to determine the optimal tirapazamine dose for phase II studies.
MATERIALS AND METHODS
This was a phase I, 3 + 3 dose-escalation study for patients with unresectable early- and intermediate-stage HCC who received 5, 10, or 20 mg/m of intra-arterial (IA) tirapazamine followed by ethiodized oil/gelatin sponge-based embolization. Key eligibilities included HCCs no more than 10 cm in diameter, prior embolization allowed, Eastern Cooperative Oncology Group performance status of 0 or 1, Child-Pugh score of 5-7, and platelet count of ≥60,000 μL. Dose-limiting toxicity (DLT) was defined as any grade 3 nonhematological or grade 4 hematological toxicity, with the exception of transient elevation of aminotransferase levels after the procedure.
RESULTS
Seventeen patients were enrolled, 59% of whom had progression from a prior HCC therapy and 35% of whom had progression or recurrence after TACE. All patients tolerated the tirapazamine TACE well without any DLT or serious adverse event. Using the modified Response Evaluation Criteria in Solid Tumors, the complete response (CR) rate was 47%, and the CR + partial response rate was 65%. The median duration of response was not reached. The median time to progression was 12.6 months (95% confidence interval, 5.1-not reached). The median overall survival was 29.3 months. The selected phase II dose was set at a fixed dose of 35 mg of IA tirapazamine.
CONCLUSIONS
IA tirapazamine with transarterial embolization was well tolerated and showed promising efficacy signals in intermediate-stage HCC, justifying pursuit of a phase II study.
Topics: Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Ethiodized Oil; Humans; Liver Neoplasms; Tirapazamine; Treatment Outcome
PubMed: 35504436
DOI: 10.1016/j.jvir.2022.04.031 -
Journal of Materials Chemistry. B May 2022With the advantages of deep tissue penetration and controllability, external X-ray-induced photodynamic therapy (X-PDT) is highly promising for combined cancer therapy....
With the advantages of deep tissue penetration and controllability, external X-ray-induced photodynamic therapy (X-PDT) is highly promising for combined cancer therapy. In addition to the low efficiency of photosensitizer (PS) delivery to tumor sites, however, the radiation- and drug-resistance of hypoxic cells inside the tumor after X-PDT also limit its benefits. Herein, we develop a combined therapeutic modality based on an intelligent nanosized platform (TAT-NP) with tumor acidity-activated TAT presenting and redox-boosted release of tirapazamine (TPZ) for more precise and synchronous X-PDT and selective hypoxia-motivated chemotherapy. After TAT-NP has accumulated in tumor tissues decreased blood clearance by masking of the TAT ligand, its targeting ability is reactivated by tumor pH (∼6.8), which enhances tumoral cellular uptake. Upon low-dose X-ray irradiation, the encapsulated verteporfin (VP) generates reactive oxygen species (ROS) to carry out X-PDT against MDA-MB-231 breast tumors. As a result of the abundant GSH-triggered degradation of ditelluride bridged bonds, the cascaded TPZ release and activation in the hypoxic environment following X-PDT would produce highly cytotoxic radicals to serve as antitumor agents to kill the remaining hypoxic tumor cells. This concept provides new avenues for the design of hierarchical-responsive drug delivery systems and represents a proof-of-concept combinatorial tumor treatment.
Topics: Antineoplastic Agents; Cell Line, Tumor; Humans; Hypoxia; Nanoparticles; Oxidation-Reduction; Photochemotherapy; Tirapazamine; X-Rays
PubMed: 35470367
DOI: 10.1039/d2tb00303a -
Pharmaceutics Apr 2022Tumor hypoxia is a hallmark of solid tumors and emerged as the therapeutic target for cancer treatments, such as a prodrug Tirapazamine (TPZ) activated in hypoxia. To...
Tumor hypoxia is a hallmark of solid tumors and emerged as the therapeutic target for cancer treatments, such as a prodrug Tirapazamine (TPZ) activated in hypoxia. To increase tumor accumulation, gold nanoparticles (GNPs) were selected to conjugate with TPZ. In this study, we successfully formulated and assessed the biochemical and therapeutic roles of the conjugated gold nanoparticles-Tirapazamine (GNPs-TPZ) on therapeutic assessments of MKN45-induced xenograft animal model. The results indicated that GNPs-TPZ was a potential nanomedicine for selectively targeting hypoxia tumors coupled with decreased side effects on healthy tissue or organs. TPZ significantly reduced cell viability of hypoxic gastric cancer MKN45 cells, but not in cells incubated in normoxia condition. For improving tumor targeting efficiency, furthermore, the GNPs drug carrier was conjugated to TPZ via biding mediator bovine serum albumin (BSA), and we demonstrated that this conjugated GNPs-TPZ retained the unique characteristics of hypoxic toxin and possessed the adequate feature of systemic bio-distributions in animals. GNPs-TPZ nanoparticles revealed their superior affinity to hypoxia tumors in the MKN45 xenograft. Moreover, GNPs-TPZ treatments did not significantly alter the biochemical parameters of blood samples acquired from animals. Taken together, TPZ, a prodrug activated by hypoxia, was conjugated with GNPs, whereas BSA severed as an excellent binding agent for preparing the conjugated GNPs-TPZ nanomedicines. We demonstrated that GNPs-TPZ enhanced tumor targeting, resulting in higher therapeutic efficacy compared to TPZ. We suggest that it may sever as an adjuvant treatment or combined therapy with other chemotherapeutics for the treatment of cancer patients in the future.
PubMed: 35456681
DOI: 10.3390/pharmaceutics14040847 -
Journal of Pharmacy & Bioallied Sciences 2021Tumor hypoxia, a predominant feature of solid tumor produces drug resistance that significantly impacts a patient's clinical outcomes. Hypoxia-inducible factor 1-alpha...
OBJECTIVE
Tumor hypoxia, a predominant feature of solid tumor produces drug resistance that significantly impacts a patient's clinical outcomes. Hypoxia-inducible factor 1-alpha (HIF1α) is the major mutation involved in establishing the microenvironment. As a consequence of its involvement in pathways that enable rapid tumor growth, it creates resistance to chemotherapeutic treatments. The propensity of medications to demonstrate drug action often diverges according to the genetic composition. The aim of this study is therefore to examine the effect of population-dependent drug response variations using mutation models.
METHODS
Genetic variations distinctive to major super-populations were identified, and the mutated gene was acquired as a result of incorporating the variants. The mutated gene sequence was transcribed and translated to obtain the target amino acid sequence. To investigate the effects of mutations, protein models were developed using homology modeling. The target templates for the backbone structure were identified by characterization of primary and secondary protein structures. The modeled proteins were then validated for structural confirmation and flexibility. Potential models were used for interaction studies with hypoxia-specific molecules (tirapazamine, apaziquone, and ENMD) using docking analysis. To verify their stability under pre-defined dynamic conditions, the complexes were subjected to molecular dynamics simulation.
RESULTS
The current research models demonstrate with the pharmacogenomic-based mutation of HIF1α the impact of individual variants in altering the person-specific drug response under tumor hypoxic conditions. It also elucidates that the therapeutic effect is altered concerning population-dependent genetic changes in the individual.
CONCLUSION
The study, therefore, asserts the need to set up a personalized drug design approach to enhance tumor hypoxia treatment efficacy.
PubMed: 35399804
DOI: 10.4103/jpbs.jpbs_766_21 -
Biomaterials Science May 2022Employing hypoxia-activated prodrugs is an appealing oncotherapy strategy, but limited by insufficient tumor hypoxia. Moreover, a standalone prodrug fails to treat...
Employing hypoxia-activated prodrugs is an appealing oncotherapy strategy, but limited by insufficient tumor hypoxia. Moreover, a standalone prodrug fails to treat tumors satisfactorily due to tumor complexity. Herein, a nanosystem (TPZ@FeMSN-GOX) was established for triple synergetic cancer starvation therapy, hypoxia-activated chemotherapy and chemodynamic therapy (CDT). TPZ@FeMSN-GOX was prepared by synthesizing iron-doped mesoporous silica nanoparticles (FeMSNs) followed by surface conjugation with glucose oxidase (GOX), and then loading with hypoxia-activated prodrug tirapazamine (TPZ). When TPZ@FeMSN-GOX entered the tumor cells, GOX could not only exhaust glucose to starve cancer cells and concomitantly produce HO, but also consume O to aggravate the hypoxia environment and amplify TPZ-mediated chemotherapy. Meanwhile, the released Fe was reduced to reactive Fe by endogenous glutathione, which ultimately decomposed the produced HO and endogenous HO into highly toxic ˙OH, guaranteeing highly efficient CDT. Together, TPZ@FeMSN-GOX could effectively kill cancer cells and significantly inhibit tumor growth, providing a good paradigm for effective tumor treatment.
Topics: Cell Line, Tumor; Glucose; Glucose Oxidase; Humans; Hydrogen Peroxide; Hypoxia; Nanoparticles; Neoplasms; Prodrugs; Tirapazamine
PubMed: 35383789
DOI: 10.1039/d1bm01944a -
ACS Biomaterials Science & Engineering May 2022The integration of reactive oxygen species (ROS)-based chemodynamic therapy (CDT) and photodynamic therapy (PDT) has attracted enormous attention for synergistic...
The integration of reactive oxygen species (ROS)-based chemodynamic therapy (CDT) and photodynamic therapy (PDT) has attracted enormous attention for synergistic antitumor therapies. However, the strategy is severely hampered by tumor hypoxia and overproduced antioxidant glutathione (GSH) in the tumor microenvironment. Inspired by the concept of metal coordination-based nanomedicines, we proposed an effective strategy for synergistic cancer treatment in response to the special tumor microenvironmental properties. Herein, we present novel metal-coordinated multifunctional nanoparticles (NPs) by the Cu-triggered assembly of photosensitizer indocyanine green (ICG) and hypoxia-activated anticancer prodrug tirapazamine (TPZ) (Cu-ICG/TPZ NPs). After accumulating within tumor sites the enhanced permeability and retention (EPR) effect, the Cu-ICG/TPZ NPs were capable of triggering a cascade of combinational therapeutic reactions, including hyperthermia, GSH elimination, and Cu-mediated OH generation and the subsequent hypoxia-triggered chemotherapeutic effect of TPZ, thus achieving synergistic tumor therapy. Both and evaluations suggested that the multifunctional Cu-ICG/TPZ NPs could realize satisfactory therapeutic efficacy with excellent biosafety. These results thus suggested the great potential of Cu-ICG/TPZ NPs to serve as a metallodrug nanoagent for synergetically enhanced tumor treatment.
Topics: Glutathione; Humans; Hypoxia; Indocyanine Green; Multifunctional Nanoparticles; Neoplasms; Tirapazamine; Tumor Microenvironment
PubMed: 35357802
DOI: 10.1021/acsbiomaterials.2c00076 -
ACS Biomaterials Science & Engineering Apr 2022The low sensitivity of hypoxic regions in solid tumors to radiotherapy and chemotherapy remains a major obstacle to cancer treatment. By taking advantage of...
The low sensitivity of hypoxic regions in solid tumors to radiotherapy and chemotherapy remains a major obstacle to cancer treatment. By taking advantage of hypoxic-activated prodrugs, tirapazamine (TPZ), generating cytotoxic reductive products and the glucose oxidase (GO)-based glucose oxidation reaction, we designed a nanodrug-loading system that combined TPZ-induced chemotherapy with GO-mediated cancer-orchestrated starvation therapy and cancer oxidation therapy. In this work, we first prepared mesoporous silica (MSN) loaded with TPZ. Then, in order to prevent the leakage of TPZ in advance, the surface was coated with a layer of carMOF formed by Fe and carbenicillin (car), and GO was adsorbed on the outermost layer to form the final nanosystem MSN-TPZ@carMOF-GO (MT@c-G). GO could effectively consume oxygen and catalyzed glucose into gluconic acid and hydrogen peroxide. First, the generated gluconic acid lowered the pH of tumor tissues, promoted the decomposition of carMOF, and released TPZ. Second, oxygen consumption could improve the degree of hypoxia in tumor tissues, so that enhanced the activity of TPZ. Furthermore, GO could generate cancer-orchestrated starvation/oxidation therapy. Therefore, our study provided a new strategy that TPZ combined with GO achieved starvation/oxidation/chemotherapy for enhancing anticancer effects in hypoxic regions.
Topics: Cell Line, Tumor; Glucose; Humans; Hypoxia; Prodrugs; Tirapazamine
PubMed: 35348331
DOI: 10.1021/acsbiomaterials.2c00104 -
Biofabrication Apr 2022cancer models that can simulate patient-specific drug responses for personalized medicine have attracted significant attention. However, the technologies used to produce...
cancer models that can simulate patient-specific drug responses for personalized medicine have attracted significant attention. However, the technologies used to produce such models can only recapitulate the morphological heterogeneity of human cancer tissue. Here, we developed a novel 3D technique to bioprint anbreast cancer model with patient-specific morphological features. This model can precisely mimic the cellular microstructures of heterogeneous cancer tissues and produce drug responses similar to those of human cancers. We established a bioprinting process for generating cancer cell aggregates with ductal and solid tissue microstructures that reflected the morphology of breast cancer tissues, and applied it to develop breast cancer models. The genotypic and phenotypic characteristics of the ductal and solid cancer aggregates bioprinted with human breast cancer cells (MCF7, SKBR3, MDA-MB-231) were respectively similar to those of early and advanced cancers. The bioprinted solid cancer cell aggregates showed significantly higher hypoxia (>8 times) and mesenchymal (>2-4 times) marker expressions, invasion activity (>15 times), and drug resistance than the bioprinted ductal aggregates. Co-printing the ductal and solid aggregates produced heterogeneous breast cancer tissue models that recapitulated three different stages of breast cancer tissue morphology. The bioprinted cancer tissue models representing advanced cancer were more and less resistant, respectively, to the anthracycline antibiotic doxorubicin and the hypoxia-activated prodrug tirapazamine; these were analogous to the results in human cancer. The present findings showed that cancer cell aggregates can mimic the pathological micromorphology of human breast cancer tissue and they can be bioprinted to produce breast cancer tissuethat can morphologically represent the clinical stage of cancer in individual patients.
Topics: Bioprinting; Breast Neoplasms; Female; Humans; Hypoxia; Precision Medicine; Printing, Three-Dimensional; Tissue Engineering
PubMed: 35334470
DOI: 10.1088/1758-5090/ac6127 -
Journal of Molecular Modeling Mar 2022New data on 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine) fluorescence has been obtained using the Perkin-Elmer Lambda 950 UV-Vis-NIR spectrophotometer...
New data on 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine) fluorescence has been obtained using the Perkin-Elmer Lambda 950 UV-Vis-NIR spectrophotometer experimental technique in combination with the extensive DFT-theory approach. Based on the results obtained, we revealed that the optical properties of the molecule under study remain significantly unchanged when the number of oxygen substitutions decreases from 2 to 0. Here we also present the results of the study of the influence of acetonitrile and ethyl acetate on the fluorescence of tirapazamine with the different number of oxygen atoms. Results of our investigation indicate the formation of anion in the case of 3-amino-1,2,4-benzotriazine 1,4-dioxide with two oxygen atoms and their transformation to tirapazamine with one oxygen atom.
Topics: Antineoplastic Agents; Oxygen; Tirapazamine; Triazines
PubMed: 35320419
DOI: 10.1007/s00894-022-05085-z -
Frontiers in Bioengineering and... 2022In recent years, sonodynamic therapy (SDT) has been widely developed for cancer research as a promising non-invasive therapeutic strategy. Here, we synthesized zeolitic...
In recent years, sonodynamic therapy (SDT) has been widely developed for cancer research as a promising non-invasive therapeutic strategy. Here, we synthesized zeolitic imidazole frameworks-8 (ZIF-8) and utilized its properties to encapsulate hydrophobic Chlorin e6 (Ce6) and hydrophilic tirapazamine (TPZ) for a synergistic sonodynamic chemotherapy, which was also accompanied by the modification of cytomembrane of gastric cancer (GC) cells. Thus, we enabled the biomimetic property to achieve targeted delivery. Ce6-mediated SDT, in combination with ultrasound irradiation, could target the release of reactive oxygen species (ROS) to aggravate further hypoxia and activate TPZ. Combining these effects could induce the pyroptosis of GC cells and play the anti-tumor function, which could provide a potential therapeutic method for cancer therapy.
PubMed: 35265591
DOI: 10.3389/fbioe.2022.796820