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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 -
Biomaterials Sep 2022Vascular disrupting agents (VDAs) have great potential in antitumor therapy, while the efficiency is limited by cardiovascular toxicity. In this study, a self-activating...
Vascular disrupting agents (VDAs) have great potential in antitumor therapy, while the efficiency is limited by cardiovascular toxicity. In this study, a self-activating nanoized plinabulin (poly (-glutamic acid) grafted Azo-Plinabulin, AzoP-NP) was constructed. The AzoP-NPs can selectively be activated to an amino derivative of plinabulin (AmP) by intrinsic tumor hypoxia, disrupting tumor vessels and amplifying hypoxia, whilst be activated by self-amplified tumor hypoxia, then selectively inhibit tumor growth. In 4T1 tumor model, the AzoP-NPs had a selective biodistribution in tumor, as the free AmP in tumors at 24 h after AzoP-NPs treatment was 18.6 fold of that after AmP treatment and significantly higher than that in other tissues. Accordingly, AzoP-NPs resulted in no obvious acute cardiovascular toxicity (plasma von Willebrand factor in PBS, AzoP-NPs and AmP group: 143.1, 184.0 and 477.6 ng/mL) and a significantly stronger tumor inhibition than AmP. And the sustained release of drug in AzoP-NPs led to a higher maximum tolerated dose (MTD) (MTD of AzoP-NPs and AmP: > 80 vs 20 mg/kg). In addition, AzoP-NPs amplified tumor hypoxic, and synergized the anti-tumor effect of Tirapazamine (TPZ), a hypoxia-activated drug in clinical trials, with an inhibition rate of 97.7% and Q value of 1.89. Therefore, our findings provide new insights into next generation VDAs and their application in tumor therapy.
Topics: Animals; Mice; Antineoplastic Agents; Cell Line, Tumor; Hypoxia; Mice, Inbred BALB C; Tissue Distribution
PubMed: 35995623
DOI: 10.1016/j.biomaterials.2022.121736 -
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 -
ACS Applied Materials & Interfaces Sep 2023The ordered and directed functionalization of targeting elements on the surface of nanomaterials for precise tumor therapy remains a challenge. To address the above...
The ordered and directed functionalization of targeting elements on the surface of nanomaterials for precise tumor therapy remains a challenge. To address the above problem, herein, we adopted a materials-based synthetic biotechnology strategy to fabricate a bioengineered fusion protein of materials-binding peptides and targeting elements, which can serve as a "molecular glue" to achieve a directional and organized assembly of targeting biological macromolecules on the surface of nanocarriers. The hypoxia microenvironment of solid tumors inspired the rapid development of starvation/chemosynergistic therapy; however, the unsatisfied spatiotemporal specific performance hindered its further development in precise tumor therapy. As a proof of concept, a bioengineered fusion protein containing a dendritic mesoporous silicon (DMSN)-binding peptide, and a tumor-targeted and acidity-decomposable ferritin heavy chain 1 (FTH1), was constructed by fusion expression and further assembled on the surface of DMSN companying with the insertion of hypoxia-activated prodrug tirapazamine (TPZ) and glucose oxidase (GOX) to establish a nanoreactor for precise starvation/chemosynergistic tumor therapy. In this context, the as-prepared therapeutic nanoreactors revealed obvious tumor-specific accumulation and an endocytosis effect. Next, the acidic tumor microenvironment triggered the structural collapse of FTH1 and the subsequent release of GOX and TPZ, in which GOX-mediated catalysis cut off the nutrition supply to realize starvation therapy based on the consumption of endogenous glucose and further provided an exacerbated hypoxia environment for TPZ in situ activation to initiate tumor chemotherapy. More significantly, the presence of "molecular glue" elevated the tumor-targeting capacity of nanoreactors and further enhanced the starvation/chemosynergistic therapeutic effect remarkably, suggesting that such a strategy provided a solution for the functionality of nanomaterials and facilitated the design of novel targeting nanomedicines. Overall, this study highlights materials-binding peptides as a new type of "molecular glue" and opens new avenues for designing and exploring active biological materials for biological functions and applications.
Topics: Humans; Biomedical Engineering; Neoplasms; Biotechnology; Glucose Oxidase; Hypoxia; Nanomedicine; Tumor Microenvironment
PubMed: 37622208
DOI: 10.1021/acsami.3c06871 -
Biochemical and Biophysical Research... Aug 2021Osteosarcoma is the most common primary orthopedic malignant bone tumor in adolescents. However, the traditional neoadjuvant chemotherapy regimen has reached the...
Osteosarcoma is the most common primary orthopedic malignant bone tumor in adolescents. However, the traditional neoadjuvant chemotherapy regimen has reached the bottleneck. TPZ is a hypoxic prodrug that has a powerful anti-tumor effect in the hypoxic microenvironment of tumors. And ferroptosis is a newly discovered cell death in 2012, and ferroptosis inducers have been used in anti-tumor therapy research in recent decades. Though, the role of TPZ and ferroptosis in osteosarcoma remains unclear. The aim of this study was to investigate the role of TPZ in osteosarcoma and the specific mechanism. MTT assay showed the extraordinary inhibition of TPZ on three osteosarcoma cells under hypoxia. And fluorescence of Fe staining was enhanced by TPZ. Western blotting showed decreased expression of SLC7A11 and GPX4. Lipid peroxidation was confirmed by MDA assay and C11 BODIPY 581/591 staining. SLC7A11 overexpression could restored the proliferation and migration abilities inhibited by TPZ. Thus, we for the first time demonstrated that TPZ could inhibit the proliferation and migration of osteosarcoma cells, and induce ferroptosis in part through inhibiting SLC7A11.
Topics: Amino Acid Transport System y+; Antineoplastic Agents; Bone Neoplasms; Cell Line, Tumor; Ferroptosis; Humans; Osteosarcoma; Tirapazamine
PubMed: 34147710
DOI: 10.1016/j.bbrc.2021.06.036 -
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 -
Acta Pharmaceutica Sinica. B Aug 2020Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy (PDT) suffers from the... (Review)
Review
Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy (PDT) suffers from the undesirable impediment of local hypoxia in tumors. Moreover, PDT could further worsen hypoxia. Therefore, developing effective strategies for manipulating hypoxia and improving the effectiveness of PDT has been a focus on antitumor treatment. In this review, the mechanism and relationship of tumor hypoxia and PDT are discussed. Moreover, we highlight recent trends in the field of nanomedicines to modulate hypoxia for enhancing PDT, such as oxygen supply systems, down-regulation of oxygen consumption and hypoxia utilization. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of PDT.
PubMed: 32963938
DOI: 10.1016/j.apsb.2020.01.004 -
ACS Applied Materials & Interfaces Aug 2023Therapeutic bioactive macromolecules hold great promise in cancer therapy, but challenges such as low encapsulation efficiency and susceptibility to inactivation during...
Therapeutic bioactive macromolecules hold great promise in cancer therapy, but challenges such as low encapsulation efficiency and susceptibility to inactivation during the targeted co-delivery hinder their widespread applications. Compartmentalized nano-metal-organic frameworks (nMOFs) can easily load macromolecules in the innermost layer, protect them from the outside environment, and selectively release them in the target location after stimulation, showing great potential in the co-delivery of biomacromolecules. Herein, the rationally designed (GOx + CAT)/ZIF-8@BSA/ZIF-8 (named GCZ@BTZ) nMOFs with compartmentalized structures are employed to deliver cascaded enzymes and the chemotherapeutic drug tirapazamine (TPZ)-conjugated bovine serum albumin (BSA). Benefiting from the compartmentalized structure and protective shell, the GCZ@BTZ system is stable during blood circulation and preferentially accumulates in the tumor. Furthermore, in response to the acidic tumor environment, GCZ@BTZ effectively released the loading enzymes and BSA. Along with the tumor starvation caused by depletion of glucose, cascaded reactions could also contribute to the enhancement of tumor hypoxia, which further activated BSA-based chemotherapy. Notably, in the mouse tumor models, GCZ@BTZ treatment significantly inhibits tumor survival and metastasis. Such a compartmentalized nMOF delivery system presents a promising avenue for the efficient delivery of bioactive macromolecules.
Topics: Animals; Mice; Neoplasms; Tirapazamine; Metal-Organic Frameworks; Drug Delivery Systems
PubMed: 37552806
DOI: 10.1021/acsami.3c04296 -
Colloids and Surfaces. B, Biointerfaces Apr 2021Radiotherapy (RT) is becoming a pervasive therapeutic pattern in clinical cancer therapy. However, the hypoxic microenvironment of tumors has a strong resistance to...
Radiotherapy (RT) is becoming a pervasive therapeutic pattern in clinical cancer therapy. However, the hypoxic microenvironment of tumors has a strong resistance to radiotherapy and could lead to a potential recurrence and metastasis after the treatment. Therefore, the use of synergistic strategies for improving and supplementing the RT efficiency is important. Herein, a novel BiS/alginate (ALG) hydrogel containing tirapazamine (TPZ) was designed for the effective suppression of tumor recurrence, by introducing Bi into the ALG, NaS and TPZ solution. In this formulation, Bi was used to crosslink with the ALG to form the hydrogel and react with S to simultaneously form BiS nanoparticles in the hydrogel matrix. The resulting BiS nanoparticles not only exhibit the superb radiosensitization effect to boost the effective eradication of tumors during RT but also manifest an excellent photothermal transforming performance for tumor hyperthermia and computed tomography (CT) imaging capacity for tumor monitoring. Furthermore, the RT caused hypoxia could activate the reductive prodrug TPZ and enhance its therapeutic efficiency. The reported hydrogel system provides an efficient and safe therapeutic strategy for current local tumor therapy.
Topics: Cell Line, Tumor; Humans; Hydrogels; Hyperthermia, Induced; Neoplasms; Prodrugs; Tirapazamine; Tumor Microenvironment
PubMed: 33548893
DOI: 10.1016/j.colsurfb.2021.111591 -
Journal of Nanobiotechnology Jan 2022Chemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, as toxic hydroxyl radical (·OH) could only be generated by Fenton...
BACKGROUND
Chemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, as toxic hydroxyl radical (·OH) could only be generated by Fenton or Fenton-like reaction in the tumor microenvironment (TME) with low pH and high level of endogenous hydrogen peroxide. However, the low concentration of catalytic metal ions, excessive glutathione (GSH) and aggressive hypoxia at tumor site seriously restrict the curative outcomes of conventional chemodynamic therapy.
RESULTS
In this study, polyethylene glycol-phenylboronic acid (PEG-PBA)-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were synthesized as a targeted nanocarrier to chelate Cu(II) and then encapsulate hypoxia-sensitive drug tirapazamine (TPZ) by the formation of hydrophobic Cu(II)/TPZ complex for hypoxia-enhanced chemo/chemodynamic therapy. The formed G5.NHAc-PEG-PBA@Cu(II)/TPZ (GPPCT) nanoplatform has good stability and hemocompatibility, and could release Cu(II) ions and TPZ quickly in weakly acidic tumor sites via pH-sensitive dissociation of Cu(II)/TPZ. In vitro experiments showed that the GPPCT nanoplatforms can efficiently target murine breast cancer cells (4T1) cells overexpressing sialic acid residues, and show a significantly enhanced inhibitory effect on hypoxic cells by the activation of TPZ. The excessive GSH in tumors could be depleted by the reduction of Cu(II) to Cu(I), and abundant of toxic ·OH would be generated in tumor cells by Fenton reaction for chemodynamic therapy. In vivo experiments demonstrated that the GPPCT nanoplatform could specifically accumulate at tumors, effectively inhibit the growth and metastasis of tumors by the combination of CDT and chemotherapy, and be metabolized with no systemic toxicity.
CONCLUSIONS
The targeted GPPCT nanoplatform may represent an effective model for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Dendrimers; Mice; Nanostructures; Tirapazamine; Tumor Microenvironment
PubMed: 35062953
DOI: 10.1186/s12951-022-01247-6