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Advanced Materials (Deerfield Beach,... Oct 2021One of the main challenges for tumor vascular infarction in combating cancer lies in failing to produce sustained complete thrombosis. Inspired by the capability of...
One of the main challenges for tumor vascular infarction in combating cancer lies in failing to produce sustained complete thrombosis. Inspired by the capability of vascular infarction in blocking the delivery of oxygen to aggravate tumor hypoxia, the performance of selective tumor thrombus inducing hypoxia activation therapy to improve the therapeutic index of coagulation-based tumor therapy is presented. By encapsulating coagulation-inducing protease thrombin and a hypoxia-activated prodrug (HAP) tirapazamine into metal-organic framework nanoparticles with a tumor-homing ligand, the obtained nanoplatform selectively activates platelet aggregation at the tumor to induce thrombosis and vascular obstruction therapy by the exposed thrombin. Meanwhile, the thrombus can cut off the blood oxygen supply and potentiate the hypoxia levels to enhance the HAP therapy. This strategy not only addresses the dissatisfaction of vascular therapy, but also conquers the dilemma of inadequate hypoxia in HAP treatment. Since clinical operations such as surgery can be used to induce coagulation, coagulation-based synergistic therapy is promising for translation into a clinical combination regimen.
Topics: Animals; Cell Survival; Hep G2 Cells; Humans; Metal-Organic Frameworks; Mice; Mice, Nude; Nanoparticles; Neoplasms; Platelet Aggregation; Prodrugs; Thrombin; Thrombosis; Tirapazamine; Transplantation, Heterologous; Tumor Hypoxia
PubMed: 34436814
DOI: 10.1002/adma.202104504 -
ACS Nano Oct 2018Shutting down glucose supply by glucose oxidase (GOx) to starve tumors has been considered to be an attractive strategy in cancerous starvation therapy. Nevertheless,...
Shutting down glucose supply by glucose oxidase (GOx) to starve tumors has been considered to be an attractive strategy in cancerous starvation therapy. Nevertheless, the in vivo applications of GOx-based starvation therapy are severely restricted by the poor GOx delivery efficiency and the self-limiting therapeutic effect. Herein, a biomimetic nanoreactor has been fabricated for starvation-activated cancer therapy by encapsulating GOx and prodrug tirapazamine (TPZ) in an erythrocyte membrane cloaked metal-organic framework (MOF) nanoparticle (TGZ@eM). The fabricated TGZ@eM nanoreactor can assist the delivery of GOx to tumor cells and then exhaust endogenous glucose and O to starve tumors efficiently. Importantly, the resulting tumor hypoxia by GOx-based starvation therapy further initiates the activation of TPZ, which is released from the nanoreactor in the acid lyso/endosome environment, for enhanced colon cancer therapy. More importantly, by integrating the biomimetic surface modification, the immunity-escaping and prolonged blood circulation characteristics endow our nanoreactor dramatically improved cancer targeting ability. The in vitro and in vivo outcomes indicate our biomimetic nanoreactor exhibits a strong synergistic cascade effect for colon cancer therapy in an accurate and facile manner.
Topics: Animals; Antineoplastic Agents; Biomimetic Materials; Cell Proliferation; Colonic Neoplasms; Drug Screening Assays, Antitumor; Erythrocyte Membrane; Female; Glucose Oxidase; Metal-Organic Frameworks; Mice; Mice, Inbred BALB C; Nanoparticles; Prodrugs; Tirapazamine; Tumor Hypoxia
PubMed: 30265804
DOI: 10.1021/acsnano.8b05200 -
Biomaterials Nov 2019Highly specific and effective cancer phototherapy remains as a great challenge. Herein, a smart nanoplatform (TENAB NP) sequentially responsive to light, low pH and...
Highly specific and effective cancer phototherapy remains as a great challenge. Herein, a smart nanoplatform (TENAB NP) sequentially responsive to light, low pH and hypoxia is demonstrated for multi-mode imaging guided synergistic cancer therapy with negligible skin phototoxicity. Upon 808-nm laser irradiation, TENAB NPs can generate hyperthermia to melt the phase change material (PCM-LASA) coat and thereafter release chemo-drug tirapazamine (TPZ). Meanwhile, under acidic pH, photosensitizer ENAB would turn "off" its charge-transfer state, generating prominent O for photodynamic therapy (PDT) and heat for photothermal therapy (PTT), respectively. Accompanied with PDT-induced hypoxia, the released TPZ can be activated into its cytotoxic form for tumor cells killing. Notably, owing to phase change material LASA coat and ENAB's pH sensitivity, TENAB NPs show negligible photosensitization to skin and normal tissues. As the multi-stimuli responsive mechanism, TENAB NPs demonstrate a promising future in cancer photo-chemo theranostics with excellent skin protection.
Topics: Animals; Drug Delivery Systems; Fatty Alcohols; Female; HeLa Cells; Humans; Linoleic Acid; Mice; Mice, Nude; Microscopy, Confocal; Photochemotherapy; Photosensitizing Agents; Skin; Tirapazamine
PubMed: 31437723
DOI: 10.1016/j.biomaterials.2019.119422 -
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 -
Materials Horizons Jul 2023Phototherapy-induced hypoxia in the tumor microenvironment (TME) is responsible for diminished therapeutic efficacy. Designing an intelligent nanosystem capable of...
Phototherapy-induced hypoxia in the tumor microenvironment (TME) is responsible for diminished therapeutic efficacy. Designing an intelligent nanosystem capable of responding to hypoxia for TME-responsive drug delivery will, to some extent, improve the therapeutic efficacy and reduce side effects. Semiconducting polymers with high photothermal conversion efficiency and photostability have tremendous potential as phototheranostics. In this paper, hypoxia-activatable tirapazamine (TPZ) was conjugated onto poly(ethylene glycol) to form a pH-sensitive poly-prodrug, PEG-TPZ, that can be triggered by the low acidity of the TME to cleave the acylamide bond for controllable drug release. PEG-TPZ was then used to encapsulate a semiconducting polymer (TDPP) for NIR-II-fluorescence-imaging-guided synergistic therapy. The reactive oxygen species (ROS) generation and ultrahigh photothermal conversion efficiency (∼58.6%) of the TDPP@PEG-TPZ NPs leads to the destruction of the tumor blood vessels, thus further activating the hypoxia-induced chemotherapy of TPZ. As a result, effective tumor regression was achieved after laser irradiation.
PubMed: 37194333
DOI: 10.1039/d3mh00242j -
CNS Neuroscience & Therapeutics Jun 2018Vulnerability to psychiatric manifestations is achieved by the influence of genetic and environment including stress and cannabis consumption. Here, we used a...
INTRODUCTION
Vulnerability to psychiatric manifestations is achieved by the influence of genetic and environment including stress and cannabis consumption. Here, we used a psychosocial stress model based on resident-intruder confrontations to study the brain corticostriatal-function, since deregulation of corticostriatal circuitries has been reported in many psychiatric disorders. CB receptors are widely expressed in the central nervous system and particularly, in both cortex and striatum brain structures.
AIMS AND METHODS
The investigation presented here is addressed to assess the impact of repeated stress following acute cannabinoid exposure on behavior and corticostriatal brain physiology by assessing mice behavior, the concentration of endocannabinoid and endocannabinoid-like molecules and changes in the transcriptome.
RESULTS
Stressed animals urinated frequently; showed exacerbated scratching activity, lower striatal N-arachidonylethanolamine (AEA) levels and higher cortical expression of cholinergic receptor nicotinic alpha 6. The cannabinoid agonist WIN55212.2 diminished locomotor activity while the inverse agonist increased the distance travelled in the center of the open field. Upon CB activation, N-oleoylethanolamide and N-palmitoylethanolamide, two AEA congeners that do not interact directly with cannabinoid receptors, were enhanced in the striatum. The co-administration with both cannabinoids induced an up-regulation of striatal FK506 binding protein 5. The inverse agonist in controls reversed the effects of WIN55212.2 on motor activity. When Rimonabant was injected under stress, the cortical levels of 2-arachidonoylglycerol were maximum. The agonist and the antagonist influenced the cortical expression of cholinergic receptor nicotinic alpha 6 and serotonin transporter neurotransmitter type 4 in opposite directions, while their co-administration tended to produce a null effect under stress.
CONCLUSIONS
The endocannabinoid system had a direct effect on serotoninergic neurotransmission and glucocorticoid signaling. Cholinergic receptor nicotinic alpha-6 was shown to be deregulated in response to stress and following synthetic cannabinoid drugs thus could confer vulnerability to cannabis addiction and psychosis. Targeting the receptors of endocannabinoids and endocannabinoid-like mediators might be a valuable option for treating stress-related neuropsychiatric symptoms.
Topics: Animals; Body Weight; Cannabinoid Receptor Antagonists; Cannabinoids; Cerebral Cortex; Corpus Striatum; Disease Models, Animal; Exploratory Behavior; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Neural Pathways; RNA, Messenger; Rimonabant; Stress, Psychological; Tacrolimus Binding Proteins; Tirapazamine
PubMed: 29388323
DOI: 10.1111/cns.12810 -
Basic & Clinical Pharmacology &... Sep 2016Tirapazamine is a hypoxia-activated prodrug which was shown to exhibit up to 300 times greater cytotoxicity under anoxic in comparison with aerobic conditions. Thus, the...
Tirapazamine is a hypoxia-activated prodrug which was shown to exhibit up to 300 times greater cytotoxicity under anoxic in comparison with aerobic conditions. Thus, the combined anticancer therapy of tirapazamine with a routinely used anticancer drug seems to be a promising solution. Because tirapazamine undergoes redox cycle transformation in this study, the effect of tirapazamine on redox hepatic equilibrium, lipid status and liver morphology was evaluated in rats exposed to cisplatin, doxorubicin and 5-fluorouracil. Rats were intraperitoneally injected with tirapazamine and a particular cytostatic. The animals were killed, and blood and liver were collected. Hepatic glucose, total cholesterol, triglycerides, NADH, NADPH glutathione and the activity of glucose-6-phosphate dehydrogenase were determined. Liver morphology and the immune expression of HMG-CoA-reductase were also assessed. Glucose, total cholesterol, triglycerides, bilirubin concentrations and the activity of aspartate and alanine aminotransferases were determined in the plasma. Tirapazamine displayed insignificant interactions with cisplatin and 5-fluorouracil referring to hepatic morphology and biochemical parameters. However, tirapazamine interacts with doxorubicin, thus leading to side changes in redox equilibrium and lipid peroxidation, but those effects are not severe enough to exclude that drug combination from further studies. Thus, tirapazamine seems to be a promising agent in successive studies on anticancer activity in similar schedules.
Topics: Alanine Transaminase; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Cholesterol; Cisplatin; Doxorubicin; Drug Interactions; Fluorouracil; Glutathione; Lipid Peroxidation; Liver; Male; Oxidation-Reduction; Rats; Rats, Wistar; Tirapazamine; Triazines; Triglycerides
PubMed: 26990033
DOI: 10.1111/bcpt.12576 -
Nature Communications Apr 2019Hypoxia-based agents (HBAs), such as anaerobic bacteria and bioreductive prodrugs, require both a permeable and hypoxic intratumoural environment to be fully effective....
Hypoxia-based agents (HBAs), such as anaerobic bacteria and bioreductive prodrugs, require both a permeable and hypoxic intratumoural environment to be fully effective. To solve this problem, herein, we report that perfluorocarbon nanoparticles (PNPs) can be used to create a long-lasting, penetrable and hypoxic tumour microenvironment for ensuring both the delivery and activation of subsequently administered HBAs. In addition to the increased permeability and enhanced hypoxia caused by the PNPs, the PNPs can be retained to further achieve the long-term inhibition of intratumoural O reperfusion while enhancing HBA accumulation for over 24 h. Therefore, perfluorocarbon materials may have great potential for reigniting clinical research on hypoxia-based drugs.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Drug Delivery Systems; Fluorocarbons; Mice; Nanoparticles; Prodrugs; Tirapazamine; Tumor Hypoxia; Tumor Microenvironment
PubMed: 30952842
DOI: 10.1038/s41467-019-09389-2 -
Analytical Chemistry Oct 2018Oxygen deprivation is a common feature in a variety of cancer tissues and associated with tumor progression, acquisition of antiapoptotic potential, and clinical...
Oxygen deprivation is a common feature in a variety of cancer tissues and associated with tumor progression, acquisition of antiapoptotic potential, and clinical therapeutic resistance. Thus, great interest has been aroused to develop new platforms or approaches of activity assays to impact on the hypoxic microenvironment and oxygen-dependent drug responses to improve the productivity of new drug discovery. In this study, an integrated microsystem is established to combine the cytotoxic and genotoxic tests together for continuous multiple measurements under mimicking hypoxic tumor microenvironment. We fabricated a double-layer chip device by combining a single-cell-arrayed agarose layer with a microfluidics-based oxygen gradient-generating layer using a PDMS membrane. Using tirapazamine (TPZ) and blemycin (BLM) as model anticancer drugs, we demonstrated its application and performance in single cell loading, cell cultivation, and subsequent drug treatment as well as in situ analysis of oxygen-dependent cytotoxicity and genotoxicity of anticancer drugs. The results demonstrated the opposite oxygen-dependent toxicity of TPZ and BLM, which also indicated that the formation of DNA breaks is related with cell apoptosis. Compared with the traditional assays, this device takes advantage of microfluidic phenomena to generate various oxygen concentrations while exhibiting the combinatorial diversities achieved by the single cell microarray, offering a powerful tool to study single cell behaviors and responses under different oxygen conditions with desired high-content and high-throughput capabilities.
Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Bleomycin; Cell Proliferation; Cell Survival; DNA Damage; DNA, Neoplasm; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Microfluidic Analytical Techniques; Mutagenicity Tests; Optical Imaging; Oxygen; Structure-Activity Relationship; Tirapazamine; Tumor Cells, Cultured
PubMed: 30168712
DOI: 10.1021/acs.analchem.8b02070 -
Biomaterials Sep 2024It is imperative to optimize chemotherapy for heightened anti-tumor therapeutic efficacy. Unrestrained tumor cell proliferation and sustained angiogenesis are pivotal...
It is imperative to optimize chemotherapy for heightened anti-tumor therapeutic efficacy. Unrestrained tumor cell proliferation and sustained angiogenesis are pivotal for cancer progression. Plinabulin, a vascular disrupting agent, selectively destroys tumor blood vessels. Tirapazamine (TPZ), a hypoxia-activated prodrug, intensifies cytotoxicity in diminishing oxygen levels within tumor cells. Despite completing Phase III clinical trials, both agents exhibited modest treatment efficiency due to dose-limiting toxicity. In this study, we employed methoxy poly(ethylene glycol)-b-poly(-lactide) (mPEG-b-PDLLA) to co-deliver Plinabulin and TPZ to the tumor site, concurrently disrupting blood vessels and eliminating tumor cells, addressing both symptoms and the root cause of tumor progression. Plinabulin was converted into a prodrug with esterase response (PSM), and TPZ was synthesized into a hexyl chain-containing derivative (TPZHex) for effective co-delivery. PSM and TPZHex were co-encapsulated with mPEG-b-PDLLA, forming nanodrugs (PT-NPs). At the tumor site, PT-NPs responded to esterase overexpression, releasing Plinabulin, disrupting blood vessels, and causing nutritional and oxygen deficiency. TPZHex was activated in response to increased hypoxia, killing tumor cells. In treating 4T1 tumors, PT-NPs demonstrated enhanced therapeutic efficacy, achieving a 92.9 % tumor suppression rate and a 20 % cure rate. This research presented an innovative strategy to enhance synergistic efficacy and reduce toxicity in combination chemotherapy.
Topics: Tirapazamine; Animals; Cell Line, Tumor; Humans; Polyethylene Glycols; Antineoplastic Agents; Female; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Triazines; Diketopiperazines
PubMed: 38718615
DOI: 10.1016/j.biomaterials.2024.122586