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Molecular Pharmaceutics May 2019Although photodynamic therapy (PDT) has been an attractive strategy for several cancer treatments in the clinical setting, PDT efficacy is attenuated by consumption of...
Although photodynamic therapy (PDT) has been an attractive strategy for several cancer treatments in the clinical setting, PDT efficacy is attenuated by consumption of oxygen. To address this photodynamic issue, we adopted a phototherapy-chemotherapy combination strategy based on targeted delivery of the near-infrared photosensitizer indocyanine green (ICG), photothermal conversion agent polydopamine (PDA), and tirapazamine (TPZ), a hypoxia-activated prodrug. Under laser irradiation, ICG consumption of oxygen and aggravated hypoxia in tumor sites can activate TPZ to damage DNA. In parallel, ICG produces reactive oxygen species which work in synergy with PDA to enhance phototherapeutic efficiency. Herein, hybrid CaCO/TPGS nanoparticles delivering ICG, PDA, and TPZ (ICG-PDA-TPZ NPs) were designed for effective and safe cancer therapy. ICG-PDA-TPZ NPs showed significantly improved cellular uptake and accumulation in tumors. Furthermore, we demonstrated that ICG-PDA-TPZ NPs showed intensive photodynamic and photothermal effects in vitro and in vivo, which synergized with TPZ in subcutaneous U87 malignant glioma growth and orthotopic B16F10 tumor inhibition, with negligible side effects. Thus, ICG-PDA-TPZ NPs could be an effective strategy for improvement of PDT.
Topics: Animals; Humans; Mice; Apoptosis; Cell Line, Tumor; Cell Survival; Drug Delivery Systems; Hyperthermia, Induced; Indocyanine Green; Indoles; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Nanoparticles; Neoplasms; Photochemotherapy; Polymers; Prodrugs; Radiation-Sensitizing Agents; Reactive Oxygen Species; Tirapazamine; Tissue Distribution; Treatment Outcome; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 30978027
DOI: 10.1021/acs.molpharmaceut.9b00119 -
Journal of Controlled Release :... May 2021Chemodynamic therapy (CDT) has been proposed to convert tumoral HO into toxic hydroxyl radicals (OH) via Fenton or Fenton-like reactions for antitumor efficacy, which is...
Chemodynamic therapy (CDT) has been proposed to convert tumoral HO into toxic hydroxyl radicals (OH) via Fenton or Fenton-like reactions for antitumor efficacy, which is frequently limited by low HO concentrations or lack of enough metal ions inside tumor tissues. In this report, we present ferrocene-containing responsive polymersome nanoreactors via loading glucose oxidase (GOD) and hypoxia-activable prodrug tirapazamine (TPZ) in the inner aqueous cavities. After intravenous injection, the polymersome nanoreactors with the optimized nanoparticle size of ~100 nm and poly(ethylene glycol) corona facilitate tumor accumulation. The tumor acidic microenvironment can trigger the permeability of the polymersome membranes to activate the nanoreactors and release the loaded TPZ prodrugs. Tumor oxygen and glucose can enter the polymersome nanoreactors and are transformed into HO under the catalysis of GOD, which are further converted into OH via Fenton reaction under catalysis of ferrocene moieties. The oxygen consumption can aggravate tumor hypoxia to activate hypoxia-responsive TPZ prodrugs which can produce benzotriazinyl (BTZ) radicals and OH. All the produced radicals synergistically kill tumor cells via the amplified CDT and suppress the tumor growth efficiently. Thus, the ferrocene-containing responsive polymersome nanoreactors loading GOD and TPZ represent a potent nanoplatform to exert amplified CDT for improved anticancer efficacy.
Topics: Cell Line, Tumor; Humans; Hydrogen Peroxide; Metallocenes; Nanotechnology; Neoplasms; Prodrugs; Tumor Microenvironment
PubMed: 33848558
DOI: 10.1016/j.jconrel.2021.04.007 -
Journal of Molecular Modeling May 2021Tirapazamine (TP) has been shown to enhance the cytotoxic effects of ionizing radiation in hypoxic cells, thus making it a candidate for a radiosensitizer. This...
Tirapazamine (TP) has been shown to enhance the cytotoxic effects of ionizing radiation in hypoxic cells, thus making it a candidate for a radiosensitizer. This selective behavior is often directly linked to the abundance of O. In this paper, we study the electronic properties of TP in vacuum, micro-hydrated from one up to three molecules of water and embedded in a continuum of water. We discuss electron affinities, charge distribution, and bond dissociation energies of TP, and find that these properties do not change significantly upon hydration. In agreement with its large electron affinity, and bond breaking triggered by electron attachment requires energies higher than 2.5 eV, ruling out the direct formation of bioactive TP radicals. Our results suggest, therefore, that the selective behavior of TP cannot be explained by a one-electron reduction from a neighboring O molecule. Alternatively, we propose that TP's hypoxic selectivity could be a consequence of O scavenging hydrogen radicals.
Topics: Models, Chemical; Models, Molecular; Radiation-Sensitizing Agents; Tirapazamine
PubMed: 34021836
DOI: 10.1007/s00894-021-04771-8 -
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 -
Acta Pharmaceutica Sinica. B Apr 2022Vulnerable atherosclerotic plaque (VASPs) is the major pathological cause of acute cardiovascular event. Early detection and precise intervention of VASP hold great...
Vulnerable atherosclerotic plaque (VASPs) is the major pathological cause of acute cardiovascular event. Early detection and precise intervention of VASP hold great clinical significance, yet remain a major challenge. Photodynamic therapy (PDT) realizes potent ablation efficacy under precise manipulation of laser irradiation. In this study, we constructed theranostic nanoprobes (NPs), which could precisely regress VASPs through a cascade of synergistic events triggered by local irradiation of lasers under the guidance of fluorescence/MR imaging. The NPs were formulated from human serum albumin (HSA) conjugated with a high affinity-peptide targeting osteopontin (OPN) and encapsulated with photosensitizer IR780 and hypoxia-activatable tirapazamine (TPZ). After intravenous injection into atherosclerotic mice, the OPN-targeted NPs demonstrated high specific accumulation in VASPs due to the overexpression of OPN in activated foamy macrophages in the carotid artery. Under the visible guidance of fluorescence and MR dual-model imaging, the precise near-infrared (NIR) laser irradiation generated massive reactive oxygen species (ROS), which resulted in efficient plaque ablation and amplified hypoxia within VASPs. In response to the elevated hypoxia, the initially inactive TPZ was successively boosted to present potent biological suppression of foamy macrophages. After therapeutic administration of the NPs for 2 weeks, the plaque area and the degree of carotid artery stenosis were markedly reduced. Furthermore, the formulated NPs displayed excellent biocompatibility. In conclusion, the developed HSA-based NPs demonstrated appreciable specific identification ability of VASPs and realized precise synergistic regression of atherosclerosis.
PubMed: 35847489
DOI: 10.1016/j.apsb.2021.12.020 -
Biomaterials Science Jun 2020To enhance the specificity and efficiency of anti-tumor therapies, we have designed a multifunctional nanoparticle platform for photochemotherapy using fluorescence (FL)...
To enhance the specificity and efficiency of anti-tumor therapies, we have designed a multifunctional nanoparticle platform for photochemotherapy using fluorescence (FL) and photoacoustic (PA) imaging guidance. Nanoparticles (NPs) composed of a eutectic mixture of natural fatty acids that undergo a solid-liquid phase transition at 39 °C were used to encapsulate materials for the rapid and uniform release of the hypoxia-activated prodrug tirapazamine (TPZ) and the photosensitizer IR780, which targets the mitochondria of tumor cells and can be used to induce hypoxic cell death via photodynamic therapy and photothermal therapy. In vitro, the NPs containing TPZ and IR7890 exhibited appreciable cell uptake and triggered drug release when irradiated with a NIR laser. In vivo, photochemotherapy of the NPs achieved the best anti-tumor efficacy under PA and FL imaging guidance and monitoring. By combining IR780 mitochondria-targeting phototherapy with TPZ, we observed improved anti-tumor effectiveness and this has the potential to reduce the side effects of traditional chemotherapy. Herein, we demonstrate a new intracellular photochemotherapy nanosystem that co-encapsulates photosensitizers and hypoxia-activated drugs to enhance the overall anti-tumor effect precisely and efficiently.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Drug Liberation; Female; Indoles; Lasers; Mice, Inbred BALB C; Nanoparticles; Neoplasms; Optical Imaging; Photoacoustic Techniques; Photochemotherapy; Photosensitizing Agents; Prodrugs; Reactive Oxygen Species; Tirapazamine
PubMed: 32352102
DOI: 10.1039/d0bm00003e -
International Journal of Molecular... Nov 2020Derivatives of tirapazamine and other heteroaromatic oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities, which are typically attributed to...
Derivatives of tirapazamine and other heteroaromatic oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities, which are typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the role of NAD(P)H:quinone oxidoreductase (NQO1) in ArN→O aerobic cytotoxicity. We synthesized 9 representatives of ArN→O with uncharacterized redox properties and examined their single-electron reduction by rat NADPH:cytochrome P-450 reductase (P-450R) and ferredoxin:NADP oxidoreductase (FNR), and by rat NQO1. NQO1 catalyzed both redox cycling and the formation of stable reduction products of ArN→O. The reactivity of ArN→O in NQO1-catalyzed reactions did not correlate with the geometric average of their activity towards P-450R- and FNR, which was taken for the parameter of their redox cycling efficacy. The cytotoxicity of compounds in murine hepatoma MH22a cells was decreased by antioxidants and the inhibitor of NQO1, dicoumarol. The multiparameter regression analysis of the data of this and a previous study (DOI: 10.3390/ijms20184602) shows that the cytotoxicity of ArN→O ( 18) in MH22a and human colon carcinoma HCT-116 cells increases with the geometric average of their reactivity towards P-450R and FNR, and with their reactivity towards NQO1. These data demonstrate that NQO1 is a potentially important target of action of heteroaromatic oxides.
Topics: Aerobiosis; Animals; Anti-Bacterial Agents; Antioxidants; Antiprotozoal Agents; Cell Line, Tumor; Cell Survival; Cyclic N-Oxides; Dicumarol; Enzyme Assays; Enzyme Inhibitors; Ferredoxin-NADP Reductase; HCT116 Cells; Hepatocytes; Humans; Kinetics; Mice; NAD(P)H Dehydrogenase (Quinone); NADPH-Ferrihemoprotein Reductase; Oxidation-Reduction; Plasmodium falciparum; Protozoan Proteins; Rats; Tirapazamine
PubMed: 33228195
DOI: 10.3390/ijms21228754 -
ACS Biomaterials Science & Engineering Nov 2022With the advantages of high safety and selectivity, photodynamic therapy (PDT) has been widely used for cancer treatments, while the anticancer efficacy is often limited...
With the advantages of high safety and selectivity, photodynamic therapy (PDT) has been widely used for cancer treatments, while the anticancer efficacy is often limited because of its relying on oxygen concentrations. Therefore, sole PDT fails to achieve the desired therapeutic effect for hypoxic tumors. To address this issue, we herein report the construction of prodrug and glucose oxidase (GOx) coloaded alginate (ALG) hydrogels for PDT-combined chemotherapy of melanoma. The hydrogels are in situ formed in tumor sites after injection of ALG solution containing semiconducting polymer nanoparticles, hypoxia-responsive prodrug tirapazamine (TPZ), and GOx, which is based on chelation of ALG by endogenous Ca. Due to the presence of semiconducting polymer nanoparticles acting as photosensitizers, the hydrogels mediate PDT to produce singlet oxygen (O) for directly killing tumor cells, in which oxygen is consumed to create a more hypoxic tumor microenvironment. Moreover, the loaded GOx within hydrogels can deplete oxygen to further aggravate tumor hypoxia. As such, TPZ is effectively activated by hypoxia to cause cancer cell death via chemotherapy. Thus, the hydrogels with laser irradiation achieve a combinational action of PDT with chemotherapy to almost completely eradicate tumors, leading to a much higher therapeutic efficacy relative to sole PDT. This study will provide a promising injectable hydrogel platform for effective treatments of cancer.
Topics: Humans; Prodrugs; Glucose Oxidase; Hydrogels; Tirapazamine; Polymers; Melanoma; Hypoxia; Oxygen; Tumor Microenvironment
PubMed: 36278808
DOI: 10.1021/acsbiomaterials.2c00992 -
ACS Macro Letters Nov 2020Hypoxia-activated prodrugs (HAPs) have emerged as important candidates for chemotherapy due to their efficient killing of hypoxic cancer cells. Traditional small...
Hypoxia-activated prodrugs (HAPs) have emerged as important candidates for chemotherapy due to their efficient killing of hypoxic cancer cells. Traditional small molecule agents, such as tirapazamine (TPZ) and its derivatives, have shown unsatisfactory therapeutic effect in clinical trials due to poor bioavailability in hypoxic tumor regions. Herein, an amphiphilic macromolecular prodrug with hypoxia-specific activity, named as hypoxia-activated macromolecular prodrug (HAMP), is prepared from poly{[poly(ethylene glycol) methacrylate]--(methacrylic acid)} [poly(PEGMA--MAA)], containing pendant TPZ residues. This polymer can self-assemble in an aqueous system into ∼37 nm sized nanoparticles. In vitro experiments indicated that HAMP shows 5× higher cytotoxicity to hypoxic cancer cells as compared to normoxic cancer cells. Therefore, the developed HAMP can be concurrently used with other therapeutic agents as a highly efficient hypoxia-activated agent.
PubMed: 35617071
DOI: 10.1021/acsmacrolett.0c00759 -
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