-
International Journal of Molecular... Sep 2019Derivatives of tirapazamine and other heteroaromatic oxides (ArN→O) exhibit promising antibacterial, antiprotozoal, and tumoricidal activities. Their action is...
Derivatives of tirapazamine and other heteroaromatic oxides (ArN→O) exhibit promising antibacterial, antiprotozoal, and tumoricidal activities. Their action is typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the mechanism(s) of aerobic mammalian cell cytotoxicity of ArN→O performing the parallel studies of their reactions with NADPH:cytochrome P-450 reductase (P-450R), adrenodoxin reductase/adrenodoxin (ADR/ADX), and NAD(P)H:quinone oxidoreductase (NQO1); we found that in P-450R and ADR/ADX-catalyzed single-electron reduction, the reactivity of ArN→O ( = 9) increased with their single-electron reduction midpoint potential (), and correlated with the reactivity of quinones. NQO1 reduced ArN→O at low rates with concomitant superoxide production. The cytotoxicity of ArN→O in murine hepatoma MH22a and human colon adenocarcinoma HCT-116 cells increased with their , being systematically higher than that of quinones. The cytotoxicity of both groups of compounds was prooxidant. Inhibitor of NQO1, dicoumarol, and inhibitors of cytochromes P-450 α-naphthoflavone, isoniazid and miconazole statistically significantly ( < 0.02) decreased the toxicity of ArN→O, and potentiated the cytotoxicity of quinones. One may conclude that in spite of similar enzymatic redox cycling rates, the cytotoxicity of ArN→O is higher than that of quinones. This is partly attributed to ArN→O activation by NQO1 and cytochromes P-450. A possible additional factor in the aerobic cytotoxicity of ArN→O is their reductive activation in oxygen-poor cell compartments, leading to the formation of DNA-damaging species similar to those forming under hypoxia.
Topics: Antineoplastic Agents; Biomarkers; Humans; Molecular Structure; NAD(P)H Dehydrogenase (Quinone); NADP; Oxidants; Oxidation-Reduction; Reactive Oxygen Species; Tirapazamine
PubMed: 31533349
DOI: 10.3390/ijms20184602 -
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 -
Biomaterials Nov 2022Hypoxia is a common feature within many types of solid tumors, which is closely associated with limited efficacy for tumor therapies. Moreover, the inability to reach...
Hypoxia is a common feature within many types of solid tumors, which is closely associated with limited efficacy for tumor therapies. Moreover, the inability to reach hypoxic tumor cells that are distant from blood vessels results in tumor-targeting and penetrating drug delivery systems in urgent need. Here, glucose oxidase (GOX) and hypoxia-activated prodrug tirapazamine (TPZ) are loaded into photothermal conversion agent polydopamine (PDA) as the glucose/oxygen-exhausting nanoreactor named PGT. We further construct a tumor cell membrane-coated nanovesicle for the targeted delivery of PGT. This biomimetic nanovesicle exhibits significantly improved tumor-targeting and tumor-penetrating abilities. After internalization by the tumor cells, the loaded drug is quickly released in response to near-infrared (NIR) laser. The PGT nanoreactor can exhaust glucose and oxygen, and further enhance hypoxia within tumor, which efficiently inhibits hypoxic tumor by combining starvation therapy and hypoxia-activated chemotherapy. Mechanically, it is revealed that the nanoreactor significantly increases hypoxia level and downregulates the expression of hypoxia-inhibitory factor-1α (HIF-1α), thereby promoting T cell activation and macrophage polarization to remodel tumor immunosuppressive microenvironment. Therefore, this tumor microenvironment-regulable nanoreactor with sustainable and cascade targeted starvation-chemotherapy provides a novel insight into the treatment of hypoxic tumor.
Topics: Humans; Biomimetics; Oxygen; Tumor Microenvironment; Glucose; Nanoparticles; Neoplasms; Hypoxia; Cell Membrane; Nanotechnology; Cell Line, Tumor
PubMed: 36201949
DOI: 10.1016/j.biomaterials.2022.121821 -
Journal of Materials Chemistry. B Nov 2021Constructing a theranostic agent for high-contrast multimodality imaging-guided synergistic therapy with long-term tumor retention and minimum systemic side effects...
Constructing a theranostic agent for high-contrast multimodality imaging-guided synergistic therapy with long-term tumor retention and minimum systemic side effects still remains a major challenge. Herein, a hybrid microbubble-based theranostic platform was developed for dual-modality ultrasound (US) and enhanced photoacoustic (PA) imaging-guided synergistic tumor therapy by combining starvation therapy, low-temperature photothermal therapy (PTT), and hypoxia-activated therapy, based on polydopamine (PDA) doped poly(vinyl alcohol) microbubbles loaded with glucose oxidase (GOx) (PDA-PVAMBs@GOx) and hypoxia-activated prodrug (HAP) tirapazamine (TPZ). For dual-modality US/enhanced PA imaging, PDA-PVAMBs provided 6.5-fold amplified PA signals relative to freely dispersed PDA nanoparticles (PDA NPs). For synergistic cancer therapy, oxygen (O) carried by PDA-PVAMBs@GOx was first released to promote starvation therapy by loaded GOx. Then, moderate near-infrared (NIR) laser irradiation triggered PTT and improved enzymatic activity of GOx with its optimal activity around 47 °C. Subsequently, GOx-mediated tumor starvation depleted O and exacerbated the hypoxia environment, thereby activating the toxicity of TPZ in the tumor site. Through dual-modality US/PA imaging monitoring, PDA-PVAMBs@GOx with long-term retention (∼7 days) combined with PTT and TPZ significantly inhibited the growth of solid tumors with minimum systemic side effects, which might be a powerful tool for effective tumor treatment.
Topics: Animals; Cell Line, Tumor; Cell Survival; Cold Temperature; Colonic Neoplasms; Female; Mice; Mice, Inbred BALB C; Microbubbles; Neoplasms; Oxygen; Photoacoustic Techniques; Theranostic Nanomedicine; Ultrasonography; Xenograft Model Antitumor Assays
PubMed: 34726226
DOI: 10.1039/d1tb01735g -
Journal of Photochemistry and... Nov 2023Photodynamic therapy (PDT) has a promising application prospect in Echinococcus granulosus (Egs), however, the hypoxic environment of Egs and the hypoxia associated with...
BACKGROUND
Photodynamic therapy (PDT) has a promising application prospect in Echinococcus granulosus (Egs), however, the hypoxic environment of Egs and the hypoxia associated with PDT will greatly limit its effects. As a hypoxic-activated pre-chemotherapeutic drug, tirapazamine (TPZ) can be only activated and produce cytotoxicity under hypoxia environment. Albendazole sulfoxide (ABZSO) is the first choice for the treatment of Egs. This study aimed to explore the effects of ABZSO nanoparticles (ABZSO NPs), TPZ combined with PDT on the activity of Egs in vitro and in vivo.
METHODS
The Egs were divided into control, ABZSO NPs, ABZSO NPs + PDT, and ABZSO NPs + TPZ + PDT groups, and the viability of Egs was determined using methylene blue staining. Then, the ROS, LDH and ATP levels were measured using their corresponding assay kit, and H2AX and TopoI protein expression was detected by western blot. The morphology of Egs with different treatments was observed using hematoxylin eosin (HE) staining and scanning electron microscopy (SEM). After that, the in vivo efficacy of ABZSO NPs, TPZ and PDT on Egs was determined in a Egs infected mouse model.
RESULTS
In vitro experiments showed that the combined treatment of TPZ, ABZSO NPs and PDT significantly inhibited Egs viability; and significantly increased ROS levels and LDH contents, while decreased ATP contents in Egs; as well as up-regulated H2AX and down-regulated TopoI protein expression. HE staining and SEM results showed that breaking-then-curing treatment seriously damaged the Egs wall. Additionally, in vivo experiments found that the combination of ABZSO NPs, PDT and TPZ had more serious calcification and damage of the wall structure of cysts.
CONCLUSIONS
ABZSO NPs combined with TPZ and PDT has a better inhibitory effect on the growth of Egs in vitro and in vivo based on the strategy of "breaking-then-curing".
Topics: Animals; Mice; Tirapazamine; Echinococcus granulosus; Reactive Oxygen Species; Hypoxia; Photochemotherapy; Echinococcosis; Nanoparticles; Adenosine Triphosphate
PubMed: 37820499
DOI: 10.1016/j.jphotobiol.2023.112798 -
Journal of Materials Chemistry. B Jan 2020Hypoxia, a state of low oxygen tension in solid tumors, is not only closely correlated with resistance to both radiotherapy and chemotherapy, but also associated with...
Hypoxia, a state of low oxygen tension in solid tumors, is not only closely correlated with resistance to both radiotherapy and chemotherapy, but also associated with poor prognosis of tumors and regional lymph node status. Herein, based on the analysis of cell samples from tumor patients, low-density lipoprotein receptor (LDLR) was found to be overexpressed on the surface of hypoxic tumor cell membranes, and confirmed to be an effective hypoxia marker through specific binding with anti-LDLR antibody in solid tumors. In addition, using the special therapeutic microenvironment of hypoxia, tirapazamine (TPZ, which can be used as both a hypoxia-activated chemotherapy prodrug and radiotherapy sensitizer) was integrated with PEGylated photosensitizer chlorin e6 (Ce6-PEG) by self-assembly, and anti-LDLR was then modified on the surface to form tumor hypoxia-targeting multifunctional nanoparticles (CPTA). CPTA possesses a multimodal antitumor effect via a simultaneous photothermal therapy (PTT)/photodynamic therapy (PDT) effect generated by Ce6, and chemotherapy/radiotherapy actions sensitized by TPZ. It is noteworthy that tumor oxygen was consumed in the process of PDT and the hypoxia was subsequently exacerbated, which can greatly increase the TPZ-sensitized chemotherapy and lead to a synergistic antitumor effect. Both in vitro and in vivo experiments demonstrated that CPTA possesses an excellent therapeutic effect through PTT, PDT, and TPZ sensitized radiotherapy and chemotherapy. This hypoxic tumor targeting synergetic therapeutic strategy has great potential for future clinical transformation.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chlorophyllides; Drug Screening Assays, Antitumor; Humans; Ligands; Materials Testing; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Experimental; Particle Size; Photochemotherapy; Photosensitizing Agents; Photothermal Therapy; Polyethylene Glycols; Porphyrins; Receptors, LDL; Surface Properties; Tirapazamine; Tumor Hypoxia
PubMed: 31898718
DOI: 10.1039/c9tb02248a -
International Journal of Nanomedicine 2022Effective therapy for rheumatoid arthritis (RA) keeps a challenge due to the complex pathogenesis of RA. It is not enough to completely inhibit the process of RA with...
PURPOSE
Effective therapy for rheumatoid arthritis (RA) keeps a challenge due to the complex pathogenesis of RA. It is not enough to completely inhibit the process of RA with any single therapy method. The purpose of the research is to compensate for the insufficiency of monotherapy using multiple treatment regimens with different mechanisms.
MATERIAL AND METHODS
In this study, we developed a new method to synthesize mesoporous silica nanoparticles hybridized with photosensitizer PCPDTBT (HNs). Branched polyethyleneimine-folic acid (PEI-FA) could be coated on the surface of HNs through electrostatic interactions. It simultaneously blocked the hypoxia-activated prodrug tirapazamine loaded into the mesopores and binded with Mcl-1 siRNA (siMcl-1) that interfered with the expression of the anti-apoptotic protein Mcl-1. Released from the co-delivery nanoparticles (PFHNs/TM) Tirapazamine and siMcl-1 upon exposure to acidic conditions of endosomes/lysosomes in activated macrophages. Under NIR irradiation, photothermal therapy and photodynamic therapy derived from PCPDTBT, hypoxia-activated chemotherapy derived from tirapazamine, and RNAi derived from siMcl-1 were used for the combined treatment for RA by killing activated macrophages. PEI-FA-coated PFHNs/TM exhibited activated macrophage-targeting characteristics, thereby enhancing the in vitro and in vivo NIR-induced combined treatment of RA.
RESULTS
The prepared PFHNs/TM have high blood compatibility (far below 5% of hemolysis) and ideal in vitro phototherapy effect while controlling the TPZ release and binding siMcl-1. We prove that PEI-FA-coated PFHNs/TM not only protect the bound siRNA but also are selectively uptaked by activated macrophages through FA receptor-ligand-mediated endocytosis, and effectively silence the target anti-apoptotic protein by siMcl-1 transfection. In vivo, PFHNs/TM have also been revealed to be selectively enriched at the inflammatory site of RA, exhibiting NIR-induced anti-RA efficacy.
CONCLUSION
Overall, these FA-functionalized, pH-responsive PFHNs/TM represent a promising platform for the co-delivery of chemical drugs and nucleic acids for the treatment of RA cooperating with NIR-induced phototherapy.
Topics: Humans; Tirapazamine; RNA Interference; Nanoparticle Drug Delivery System; Myeloid Cell Leukemia Sequence 1 Protein; Phototherapy; Nanoparticles; Arthritis, Rheumatoid; RNA, Small Interfering; Folic Acid; Hypoxia
PubMed: 36531117
DOI: 10.2147/IJN.S382252 -
International Journal of Nanomedicine 2024Combination therapy provides better outcomes than a single therapy and becomes an efficient strategy for cancer treatment. In this study, we designed a hypoxia- and...
INTRODUCTION
Combination therapy provides better outcomes than a single therapy and becomes an efficient strategy for cancer treatment. In this study, we designed a hypoxia- and singlet oxygen-responsive polymeric micelles which contain azo and nitroimidazole groups for enhanced cellular uptake, repaid cargo release, and codelivery of photosensitizer Ce6 and hypoxia-activated prodrug tirapazamine TPZ (DHM-Ce6@TPZ), which could be used for combining Ce6-mediated photodynamic therapy (PDT) and PDT-activated chemotherapy to enhance the therapy effect of cancer.
METHODS
The hypoxia- and singlet oxygen-responsive polymeric micelles DHM-Ce6@TPZ were prepared by film hydration method. The morphology, physicochemical properties, stimuli responsiveness, in vitro singlet oxygen production, cellular uptake, and cell viability were evaluated. In addition, the in vivo therapeutic effects of the micelles were verified using a tumor xenograft mice model.
RESULTS
The resulting dual-responsive micelles not only increased the concentration of intracellular photosensitizer and TPZ, but also facilitated photosensitizer and TPZ release for enhanced integration of photodynamic and chemotherapy therapy. As a photosensitizer, Ce6 induced PDT by generating toxic singlet reactive oxygen species (ROS), resulting in a hypoxic tumor environment to activate the prodrug TPZ to achieve efficient chemotherapy, thereby evoking a synergistic photodynamic and chemotherapy therapeutic effect. The cascade synergistic therapeutic effect of DHM-Ce6@TPZ was effectively evaluated both in vitro and in vivo to inhibit tumor growth in a breast cancer mice model.
CONCLUSION
The designed multifunctional micellar nano platform could be a convenient and powerful vehicle for the efficient co-delivery of photosensitizers and chemical drugs for enhanced synergistic photodynamic and chemotherapy therapeutic effect of cancer.
Topics: Humans; Animals; Mice; Photosensitizing Agents; Micelles; Singlet Oxygen; Photochemotherapy; Cell Line, Tumor; Hypoxia; Polymers; Prodrugs; Nanoparticles
PubMed: 38229704
DOI: 10.2147/IJN.S432407 -
Journal of Nanobiotechnology Sep 2021Hypoxia is a characteristic of solid tumors that can lead to tumor angiogenesis and early metastasis, and addressing hypoxia presents tremendous challenges. In this...
BACKGROUND
Hypoxia is a characteristic of solid tumors that can lead to tumor angiogenesis and early metastasis, and addressing hypoxia presents tremendous challenges. In this work, a nanomedicine based on oxygen-absorbing perfluorotributylamine (PFA) and the bioreductive prodrug tirapazamine (TPZ) was prepared by using a polydopamine (PDA)-coated UiO-66 metal organic framework (MOF) as the drug carrier.
RESULTS
The results showed that TPZ/PFA@UiO-66@PDA nanoparticles significantly enhanced hypoxia, induced cell apoptosis in vitro through the oxygen-dependent HIF-1α pathway and decreased oxygen levels in vivo after intratumoral injection. In addition, our study demonstrated that TPZ/PFA@UiO-66@PDA nanoparticles can accumulate in the tumor region after tail vein injection and effectively inhibit tumor growth when combined with photothermal therapy (PTT). TPZ/PFA@UiO-66@PDA nanoparticles increased HIF-1α expression while did not promote the expression of CD31 in vivo during the experiment.
CONCLUSIONS
By using TPZ and PFA and the enhanced permeability and retention effect of nanoparticles, TPZ/PFA@UiO-66@PDA can target tumor tissues, enhance hypoxia in the tumor microenvironment, and activate TPZ. Combined with PTT, the growth of osteosarcoma xenografts can be effectively inhibited.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Fluorocarbons; Humans; Indoles; Male; Metal-Organic Frameworks; Mice; Mice, Nude; Nanoparticles; Osteosarcoma; Phthalic Acids; Polymers; Tirapazamine; Tumor Hypoxia
PubMed: 34592996
DOI: 10.1186/s12951-021-01013-0 -
Biomaterials Jul 2020Tumor cell populations are highly heterogeneous, which limit the homogeneous distribution and optimal delivery of nanomedicines, thereby inducing insufficient...
Tumor cell populations are highly heterogeneous, which limit the homogeneous distribution and optimal delivery of nanomedicines, thereby inducing insufficient therapeutic benefits. We develop tumor microenvironment activatable and external stimuli-responsive drug delivery system (NPs), which can improve photodynamic therapy (PDT) induced bioreductive chemotherapy in different tumor cells both proximal and distal to vessels. The TAT peptide on the surface of NPs can both facilitate the cell uptake and the penetration of NPs, owing to its responsiveness to tumor stimuli pH. NPs can keep the cargoes (photosensitizer chlorine e6 (Ce6) and hypoxia activatable prodrug tirapazamine (TPZ)) and highly accumulate within tumor cells proximity and distal to vessels. The Azo-benzene bonds as the linkers between amphiphilic polymers remain stable under normoxia, but quite break at hypoxic conditions. Upon external laser irradiation, the intratumoral fate of NPs involved two processes: 1) NPs achieve efficient PDT on tumor cells proximal to vessel, since sufficient O supply; and 2) PDT-induced more hypoxia can trigger TPZ release by breakage of Azo-benzene bond as well as accelerate the activation of TPZ for improvingcombination therapy efficacy in tumor cells distal to vessel. This study gives a direction for the development of stepwise-activatable hypoxia triggered nanosystem for PDT-induced bioreductive chemotherapy for tumor cells in different distances to vessels.
Topics: Cell Hypoxia; Cell Line, Tumor; Humans; Hypoxia; Nanoparticles; Photochemotherapy; Photosensitizing Agents; Tirapazamine
PubMed: 32224374
DOI: 10.1016/j.biomaterials.2020.119982