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Journal of Nanobiotechnology Jun 2024Hypoxia-activated prodrug (HAP) is a promising candidate for highly tumor-specific chemotherapy. However, the oxygenation heterogeneity and dense extracellular matrix...
BACKGROUND
Hypoxia-activated prodrug (HAP) is a promising candidate for highly tumor-specific chemotherapy. However, the oxygenation heterogeneity and dense extracellular matrix (ECM) of tumor, as well as the potential resistance to chemotherapy, have severely impeded the resulting overall efficacy of HAP.
RESULTS
A HAP potentiating strategy is proposed based on ultrasound responsive nanodroplets (PTP@PLGA), which is composed of protoporphyrin (PpIX), perfluoropropane (PFP) and a typical HAP, tirapazamine (TPZ). The intense vaporization of PFP upon ultrasound irradiation can magnify the sonomechanical effect, which loosens the ECM to promote the penetration of TPZ into the deep hypoxic region. Meanwhile, the PpIX enabled sonodynamic effect can further reduce the oxygen level, thus activating the TPZ in the relatively normoxic region as well. Surprisingly, abovementioned ultrasound effect also results in the downregulation of the stemness of cancer cells, which is highly associated with drug-refractoriness.
CONCLUSIONS
This work manifests an ideal example of ultrasound-based nanotechnology for potentiating HAP and also reveals the potential acoustic effect of intervening cancer stem-like cells.
Topics: Humans; Tirapazamine; Protoporphyrins; Fluorocarbons; Prodrugs; Cell Line, Tumor; Nanoparticles; Neoplastic Stem Cells; Antineoplastic Agents; Ultrasonic Waves; Animals; Extracellular Matrix; Mice; Neoplasms
PubMed: 38907270
DOI: 10.1186/s12951-024-02623-0 -
Small (Weinheim An Der Bergstrasse,... Jun 2024Radiofrequency ablation (RFA) is one of the most common minimally invasive techniques for the treatment of solid tumors, but residual malignant tissues or small...
Radiofrequency ablation (RFA) is one of the most common minimally invasive techniques for the treatment of solid tumors, but residual malignant tissues or small satellite lesions after insufficient RFA (iRFA) are difficult to remove, often leading to metastasis and recurrence. Here, Fe-TPZ nanoparticles are designed by metal ion and (TPZ) ligand complexation for synergistic enhancement of RFA residual tumor therapy. Fe-TPZ nanoparticles are cleaved in the acidic microenvironment of the tumor to generate Fe and TPZ. TPZ, an anoxia-dependent drug, is activated in residual tumors and generates free radicals to cause tumor cell death. Elevated Fe undergoes a redox reaction with glutathione (GSH), inducing a strong Fenton effect and promoting the production of the highly toxic hydroxyl radical (•OH). In addition, the ROS/GSH imbalance induced by this treatment promotes immunogenic cell death (ICD), which triggers the release of damage-associated molecular patterns, macrophage polarization, and lymphocyte infiltration, thus triggering a systemic antitumor immune response and noteworthy prevention of tumor metastasis. Overall, this integrated treatment program driven by multiple microenvironment-dependent pathways overcomes the limitations of the RFA monotherapy approach and thus improves tumor prognosis. Furthermore, these findings aim to provide new research ideas for regulating the tumor immune microenvironment.
PubMed: 38898764
DOI: 10.1002/smll.202311244 -
Journal of Controlled Release :... Jun 2024Transarterial chemoembolization (TACE) is the standard of care for patients with advanced hepatocellular carcinoma (HCC), but facing the problem of low therapeutic...
Transarterial chemoembolization (TACE) is the standard of care for patients with advanced hepatocellular carcinoma (HCC), but facing the problem of low therapeutic effect. Conventional TACE formulations contain Lipiodol (LP) and chemotherapeutic agents characterized by burst release due to the unstable emulsion. Herein, we developed a novel TACE system by inducing bovine serum albumin (BSA) loaded hypoxia-activated prodrug (tirapazamine, TPZ) nanoparticle (BSA) for sustained drug release. In the rabbit VX2 liver cancer model, TACE treatment induced a long-term hypoxic tumor microenvironment as demonstrated by increased expression of HIF-1α in the tumor. BSA nanoparticles combined with LP greatly enhanced the anti-tumor effects of the TACE treatment. Compared to conventional TACE treatment, BSA nanoparticle-based TACE therapy more significantly delayed tumor progression and inhibited the metastases in the lungs. The effects could be partially mediated by the rebuilt immune responses, as BSA nanoparticle can served as an immunogenic cell death (ICD) inducer. Collectively, our results suggest that BSA nanoparticle-based TACE therapy could be a promising strategy to improve clinical outcomes for patients with HCC and provide a preclinical rationale for evaluating TPZ therapy in clinical studies.
PubMed: 38879131
DOI: 10.1016/j.jconrel.2024.06.026 -
Biomaterials Oct 2024The hypoxic nature of pancreatic cancer, one of the most lethal malignancies worldwide, significantly impedes the effectiveness of chemoradiotherapy. Although the...
The hypoxic nature of pancreatic cancer, one of the most lethal malignancies worldwide, significantly impedes the effectiveness of chemoradiotherapy. Although the development of oxygen carriers and hypoxic sensitizers has shown promise in overcoming tumor hypoxia. The heterogeneity of hypoxia-primarily caused by limited oxygen penetration-has posed challenges. In this study, we designed a hypoxia-responsive nano-sensitizer by co-loading tirapazamine (TPZ), KP372-1, and MK-2206 in a metronidazole-modified polymeric vesicle. This nano-sensitizer relies on efficient endogenous NAD(P)H quinone oxidoreductase 1-mediated redox cycling induced by KP372-1, continuously consuming periphery oxygen and achieving evenly distributed hypoxia. Consequently, the normalized tumor microenvironment facilitates the self-amplified release and activation of TPZ without requiring deep penetration. The activated TPZ and metronidazole further sensitize radiotherapy, significantly reducing the radiation dose needed for extensive cell damage. Additionally, the coloaded MK-2206 complements inhibition of therapeutic resistance caused by Akt activation, synergistically enhancing the hypoxic chemoradiotherapy. This successful hypoxia normalization strategy not only overcomes hypoxia resistance in pancreatic cancer but also provides a potential universal approach to sensitize hypoxic tumor chemoradiotherapy by reshaping the hypoxic distribution.
Topics: Pancreatic Neoplasms; Humans; Tirapazamine; Chemoradiotherapy; Cell Line, Tumor; Animals; Drug Liberation; Mice, Nude; Heterocyclic Compounds, 3-Ring; Nanoparticles; Mice; Antineoplastic Agents; Tumor Hypoxia; Mice, Inbred BALB C; Metronidazole; Tumor Microenvironment
PubMed: 38823195
DOI: 10.1016/j.biomaterials.2024.122634 -
Chemical Biology & Drug Design May 2024Inhibition of prolylhydroxylase-2 (PHD-2) in both normoxic and hypoxic cells is a critical component of solid tumours. The present study aimed to identify small...
Inhibition of prolylhydroxylase-2 (PHD-2) in both normoxic and hypoxic cells is a critical component of solid tumours. The present study aimed to identify small molecules with PHD-2 activation potential. Virtually screening 4342 chemical compounds for structural similarity to R59949 and docking with PHD-2. To find the best drug candidate, hits were assessed for drug likeliness, antihypoxic and antineoplastic potential. The selected drug candidate's PHD-2 activation, cytotoxic and apoptotic potentials were assessed using 2-oxoglutarate, MTT, AO/EtBr and JC-1 staining. The drug candidate was also tested for its in-vivo chemopreventive efficacy against DMBA-induced mammary gland cancer alone and in combination with Tirapazamine (TPZ). Virtual screening and 2-oxoglutarate assay showed BBAP-6 as lead compound. BBAP-6 exhibited cytotoxic and apoptotic activity against ER+ MCF-7. In carmine staining and histology, BBAP-6 alone or in combination with TPZ restored normal surface morphology of the mammary gland after DMBA produced malignant alterations. Immunoblotting revealed that BBAP-6 reduced NF-κB expression, activated PHD-2 and induced intrinsic apoptotic pathway. Serum metabolomics conducted with 1H NMR confirmed that BBAP-6 prevented HIF-1α and NF-κB-induced metabolic changes in DMBA mammary gland cancer model. In a nutshell, it can be concluded that BBAP-6 activates PHD-2 and exhibits anticancer potential.
Topics: Humans; Female; Animals; Breast Neoplasms; Hypoxia-Inducible Factor-Proline Dioxygenases; Apoptosis; Mice; Cell Hypoxia; Molecular Docking Simulation; Antineoplastic Agents; MCF-7 Cells; Cell Line, Tumor; NF-kappa B; Tirapazamine
PubMed: 38726798
DOI: 10.1111/cbdd.14531 -
Advanced Materials (Deerfield Beach,... May 2024Intrinsic characteristics of microorganisms, including non-specific metabolism sites, toxic byproducts, and uncontrolled proliferation constrain their exploitation in...
Intrinsic characteristics of microorganisms, including non-specific metabolism sites, toxic byproducts, and uncontrolled proliferation constrain their exploitation in medical applications such as tumor therapy. Here, the authors report an engineered biohybrid that can efficiently target cancerous sites through a pre-determined metabolic pathway to enable precise tumor ablation. In this system, DH5α Escherichia coli is engineered by the introduction of hypoxia-inducible promoters and lactate oxidase genes, and further surface-armored with iron-doped ZIF-8 nanoparticles. This bioengineered E. coli can produce and secrete lactate oxidase to reduce lactate concentration in response to hypoxic tumor microenvironment, as well as triggering immune activation. The peroxidase-like functionality of the nanoparticles extends the end product of the lactate metabolism, enabling the conversion of hydrogen peroxide (HO) into highly cytotoxic hydroxyl radicals. This, coupled with the transformation of tirapazamine loaded on nanoparticles to toxic benzotriazinyl, culminates in severe tumor cell ferroptosis. Intravenous injection of this biohybrid significantly inhibits tumor growth and metastasis.
PubMed: 38723206
DOI: 10.1002/adma.202404901 -
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 -
ACS Macro Letters May 2024The high glutathione (GSH) level of the tumor microenvironment severely affects the efficacy of photodynamic therapy (PDT). The current GSH depletion strategies have...
The high glutathione (GSH) level of the tumor microenvironment severely affects the efficacy of photodynamic therapy (PDT). The current GSH depletion strategies have difficulty meeting the dual needs of security and efficiency. In this study, we report a photosensitizer Chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) coloaded cross-linked multifunctional polymersome (TPZ/Ce6@SSPS) with GSH-triggered continuous GSH depletion for enhanced photodynamic therapy and hypoxia-activated chemotherapy. At tumor sites, the disulfide bonds of TPZ/Ce6@SSPS react with GSH to realize decross-linking for on-demand drug release. Meanwhile, the generated highly reactive quinone methide (QM) can further deplete GSH. This continuous GSH depletion will amplify tumor oxidative stress, enhancing the PDT effect of Ce6. Aggravated tumor hypoxia induced by PDT activates the prodrug TPZ, resulting in an enhanced combination of PDT and hypoxia-activated chemotherapy. Both and results demonstrate the efficient GSH depletion and potent antitumor activities by TPZ/Ce6@SSPS. This work provides a strategy for the design of a continuous GSH depletion platform, which holds great promise for enhanced combination tumor therapy.
Topics: Glutathione; Photochemotherapy; Tirapazamine; Animals; Mice; Humans; Photosensitizing Agents; Prodrugs; Chlorophyllides; Porphyrins; Antineoplastic Agents; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38683197
DOI: 10.1021/acsmacrolett.4c00125 -
Journal of Nanobiotechnology Apr 2024The elevated level of hydrogen sulfide (HS) in colon cancer hinders complete cure with a single therapy. However, excessive HS also offers a treatment target. A...
The elevated level of hydrogen sulfide (HS) in colon cancer hinders complete cure with a single therapy. However, excessive HS also offers a treatment target. A multifunctional cascade bioreactor based on the HS-responsive mesoporous CuCl(OH)-loaded hypoxic prodrug tirapazamine (TPZ), in which the outer layer was coated with hyaluronic acid (HA) to form TPZ@CuCl(OH)-HA (TCuH) nanoparticles (NPs), demonstrated a synergistic antitumor effect through combining the HS-driven cuproptosis and mild photothermal therapy. The HA coating endowed the NPs with targeting delivery to enhance drug accumulation in the tumor tissue. The presence of both the high level of HS and the near-infrared II (NIR II) irradiation achieved the in situ generation of photothermic agent copper sulfide (CuS) from the TCuH, followed with the release of TPZ. The depletion of HS stimulated consumption of oxygen, resulting in hypoxic state and mitochondrial reprogramming. The hypoxic state activated prodrug TPZ to activated TPZ (TPZ-ed) for chemotherapy in turn. Furthermore, the exacerbated hypoxia inhibited the synthesis of adenosine triphosphate, decreasing expression of heat shock proteins and subsequently improving the photothermal therapy. The enriched Cu induced not only cuproptosis by promoting lipoacylated dihydrolipoamide S-acetyltransferase (DLAT) heteromerization but also performed chemodynamic therapy though catalyzing HO to produce highly toxic hydroxyl radicals ·OH. Therefore, the nanoparticles TCuH offer a versatile platform to exert copper-related synergistic antitumor therapy.
Topics: Photothermal Therapy; Hydrogen Sulfide; Animals; Copper; Mice; Humans; Mitochondria; Prodrugs; Tirapazamine; Nanoparticles; Hyaluronic Acid; Cell Line, Tumor; Colonic Neoplasms; Mice, Inbred BALB C; Antineoplastic Agents; Mice, Nude
PubMed: 38658965
DOI: 10.1186/s12951-024-02480-x -
Journal of Biochemical and Molecular... Apr 2024Normoxic inactivation of prolyl hydroxylase-2 (PHD-2) in tumour microenvironment paves the way for cancer cells to thrive under the influence of HIF-1α and NF-κB....
Normoxic inactivation of prolyl hydroxylase-2 (PHD-2) in tumour microenvironment paves the way for cancer cells to thrive under the influence of HIF-1α and NF-κB. Henceforth, the present study is aimed to identify small molecule activators of PHD-2. A virtual screening was conducted on a library consisting of 265,242 chemical compounds, with the objective of identifying molecules that exhibit structural similarities to the furan chalcone scaffold. Further, PHD-2 activation potential of screened compound was determined using in vitro 2-oxoglutarate assay. The cytotoxic activity and apoptotic potential of screened compound was determined using various staining techniques, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, 4',6-diamidino-2-phenylindole (DAPI), 1,1',3,3'-tetraethylbenzimi-dazolylcarbocyanine iodide (JC-1), and acridine orange/ethidium bromide (AO/EB), against MCF-7 cells. 7,12-Dimethylbenz[a]anthracene (DMBA) model of mammary gland cancer was used to study the in vivo antineoplastic efficacy of screened compound. [(E)-1-(4-fluorophenyl)-3-(furan-2-yl) prop-2-en-1-one] (BBAP-7) was screened and validated as a PHD-2 activator by an in vitro 2-oxo-glutarate assay. The IC of BBAP-7 on MCF-7 cells is 18.84 µM. AO/EB and DAPI staining showed nuclear fragmentation, blebbing and condensation in MCF-7 cells following BBAP-7 treatment. The red-to-green intensity ratio of JC-1 stained MCF-7 cells decreased after BBAP-7 treatment, indicating mitochondrial-mediated apoptosis. DMBA caused mammary gland dysplasia, duct hyperplasia and ductal carcinoma in situ. Carmine staining, histopathology, and scanning electron microscopy demonstrated that BBAP-7, alone or with tirapazamine, restored mammary gland surface morphology and structural integrity. Additionally, BBAP-7 therapy significantly reduced oxidative stress and glycolysis. The findings reveal that BBAP-7 activates PHD-2, making it a promising anticancer drug.
Topics: Humans; Prolyl Hydroxylases; Chalcones; Antineoplastic Agents; Acridine Orange; Apoptosis; Chalcone; Carcinoma; Tumor Microenvironment; Benzimidazoles; Carbocyanines
PubMed: 38486411
DOI: 10.1002/jbt.23679