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Advanced Materials (Deerfield Beach,... Jan 2024Combination therapy has emerged as a promising approach for effective tumor treatment. However, the combination of sonodynamic therapy (SDT) and hypoxia-activated...
Combination therapy has emerged as a promising approach for effective tumor treatment. However, the combination of sonodynamic therapy (SDT) and hypoxia-activated prodrugs (HAPs) has not been explored due to the contradictory requirement of oxygen (O ) for reactive oxygen species (ROS) generation and the necessity to avoid O for the activation of HAPs. In this study, this challenge is addressed by developing BiOCl-Au-Ag S Z-scheme heterostructure nanoparticles loaded with tirapazamine (TPZ) to achieve O -independent therapy. These nanoparticles demonstrate efficient electron-hole separation under ultrasound irradiation while maintaining a high redox potential. The generated holes react with water to efficiently produce hydroxyl radicals, while the electrons autonomously activate TPZ, negating the need for O . In vitro and in vivo assessments validate the effective tumor elimination by these Z-scheme nanoparticles without disrupting the hypoxic environment. This innovative design overcomes the limitations associated with O requirement in SDT and introduces a novel strategy for HAP activation and synergistic therapy between ROS and HAPs-based therapy.
Topics: Humans; Oxygen; Reactive Oxygen Species; Prodrugs; Tirapazamine; Hypoxia; Neoplasms; Cell Line, Tumor; Nanoparticles
PubMed: 37856705
DOI: 10.1002/adma.202307929 -
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 -
ACS Applied Bio Materials Sep 2023Hypoxia may enhance the chemoresistance of cancer cells and can significantly compromise the effectiveness of chemotherapy. Many efforts have been made to relieve or...
Hypoxia may enhance the chemoresistance of cancer cells and can significantly compromise the effectiveness of chemotherapy. Many efforts have been made to relieve or reverse hypoxia by introducing more oxygen into the tumor microenvironment (TME). Acting in a diametrically opposite way, in the current study, a novel nanocarrier was designed to further exhaust the oxygen level of the hypoxic TME. By creating such an oxygen depleted TME, the hypoxia-selective cytotoxin can work effectively, and oxygen exhaustion triggered chemotherapy can be achieved. Herein, deoxygenation agent, FDA-approved perfluorocarbon (PFC) and photosensitizer indocyanine green (ICG) for oxygen depletion, along with the hypoxia-activating drug tirapazamine (TPZ), were coincorporated within the poly(lactic--glycolic acid) (PLGA) nanoemulsion (ICG/TPZ@PPs) for the treatment of hypoxic tumors. Following hypoxia amplifying through physical oxygen dissolution and photodynamic depletion in tumors, hypoxic chemotherapy could be effectively activated to improve multitreatment synergy. After achieving local tumor enrichment, PFC-mediated oxygen dissolution combined with further ICG-mediated photodynamic therapy (PDT) under near-infrared (NIR) laser irradiation could induce enhanced hypoxia, which would activate the antitumor activity of codelivered TPZ to synergize cytotoxicity. Remarkably, experimental results exhibited that deoxygenated ICG/TPZ@PPs-based photothermal therapy (PTT), PDT, and hypoxia activated chemotherapy have an excellent synergistic ablation of tumors without obvious side effects, and therefore, a broad prospect of application of this nanocarrier could be expected.
Topics: Humans; Prodrugs; Solubility; Hypoxia; Oxygen; Fluorocarbons; Indocyanine Green
PubMed: 37644623
DOI: 10.1021/acsabm.3c00566 -
Cells Aug 2023Although melanoma accounts for only 5.3% of skin cancer, it results in >75% of skin-cancer-related deaths. To avoid disfiguring surgeries on the head and neck associated...
Although melanoma accounts for only 5.3% of skin cancer, it results in >75% of skin-cancer-related deaths. To avoid disfiguring surgeries on the head and neck associated with surgical excision, there is a clear unmet need for other strategies to selectively remove cutaneous melanoma lesions. Mohs surgery is the current treatment for cutaneous melanoma lesions and squamous and basal cell carcinoma. While Mohs surgery is an effective way to remove melanomas in situ, normal tissue is also excised to achieve histologically negative margins. This paper describes a novel combination therapy of nonthermal plasma (NTP) which emits a multitude of reactive oxygen species (ROS) and the injection of a pharmaceutical agent. We have shown that the effects of NTP are augmented by the DNA-damaging prodrug, tirapazamine (TPZ), which becomes a free radical only in conditions of hypoxemia, which is often enhanced in the tumor microenvironment. In this study, we demonstrate the efficacy of the combination therapy through experiments with B16-F10 and 1205 Lu metastatic melanoma cells both in vitro and in vivo. We also show the safety parameters of the therapy with no significant effects of the therapy when applied to porcine skin. We show the need for the intratumor delivery of TPZ in combination with the surface treatment of NTP and present a model of a medical device to deliver this combination therapy. The importance of functional gap junctions is indicated as a mechanism to promote the therapeutic effect. Collectively, the data support a novel therapeutic combination to treat melanoma and the development of a medical device to deliver the treatment in situ.
Topics: Swine; Animals; Melanoma; Skin Neoplasms; Tirapazamine; Combined Modality Therapy; Tumor Microenvironment; Melanoma, Cutaneous Malignant
PubMed: 37626923
DOI: 10.3390/cells12162113 -
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 -
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 -
Journal of Colloid and Interface Science Dec 2023One of the major challenges in effective cancer therapy arises because of the hypoxic microenvironment in the tumor. This compromises the efficacy of both chemo- and...
One of the major challenges in effective cancer therapy arises because of the hypoxic microenvironment in the tumor. This compromises the efficacy of both chemo- and radiotherapy, and thus hinders patient outcomes. To solve this problem, we constructed polydopamine (PDA)-cloaked Fe-based metal organic frameworks (MOFs) loaded with d-arginine (d-Arg), glucose oxidase (GOX), and the chemotherapeutic drug tirapazamine (TPZ). These offer simultaneous multifaceted therapy combining chemodynamic therapy (CDT)/radiotherapy (RT)/starvation therapy (ST)/gas therapy (GT) and chemotherapy. The particles further can act as contrast agents in magnetic resonance imaging. GOX catalyses the conversion of endogenous glucose and O to hydrogen peroxide and gluconic acid, blocking the cells' energy supply and providing ST. With the resultant acidification of the local environment, the breakdown of the MOF releases TPZ (for chemotherapy) and Fe, which reacts with HO to produce reactive oxygen species and thus stimulates the conversion of d-Arg to NO for GT and RT sensitization. The PDA coating not only seals the pores and chelates Fe to enhance the T-weighted magnetic resonance imaging (MRI) properties, but also is used to graft folate bovine serum albumin (FA-BSA) and thereby target the tumor site. The combined administration of low doses of X-ray irradiation and nanoparticles reduces the side effects on healthy tissue and can prevent lung metastases in mice. This work highlights the synergistic treatment of osteosarcoma via ST/GT/CDT/RT/MRI/ chemotherapy using a PDA-cloaked MOF system.
Topics: Mice; Animals; Metal-Organic Frameworks; Hydrogen Peroxide; Neoplasms; Osteosarcoma; Nanoparticles; Bone Neoplasms; Cell Line, Tumor; Glucose Oxidase; Tumor Microenvironment
PubMed: 37540932
DOI: 10.1016/j.jcis.2023.07.146 -
Biomaterials Oct 2023The efficacy of photodynamic therapy (PDT) is severely limited by the hypoxic tumor microenvironment (TME), while the performance of PDT-aroused antitumor immunity is...
The efficacy of photodynamic therapy (PDT) is severely limited by the hypoxic tumor microenvironment (TME), while the performance of PDT-aroused antitumor immunity is frustrated by the immunosuppressive TME and deficient immunogenic cell death (ICD) induction. To simultaneously tackle these pivotal problems, we herein create an albumin-based nanoplatform co-delivering IR780, NLG919 dimer and a hypoxia-activated prodrug tirapazamine (TPZ) as the dual enhancer for synergistic cancer therapy. Under NIR irradiation, IR780 generates O for PDT, which simultaneously cleaves the ROS-sensitive linker for triggered TPZ release, and activates its chemotherapy via exacerbated tumor hypoxia. Meanwhile, firstly found by us, TPZ-mediated chemotherapy boosts PDT-induced tumor ICD to evoke stronger antitumor immunity including the development of tumor-specific cytotoxic T lymphocytes (CTLs). Eventually, enriched intratumoral GSH triggers the activation of NLG919 to mitigate the immunosuppressive TME via specific indoleamine 2,3-dioxygenase 1 (IDO-1) inhibition, consequently promoting the intratumoral infiltration of CTLs and the killing of both primary and distant tumors, while the resultant memory T cells allows nearly 100% suppression of tumor recurrence and metastasis. This nanoplatform sets up an example for dully enhanced photodynamic immunotherapy of breast cancer via hypoxia-activated chemotherapy, and paves a solid way for the treatment of other hypoxic and immunosuppressive malignant tumors.
Topics: Humans; Photochemotherapy; Neoplasm Recurrence, Local; Tirapazamine; Hypoxia; Neoplasms; Immunotherapy; Cell Line, Tumor; Photosensitizing Agents; Tumor Microenvironment; Nanoparticles
PubMed: 37531778
DOI: 10.1016/j.biomaterials.2023.122257 -
Chembiochem : a European Journal of... Oct 2023BODIPY photosensitizers have been integrated with a hypoxia-activated prodrug to achieve synergistic photodynamic therapy (PDT) and chemotherapy. A novel BODIPY...
BODIPY photosensitizers have been integrated with a hypoxia-activated prodrug to achieve synergistic photodynamic therapy (PDT) and chemotherapy. A novel BODIPY derivative BDP-CN was designed and synthesized. It had two cyano groups to make it complex well with a water-soluble pillar[5]arene. Their association constant was calculated to be (6.8±0.9)×10 M . After self-assembly in water, regular spherical nanocarriers can be formed; these were used to encapsulate the hypoxia-activated prodrug tirapazamine (TPZ). BDP-CN displayed excellent photodynamic activity to complete PDT. In this process, O can be continuously consumed to activate TPZ to allow it to be converted to a benzotriazinyl (BTZ) radical with high cytotoxicity to complete chemotherapy. As a result, the formed nanoparticles showed excellent synergistic photodynamic therapy and chemotherapy efficacy. The synergistic therapy mechanism is discussed in detail.
PubMed: 37463099
DOI: 10.1002/cbic.202300461 -
Biomaterials Science Aug 2023Moderate oxygen (O) supply and uneven distribution of oxygen at the tumor site usually hinder the therapeutic efficacy of hypoxia-activated prodrugs. In this report, we...
Moderate oxygen (O) supply and uneven distribution of oxygen at the tumor site usually hinder the therapeutic efficacy of hypoxia-activated prodrugs. In this report, we designed a ferrocene-containing supramolecular nanomedicine (PFC/GOD-TPZ) with the PEG corona and disulfide-bond cross-linked core to co-encapsulate 4-di--oxide tirapazamine (TPZ) and glucose oxidase (GOD). The PEG corona of PFC/GOD-TPZ could be weakly acidic tumor pH-responsively detached for an enhanced cellular internalization, while the disulfide-bond cross-linked core could be cleavaged by intracellular glutathione (GSH) to present a GSH-triggered drug-release behavior. Subsequently, the cascade reactions, including catalytic reactions among the released GOD, glucose, and O to generate HO and the subsequent Fenton reaction between ferrocene and HO, occurred. With the depletion of O, the non-toxic TPZ was activated and converted into the cytotoxic therapeutic agent benzotriazinyl (BTZ) radical under the exacerbated hypoxic microenvironment. Collectively, the PFC/GOD-TPZ provides a promising strategy for effective combination therapy of GOD-mediated starvation therapy, chemodynamic therapy (CDT), and hypoxia-activated chemotherapy (CT).
Topics: Humans; Nanomedicine; Metallocenes; Hydrogen Peroxide; Antineoplastic Agents; Tirapazamine; Neoplasms; Oxygen; Hypoxia; Glutathione; Disulfides; Hydrogen-Ion Concentration; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37439102
DOI: 10.1039/d3bm00519d