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Journal of Colloid and Interface Science Jan 2023The hypoxic tumor microenvironment and photodynamic therapy (PDT)-aggravated hypoxia compromise the anticancer efficacy of chemotherapy, immunotherapy, and PDT. Thus,...
The hypoxic tumor microenvironment and photodynamic therapy (PDT)-aggravated hypoxia compromise the anticancer efficacy of chemotherapy, immunotherapy, and PDT. Thus, sophisticated nanomedicines that can activate their anticancer capability in situ in response to specific stimuli need to be developed. This study aimed to construct a hybrid nanomedicine that activated chemotherapy by inducing hypoxia, which synergized with PDT to promote antitumor outcomes, contrary to the strategies focusing on reversing tumor hypoxia. The hybridization of a porphyrin metal-organic framework (MOF) and gold nanoparticles (AuNPs) enhanced the stability of the hybrid nanomedicine against the phosphate in blood, thereby preventing the premature drug release during blood circulation. The surface modification with polyethylene glycol (PEG) markedly increased the tumor accumulation of the hybrid MOF nanomedicine, which encapsulated a hypoxia-activated prodrug (tirapazamine, TPZ), by enhancing its colloidal stability and pharmacokinetics. The loaded TPZ was rapidly released from the nanomedicine in response to the concentrated intracellular phosphate after cellular uptake, and was then converted into a potent anticancer drug in a hypoxic microenvironment exacerbated by continuous O consumption during PDT. In vitro and in vivo experiments demonstrated that the synergistic PDT and hypoxia-activated chemotherapy exhibited enhanced antitumor therapeutic efficiency and superior antimetastatic effect, and effectively ablated the tumor without recurrence. Therefore, the sophisticated nanomedicine reported here, which eliminated cancer cells by inducing a hypoxic tumor microenvironment, showed translational potential in future therapeutic development.
Topics: Humans; Photosensitizing Agents; Nanomedicine; Metal-Organic Frameworks; Gold; Photochemotherapy; Metal Nanoparticles; Neoplasms; Hypoxia; Phosphates; Cell Line, Tumor; Nanoparticles; Tumor Microenvironment
PubMed: 36162395
DOI: 10.1016/j.jcis.2022.09.061 -
Journal of Controlled Release :... Nov 2022Photodynamic therapy (PDT) can produce a large amount of reactive oxygen species (ROS) in the radiation field to kill tumor cells. However, the sustainable anti-tumor...
Photodynamic therapy (PDT) can produce a large amount of reactive oxygen species (ROS) in the radiation field to kill tumor cells. However, the sustainable anti-tumor efficacy of PDT is limited due to the hypoxic microenvironment of tumor. In this study, classic PDT agent indocyanine green (ICG) and hypoxia-activated chemotherapeutic drug tirapazamine (TPZ) were loaded on mesoporous polydopamine (PDA) to construct PDA@ICG-TPZ nanoparticles (PIT). Then, PIT was camouflaged with cyclic arginine-glycine-aspartate (cRGD) modified tumor cell membranes to obtain the engineered membrane-coated nanoreactor (cRGD-mPIT). The nanoreactor cRGD-mPIT could achieve the dual-targeting ability via tumor cell membrane mediated homologous targeting and cRGD mediated active targeting. With the enhanced tumor-targeting and penetrating delivery system, PIT could efficiently accumulate in hypoxic tumor cells and the loaded drugs were quickly released in response to near-infrared (NIR) laser. The nanoreactor might produce cytotoxic ROS under NIR and further enhance hypoxia within tumor to activate TPZ, which efficiently inhibited hypoxic tumor by synergistic photodynamic-chemotherapy. Mechanically, hypoxia-inhibitory factor-1α (HIF-1α) was down-regulated by the synergistic therapy. Accordingly, the cRGD-mPIT nanoreactor with sustainable and cascade anti-tumor effects and satisfied biosafety might be a promising strategy in hypoxic tumor therapy.
Topics: Humans; Reactive Oxygen Species; Biomimetics; Tirapazamine; Photochemotherapy; Neoplasms; Indocyanine Green; Hypoxia; Nanoparticles; Nanotechnology; Cell Line, Tumor; Photosensitizing Agents; Tumor Microenvironment
PubMed: 36122895
DOI: 10.1016/j.jconrel.2022.09.020 -
Biomaterials Oct 2022Hypoxia is one of the prominent features of solid tumors. Hypoxia activated prodrugs (HAPs), selectively killing hypoxic cells, possess the potential to transform...
Hypoxia is one of the prominent features of solid tumors. Hypoxia activated prodrugs (HAPs), selectively killing hypoxic cells, possess the potential to transform hypoxia from a nuisance to an advantage in precision therapy. Exhibiting a more significant hypoxic microenvironment, gliomas, as the most frequent and incurable neurological tumors, provide HAPs a more attractive therapeutic prospect. However, the insufficient hypoxia and the obstruction of the blood-brain barrier (BBB) severely limit the activation and bio-availability of HAPs. Herein, a novel nanoparticle iRGD@ZnPc + TPZ was designed and synthesized to achieve gliomas inhibition by encapsulating tirapazamine (TPZ) as a HAP and zinc phthalocyanine (ZnPc) as a photosensitizer to enhance hypoxia. iRGD@ZnPc + TPZ can realize breakthrough BBB, deep penetration, and significant retention in gliomas, which is attributed to the iRGD-mediated receptor targeting and active transport. After being internalized by tumor cells and radiated, ZnPc efficiently consumes intratumoral O to produce reactive oxygen species, which not only implements tumor suppression, but also intensify hypoxia to activate TPZ for amplifying chemotherapy. The photosensitizer-enhanced activation of HAPs inhibits gliomas growth. This study provides a new strategy with sensitizing and activating HAPs for gliomas treatment in clinical.
Topics: Antineoplastic Agents; Cell Line, Tumor; Glioma; Humans; Hypoxia; Indoles; Isoindoles; Neoplasms; Organometallic Compounds; Photosensitizing Agents; Prodrugs; Reactive Oxygen Species; Tirapazamine; Tumor Microenvironment; Zinc Compounds
PubMed: 36075142
DOI: 10.1016/j.biomaterials.2022.121770 -
Acta Biomaterialia Oct 2022Sonodynamic therapy (SDT) is a promising strategy for tumor treatment that satisfies all requirements of penetrating deep-seated tissues without causing additional...
Sonodynamic therapy (SDT) is a promising strategy for tumor treatment that satisfies all requirements of penetrating deep-seated tissues without causing additional trauma. However, the hypoxic tumor microenvironment impairs the therapeutic effect of SDT. The synergistic treatment of oxygen concentration-dependent SDT and bio-reductive therapy has been proven to be an effective approach to improve the therapeutic efficiency of SDT by exploiting tumor hypoxia. Herein, a biomimetic drug delivery system (C-TiO/TPZ@CM) was successfully synthesized for combined SDT and hypoxia-activated chemotherapy, which was composed of tirapazamine (TPZ)-loaded C-TiO hollow nanoshells (HNSs) as the inner cores and cancer cell membrane (CM) as the outer shells. C-TiO HNSs coated with CM achieved tumor targeting via homologous binding. C-TiO@CM as a nanocarrier loaded with TPZ in the presence of the trapping ability of CM and the special cavity structure of C-TiO HNSs. Moreover, C-TiO HNSs as sonosensitizers killed cancer cells under ultrasound (US) irradiation. Oxygen depletion during SDT induced a hypoxic environment in the tumor to activate the killing effect of co-delivered TPZ, thereby obtaining satisfactory synergistic therapeutic effects. In addition, C-TiO@CM exhibited remarkable biocompatibility without manifest damage and toxicity to the blood and major organs of the mice. The study highlighted that C-TiO/TPZ@CM served as a powerful biomimetic drug delivery system for effective SDT by exploiting tumor hypoxia. STATEMENT OF SIGNIFICANCE: • C-TiO@CM achieved tumor targeting via homologous binding. • C-TiO hollow nanoshells could be used as a sonosensitizer and drug carrier for synergistic SDT and hypoxia-activated chemotherapy. • C-TiO/TPZ@CM showed no obvious toxicity under the injection dose.
Topics: Animals; Cell Line, Tumor; Cell Membrane; Drug Carriers; Hypoxia; Mice; Nanoshells; Neoplasms; Oxygen; Reactive Oxygen Species; Tirapazamine; Titanium; Ultrasonic Therapy
PubMed: 36067874
DOI: 10.1016/j.actbio.2022.08.067 -
Biomaterials Sep 2022Vascular disrupting agents (VDAs) have great potential in antitumor therapy, while the efficiency is limited by cardiovascular toxicity. In this study, a self-activating...
Vascular disrupting agents (VDAs) have great potential in antitumor therapy, while the efficiency is limited by cardiovascular toxicity. In this study, a self-activating nanoized plinabulin (poly (-glutamic acid) grafted Azo-Plinabulin, AzoP-NP) was constructed. The AzoP-NPs can selectively be activated to an amino derivative of plinabulin (AmP) by intrinsic tumor hypoxia, disrupting tumor vessels and amplifying hypoxia, whilst be activated by self-amplified tumor hypoxia, then selectively inhibit tumor growth. In 4T1 tumor model, the AzoP-NPs had a selective biodistribution in tumor, as the free AmP in tumors at 24 h after AzoP-NPs treatment was 18.6 fold of that after AmP treatment and significantly higher than that in other tissues. Accordingly, AzoP-NPs resulted in no obvious acute cardiovascular toxicity (plasma von Willebrand factor in PBS, AzoP-NPs and AmP group: 143.1, 184.0 and 477.6 ng/mL) and a significantly stronger tumor inhibition than AmP. And the sustained release of drug in AzoP-NPs led to a higher maximum tolerated dose (MTD) (MTD of AzoP-NPs and AmP: > 80 vs 20 mg/kg). In addition, AzoP-NPs amplified tumor hypoxic, and synergized the anti-tumor effect of Tirapazamine (TPZ), a hypoxia-activated drug in clinical trials, with an inhibition rate of 97.7% and Q value of 1.89. Therefore, our findings provide new insights into next generation VDAs and their application in tumor therapy.
Topics: Animals; Mice; Antineoplastic Agents; Cell Line, Tumor; Hypoxia; Mice, Inbred BALB C; Tissue Distribution
PubMed: 35995623
DOI: 10.1016/j.biomaterials.2022.121736 -
Journal of Photochemistry and... Sep 2022The treatment efficacy of anticancer drugs in complex physiological environments is still restricted by multi-drug resistance. To overcome this issue, a nanodrug system...
Enhanced photo-hypoxia-activated combination therapy traced by AIE photosensitizer and targeted by hyaluronic acid: Disulphide bond interference of detoxification barrier.
The treatment efficacy of anticancer drugs in complex physiological environments is still restricted by multi-drug resistance. To overcome this issue, a nanodrug system of HA-SS@CuS@ZIF-8@TPZ&TBMACN (HSCZTT) that breaks through the detoxification barrier for tirapazamine (TPZ) delivery was developed in this manuscript. In addition to the photothermal effect aroused by CuS in HSCZTT, which can damage tumour cells, TBMACN with photostable fluorescence in the aggregate state can also generate sufficient reactive oxygen species (ROS) to destroy tumour cells. The continuous consumption of oxygen in PDT aggravates the hypoxic environment of tumours, which further activates the TPZ released in the acidic microenvironment of the tumour to achieve apoptosis of the tumour cells. The HSCZTT can not only target the CD44 receptor overexpressed on the surface of the cancer cell, but can also effectively consume a large amount of glutathione (GSH) through the disulphide bond-modified hyaluronic acid, which serves as a targeted disulphide bond, interfering with the detoxification barrier. Our finding presents a rational strategy to overcome multidrug resistance for the improved efficacy of anticancer drugs by the targeting of Hyaluronic acid (HA), release of the drug by the acid response of ZIF-8, breakthrough of the detoxification barrier, precise positioning of the drug release and combined treatment with phototherapy and hypoxia-activated chemotherapy.
Topics: Antineoplastic Agents; Cell Line, Tumor; Disulfides; Humans; Hyaluronic Acid; Hypoxia; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Tirapazamine; Tumor Microenvironment
PubMed: 35930948
DOI: 10.1016/j.jphotobiol.2022.112535 -
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 -
Technology in Cancer Research &... 2022The tumor microenvironment is complex and changeable, so the design of a nano-delivery system for the tumor microenvironment has attracted wide attention. Based on this,...
The tumor microenvironment is complex and changeable, so the design of a nano-delivery system for the tumor microenvironment has attracted wide attention. Based on this, we designed an intelligent nano-reactor for the characteristics of acidic pH and hypoxia in the tumor microenvironment. Firstly, the silver nano-balls were synthesized by the biological template method, which exhibited a good photothermal conversion efficiency and can realize the photothermal treatment of tumor sites. Subsequently, the hypoxic prodrug tirapazamine (TPZ) and polydopamine (PDA) for chemotherapy were self-assembled. After PDA arrived at the tumor site (pH 5.5) from the normal physiological environment (pH 7.4), the hypoxic prodrug TPZ was released in pH response by PDA. Subsequently, TPZ selectively induced obvious cell damage under tumor hypoxia stimulation but had no toxic effect on normal cells under normal oxygen. In addition, the nano-converter was loaded with iRGD on the surface, which enhanced the targeted delivery of the nano-reactor to achieve a highly effective antitumor effect. The nano-reactor was capable of combining photothermal/chemotherapy therapy. Importantly, it can selectively kill tumor cells without damaging normal cells based on the characteristics of the tumor microenvironment, with high bio-safety and clinical transformation potential.
Topics: Cell Line, Tumor; Humans; Nanoparticles; Neoplasms; Prodrugs; Tirapazamine; Tumor Microenvironment
PubMed: 35712964
DOI: 10.1177/15330338221095670 -
Biomedicine & Pharmacotherapy =... Jul 2022Tirapazamine (TPZ) is a promising hypoxia-selective cytotoxic agent that may exert synergistic tumor-killing activity with transcatheter arterial embolization (TAE) for...
Tirapazamine (TPZ) is a promising hypoxia-selective cytotoxic agent that may exert synergistic tumor-killing activity with transcatheter arterial embolization (TAE) for liver cancer. To investigated whether TPZ-loaded microspheres enhance the synergy between TPZ and TAE in liver cancer, we prepared TPZ-loaded CalliSpheres microspheres (CSMTPZs) and characterized their properties as a chemoembolization agent in vitro. Tumor hypoxia after TAE was detected in the rabbit VX2 model of liver cancer using a modified Clark-type microelectrode research system. CSMTPZ therapy was performed in the animal model. The plasma and tumor concentrations of TPZ and its metabolites were measured, and the efficacy and safety of CSMTPZ therapy were evaluated and compared with those of the conventional combination of intraarterial TPZ injection and embolization. The results showed that CSMTPZs displayed favorable in vitro properties including drug loading and release and microsphere size, shape, and surface profiles. TAE induced acute tumor hypoxia, but residual tumor cells responded to hypoxia through hypoxia-inducible factor 1α. CSMTPZ therapy improved TPZ delivery into tumor tissue with minimal systemic exposure. Accordingly, CSMTPZ therapy exhibited advantages in terms of hypoxia-selected cytotoxicity, tumor apoptosis and necrosis, animal survival, and safety over the conventional combination of TPZ and TAE. We revealed the improved synergistic anti-tumor effects of CSMTPZ therapy in the rabbit VX2 liver cancer model. Our data support the clinical evaluation of CSMTPZs in the treatment of hepatocellular carcinoma, and CSMTPZ administration might serve as a successful therapeutic strategy for this malignancy.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Embolization, Therapeutic; Hypoxia; Liver Neoplasms; Microspheres; Rabbits; Tirapazamine
PubMed: 35594702
DOI: 10.1016/j.biopha.2022.113123 -
Chemical Communications (Cambridge,... May 2022Nanosheet carriers loaded with drugs and phototherapeutics are used for effective cancer therapy, but the process remains challenging. Here, we prepared sulfur...
Nanosheet carriers loaded with drugs and phototherapeutics are used for effective cancer therapy, but the process remains challenging. Here, we prepared sulfur nanosheets (S-NSs) and then loaded tirapazamine (TPZ) and indocyanine green (ICG) with a loading efficiency of 6.3% and 94%, respectively. The obtained S-NSs-TPZ-ICG exhibits near-infrared (NIR) fluorescence, high O generation and photothermal conversion capabilities, good biocompatibility, and tumor microenvironment responsiveness. and experiments reveal that S-NSs-TPZ-ICG can be selectively decomposed under acidic and HO conditions to release TPZ and ICG, and significantly inhibit tumor growth under laser irradiation without obvious toxic side effects.
Topics: Cell Line, Tumor; Humans; Hydrogen Peroxide; Indocyanine Green; Nanoparticles; Neoplasms; Phototherapy; Sulfur; Tirapazamine; Tumor Microenvironment
PubMed: 35510707
DOI: 10.1039/d2cc01165d