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Science Advances Mar 2021Various cancers treated with cisplatin almost invariably develop drug resistance that is frequently caused by substantial DNA repair. We searched for acquired...
Various cancers treated with cisplatin almost invariably develop drug resistance that is frequently caused by substantial DNA repair. We searched for acquired vulnerabilities of cisplatin-resistant cancers to identify undiscovered therapy. We herein found that cisplatin resistance of cancer cells comes at a fitness cost of increased intracellular hypoxia. Then, we conceived an inspired strategy to combat the tumor drug resistance by exploiting the increased intracellular hypoxia that occurs as the cells develop drug resistance. Here, we constructed a hypoxia-amplifying DNA repair-inhibiting liposomal nanomedicine (denoted as HYDRI NM), which is formulated from a platinum(IV) prodrug as a building block and payloads of glucose oxidase (GOx) and hypoxia-activatable tirapazamine (TPZ). In studies on clinically relevant models, including patient-derived organoids and patient-derived xenograft tumors, the HYDRI NM is able to effectively suppress the growth of cisplatin-resistant tumors. Thus, this study provides clinical proof of concept for the therapy identified here.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cisplatin; DNA Repair; Humans; Hypoxia; Nanomedicine; Neoplasms; Tirapazamine
PubMed: 33771859
DOI: 10.1126/sciadv.abc5267 -
Frontiers in Bioengineering and... 2023Cancer selectivity, including targeted internalization and accelerated drug release in tumor cells, remains a major challenge for designing novel stimuli-responsive...
Cancer selectivity, including targeted internalization and accelerated drug release in tumor cells, remains a major challenge for designing novel stimuli-responsive nanocarriers to promote therapeutic efficacy. The hypoxic microenvironment created by photodynamic therapy (PDT) is believed to play a critical role in chemoresistance. We construct dual-responsive carriers (NP) that encapsulate the photosensitizer chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) to enable efficient PDT and PDT-boosted hypoxia-activated chemotherapy. Due to TAT masking, NP prolonged payload circulation in the bloodstream, and selective tumor cell uptake occurred via acidity-triggered TAT presentation. PDT was performed with a spatially controlled 660-nm laser to enable precise cell killing and exacerbate hypoxia. Hypoxia-responsive conversion of the hydrophobic NI moiety led to the disassembly of NP, facilitating TPZ release. TPZ was reduced to cytotoxic radicals under hypoxic conditions, contributing to the chemotherapeutic cascade. This work offers a sophisticated strategy for programmed chemo-PDT.
PubMed: 37362218
DOI: 10.3389/fbioe.2023.1197404 -
Biomaterials Science Aug 2019Tumor hypoxia, which is indispensable to tumor propagation and therapy resistance, has been one of the most important factors influencing clinical outcomes. To modulate...
Tumor hypoxia, which is indispensable to tumor propagation and therapy resistance, has been one of the most important factors influencing clinical outcomes. To modulate the hypoxia microenvironment, we herein developed reactive oxygen species (ROS)-sensitive arylboronic ester-based biomimetic nanocarriers co-encapsulated with a photosensitizer chlorin e6 (Ce6) and a hypoxia-activated prodrug tirapazamine (TPZp) for tumor-specific release and synergistic photodynamic chemotherapy. In order to bypass macrophage uptake and improve tumor penetration, the nanocarriers were further modified with the red blood cell membrane and iRGD peptide (denoted as NPs@i-RBMCe6+TPZp). After administration, NPs@i-RBMCe6+TPZp exhibited prolonged blood circulation, selective tumor accumulation and excellent penetration into the tumor interior. Upon light irradiation, ROS were generated by Ce6 for photodynamic therapy (PDT), which subsequently caused dissociation of the ROS-responsive nanocarriers. An enhanced therapeutic effect was further achieved through the activation of TPZp in the aggravated local hypoxia microenvironment. The synergistic cancer therapy based on NPs@i-RBMCe6+TPZp significantly suppressed tumor growth with negligible side effects. The biomimetic nanocarriers have great potential to overcome hypoxia-limited PDT, and significantly improve the anticancer efficacy by synergistic tumor-targeted PDT and hypoxia-activated chemotherapy.
Topics: Animals; Antineoplastic Agents; Biomimetic Materials; Breast Neoplasms; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Carriers; Drug Screening Assays, Antitumor; Female; Mice; Molecular Structure; Nanoparticles; Photochemotherapy; Photosensitizing Agents; Prodrugs; Reactive Oxygen Species; Structure-Activity Relationship; Tirapazamine
PubMed: 31187794
DOI: 10.1039/c9bm00634f -
Journal of Materials Chemistry. B Nov 2021Multimodal synergistic therapy has gained increasing attention in cancer treatment to overcome the limitations of monotherapy and achieve high anticancer efficacy. In...
A triple-stimulus responsive melanin-based nanoplatform with an aggregation-induced emission-active photosensitiser for imaging-guided targeted synergistic phototherapy/hypoxia-activated chemotherapy.
Multimodal synergistic therapy has gained increasing attention in cancer treatment to overcome the limitations of monotherapy and achieve high anticancer efficacy. In this study, a synergistic phototherapy and hypoxia-activated chemotherapy nanoplatform based on natural melanin nanoparticles (MPs) loaded with the bioreduction prodrug tirapazamine (TPZ) and decorated with hyaluronic acid (HA) was developed. A self-reporting aggregation-induced emission (AIE)-active photosensitizer (PS) (BATTMN) was linked to the prepared nanoparticles by boronate ester bonds. The MPs and BATTMN-HA played roles as quenchers for PS and cancer targeting/photodynamic moieties, respectively. As a pH sensitive bond, the borate ester bonds between HA and BATTMN are hydrolysed in the acidic cancer environment, thereby separating BATTMN from the nanoparticles and leading to the induction of fluorescence for imaging-guided synergistic phototherapy/hypoxia-activated chemotherapy under dual irradiation. TPZ can be released upon activation by pH, near-infrared (NIR) and hyaluronidase (Hyal). Particularly, the hypoxia-dependent cytotoxicity of TPZ was amplified by oxygen consumption in the tumor intracellular environment induced by the AIE-active PS in photodynamic therapy (PDT). The nanoparticles developed in our research showed favorable photothermal conversion efficiency ( = 37%), desired cytocompatibility, and excellent synergistic therapeutic efficacy. The proposed nanoplatform not only extends the application scope of melanin materials with AIE-active PSs, but also offers useful insights into developing multistimulus as well as multimodal synergistic tumor treatment.
Topics: Animals; Antineoplastic Agents; Boronic Acids; Combined Modality Therapy; Drug Carriers; Drug Therapy; Female; Humans; MCF-7 Cells; Melanins; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Photosensitizing Agents; Photothermal Therapy; Prodrugs; Tirapazamine; Tumor Hypoxia; Xenograft Model Antitumor Assays; Mice
PubMed: 34693960
DOI: 10.1039/d1tb01657a -
Advanced Healthcare Materials Jan 2020Sonodynamic therapy (SDT) shows tremendous potential to induce immunogenic cell death (ICD) and activate antitumor immunity. However, it can aggravate hypoxia and...
Sonodynamic therapy (SDT) shows tremendous potential to induce immunogenic cell death (ICD) and activate antitumor immunity. However, it can aggravate hypoxia and release platelet (PLT)-associated danger-associated molecular patterns (DAMPs), which impede therapeutic efficacy and promote tumor metastasis. In order to solve these problems, a biomimetic decoy (designated as Lipo-Ce6/TPZ@M ) is constructed to reverse the drawbacks of SDT by loading sonosensitizer chlorin e6 (Ce6) and hypoxia-activated tirapazamine (TPZ) in the red blood cells-PLTs hybrid membrane (M )-camouflaged pH-sensitive liposome. After administration, the decoy exhibits enhanced cancer accumulation and retention abilities due to the immune escape and specific targeting behaviors by biomimetic surface coating. Upon local ultrasound, Ce6 produces toxic reactive oxygen species for SDT, and the resulting hypoxia microenvironment activates TPZ, which can realize a high-effective synergistic therapy. Meanwhile, DAMPs-mediated tumor metastasis is significantly inhibited, because the decoy retains platelet binding functions but is incapable of platelet-mediated metastasis. In addition, ICD-mediated strong antitumor immunities further prevent the growth and metastasis of the residual tumors left behind after synergistic treatment. Taken together, this study highlights the potential of using this cascade therapeutic therapy plus biomemitic decoy in one nanosystem to both eliminate melanoma in situ and suppress lung metastasis.
Topics: Animals; Antineoplastic Agents; Apoptosis; Biomimetic Materials; Cell Hypoxia; Cell Line, Tumor; Chlorophyllides; Humans; Liposomes; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Porphyrins; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Tirapazamine; Tissue Distribution; Ultrasonic Therapy; Xenograft Model Antitumor Assays
PubMed: 31762228
DOI: 10.1002/adhm.201901335 -
ACS Applied Materials & Interfaces Jul 2018The oxygen-dependent feature of most photosensitizers (PSs) and the aggravated hypoxia tumor microenvironment seriously impede the photodynamic therapy (PDT)...
The oxygen-dependent feature of most photosensitizers (PSs) and the aggravated hypoxia tumor microenvironment seriously impede the photodynamic therapy (PDT) effectiveness. However, this undesirable impediment can be utilized to further trigger the activation of hypoxia-sensitive prodrugs. Moreover, a combined therapy can be used by associating PDT with hypoxia-activated chemotherapy. Herein, a multifunctional Hf-porphyrin nanoscale metal-organic framework (NMOF) platform [Hf/tetra(4-carboxyphenyl)porphine (TCPP)] has been synthesized, with a high porphyrin loading capacity and a well-ordered coordination array preventing porphyrin self-quenching, thus greatly improving the generation efficiency of reactive oxygen species (ROS), which is helpful for PDT. As-synthesized Hf-TCPP nanoparticles possess more than 50 wt % of TCPP PS content, good crystallization, and a large Brunauer-Emmett-Teller surface for further loading the hypoxia-activated prodrug [tirapazamine (TPZ)] in a high-loading content. Additionally, subsequent surface modification with a dopamine-derived polymer (DOPA-PIMA-mPEG) significantly improves their dispersibility and structural stability, and the controlled release kinetics of TPZ. Such a nanoplatform can efficiently produce ROS for PDT upon irradiation, and also the depletion of the oxygen could further aggravate the hypoxic environment of tumors to induce the activation of TPZ for achieving an enhanced treatment efficacy. This work demonstrates the great advantages of an NMOF-based platform in antitumor therapies for combined PDT and hypoxia-activated chemotherapy.
Topics: Cell Hypoxia; Humans; Metal-Organic Frameworks; Neoplasms; Photochemotherapy; Photosensitizing Agents
PubMed: 29957930
DOI: 10.1021/acsami.8b07570 -
Small (Weinheim An Der Bergstrasse,... Aug 2020Fenton reaction-mediated chemodynamic therapy (CDT) can kill cancer cells via the conversion of H O to highly toxic HO•. However, problems such as insufficient H O...
Fenton reaction-mediated chemodynamic therapy (CDT) can kill cancer cells via the conversion of H O to highly toxic HO•. However, problems such as insufficient H O levels in the tumor tissue and low Fenton reaction efficiency severely limit the performance of CDT. Here, the prodrug tirapazamine (TPZ)-loaded human serum albumin (HSA)-glucose oxidase (GOx) mixture is prepared and modified with a metal-polyphenol network composed of ferric ions (Fe ) and tannic acid (TA), to obtain a self-amplified nanoreactor termed HSA-GOx-TPZ-Fe -TA (HGTFT) for sustainable and cascade cancer therapy with exogenous H O production and TA-accelerated Fe /Fe conversion. The HGTFT nanoreactor can efficiently convert oxygen into HO• for CDT, consume glucose for starvation therapy, and provide a hypoxic environment for TPZ radical-mediated chemotherapy. Besides, it is revealed that the nanoreactor can significantly elevate the intracellular reactive oxygen species content and hypoxia level, decrease the intracellular glutathione content, and release metal ions in the tumors for metal ion interference therapy (also termed "ion-interference therapy" or "metal ion therapy"). Further, the nanoreactor can also increase the tumor's hypoxia level and efficiently inhibit tumor growth. It is believed that this tumor microenvironment-regulable nanoreactor with sustainable and cascade anticancer performance and excellent biosafety represents an advance in nanomedicine.
Topics: Glucose; Glucose Oxidase; Humans; Hypoxia; Nanomedicine; Neoplasms; Oxygen; Tumor Microenvironment
PubMed: 32537936
DOI: 10.1002/smll.202000897 -
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 -
ACS Applied Materials & Interfaces Jan 2018The combination of WO and tirapazamine (TPZ) core has been first introduced into the preparation of poly(ε-caprolactone)-poly(ethylene glycol) (PL) surrounded...
The combination of WO and tirapazamine (TPZ) core has been first introduced into the preparation of poly(ε-caprolactone)-poly(ethylene glycol) (PL) surrounded nanoparticles (NPs). The aim of using WO is employing its capability of reacting with the absorbed O to generate reactive oxygen species (ROS) when exposed to a long-wavelength laser at 808 nm to increase skin penetration and body tolerance. In this work, we have demonstrated that WO unit gives rise to more hypoxic tumor microenvironment and activates the prodrug TPZ to achieve hypoxia-activated chemotherapy, which could be monitored by the intracellular ROS/hypoxia detection and in vivo positron emission tomography imaging. In addition, the successful introduction of WO into PL-WO-TPZ NPs could render the photothermal therapy under the irradiation of an 808 nm laser. As a result, in vivo antitumor results have clearly shown that PL-WO-TPZ NPs could efficiently erase the solid tumor tissues by means of simultaneous hypoxia-activated chemotherapy and photothermal therapy. In comparison to the costly small-molecule photosensitizer chlorine e6 used in hypoxia-activated chemotherapy, WO NPs have two advantages of large-scale preparation and additional photothermal therapy effect, which could provide new insight into future clinical applications.
Topics: Antineoplastic Agents; Cell Hypoxia; Humans; Hypoxia; Nanoparticles; Neoplasms; Photosensitizing Agents; Triazines
PubMed: 29313656
DOI: 10.1021/acsami.7b17323 -
Drug Delivery Dec 2022Photodynamic therapy (PDT) has been applied in cancer treatment by utilizing reactive oxygen species (ROS) to kill cancer cells. However, the effectiveness of PDT is...
Photodynamic therapy (PDT) has been applied in cancer treatment by utilizing reactive oxygen species (ROS) to kill cancer cells. However, the effectiveness of PDT is greatly reduced due to local hypoxia. Hypoxic activated chemotherapy combined with PDT is expected to be a novel strategy to enhance anti-cancer therapy. Herein, a novel liposome (LCT) incorporated with photosensitizer (PS) and bioreductive prodrugs was developed for PDT-activated chemotherapy. In the design, CyI, an iodinated cyanine dye, which could simultaneously generate enhanced ROS and heat than other commonly used cyanine dyes, was loaded into the lipid bilayer; while tirapazamine (TPZ), a hypoxia-activated prodrug was encapsulated in the hydrophilic nucleus. Upon appropriate near-infrared (NIR) irradiation, CyI could simultaneously produce ROS and heat for synergistic PDT and photothermal therapy (PTT), as well as provide fluorescence signals for precise real-time imaging. Meanwhile, the continuous consumption of oxygen would result in a hypoxia microenvironment, further activating TPZ free radicals for chemotherapy, which could induce DNA double-strand breakage and chromosome aberration. Moreover, the prepared LCT could stimulate acute immune response through PDT activation, leading to synergistic PDT/PTT/chemo/immunotherapy to kill cancer cells and reduce tumor metastasis. Both and results demonstrated improved anticancer efficacy of LCT compared with traditional PDT or chemotherapy. It is expected that these iodinated cyanine dyes-based liposomes will provide a powerful and versatile theranostic strategy for tumor target phototherapy and PDT-induced chemotherapy.
Topics: Animals; Antineoplastic Agents; Cell Survival; Chemistry, Pharmaceutical; Chromosome Aberrations; DNA Damage; Drug Carriers; Drug Liberation; Hypoxia; Liposomes; Mice; Mice, Inbred BALB C; Nanoparticle Drug Delivery System; Particle Size; Photosensitizing Agents; Phototherapy; Reactive Oxygen Species; Surface Properties; Tirapazamine; Xenograft Model Antitumor Assays
PubMed: 35001784
DOI: 10.1080/10717544.2021.2023701