RESUMEN
Solid tumors create a hypoxic microenvironment and this character can be utilized for cancer therapy, but the hypoxia levels are insufficient to achieve satisfactory therapeutic benefits. Some tactics have been used to improve hypoxia, which however will cause side effects due to the uncontrolled drug release. We herein report near-infrared (NIR) photoactivatable three-in-one nanoagents (PCT) to aggravate tumor hypoxia and enable amplified photo-combinational chemotherapy. PCT are formed based on a thermal-responsive liposome nanoparticle containing three therapeutic agents: a hypoxia responsive prodrug tirapazamine (TPZ) for chemotherapy, a vascular targeting agent combretastatin A-4 (CA4) for vascular disturbance and a semiconducting polymer for both photodynamic therapy (PDT) and photothermal therapy (PTT). With NIR laser irradiation, PCT generate heat for PTT and destructing thermal-responsive liposomes to achieve activatable releases of TPZ and CA4. Moreover, PCT produce singlet oxygen (1O2) for PDT via consuming tumor oxygen. CA4 can disturb the blood vessels in tumor microenvironment to aggravate the hypoxic microenvironment, which results in the activation of TPZ for amplified chemotherapy. PCT thus enable PTT, PDT and hypoxia-amplified chemotherapy to afford a high therapeutic efficacy to almost absolutely eradicate subcutaneous 4 T1 tumors and effectively inhibit tumor metastases in lung and liver. This work presents an activatable three-in-one therapeutic nanoplatform with remotely controllable and efficient therapeutic actions to treat cancer.
Asunto(s)
Rayos Infrarrojos , Liposomas , Nanopartículas , Fotoquimioterapia , Tirapazamina , Animales , Humanos , Fotoquimioterapia/métodos , Tirapazamina/farmacología , Tirapazamina/química , Tirapazamina/uso terapéutico , Nanopartículas/química , Nanopartículas/uso terapéutico , Ratones , Microambiente Tumoral/efectos de los fármacos , Línea Celular Tumoral , Terapia Fototérmica/métodos , Estilbenos/farmacología , Estilbenos/uso terapéutico , Estilbenos/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Profármacos/farmacología , Profármacos/química , Profármacos/uso terapéutico , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Hipoxia Tumoral/efectos de los fármacosRESUMEN
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".
Asunto(s)
Equinococosis , Echinococcus granulosus , Nanopartículas , Fotoquimioterapia , Animales , Ratones , Tirapazamina/farmacología , Tirapazamina/química , Tirapazamina/uso terapéutico , Echinococcus granulosus/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Hipoxia , Fotoquimioterapia/métodos , Equinococosis/tratamiento farmacológico , Nanopartículas/química , Adenosina TrifosfatoRESUMEN
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 1O2 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.
Asunto(s)
Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Tirapazamina/uso terapéutico , Hipoxia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Inmunoterapia , Línea Celular Tumoral , Fármacos Fotosensibilizantes , Microambiente TumoralRESUMEN
Pseudomonas aeruginosa is the most common pathogen infecting cystic fibrosis (CF) lungs, causing acute and chronic infections. Intrinsic and acquired antibiotic resistance allow P. aeruginosa to colonize and persist despite antibiotic treatment, making new therapeutic approaches necessary. Combining high-throughput screening and drug repurposing is an effective way to develop new therapeutic uses for drugs. This study screened a drug library of 3,386 drugs, mostly FDA approved, to identify antimicrobials against P. aeruginosa under physicochemical conditions relevant to CF-infected lungs. Based on the antibacterial activity, assessed spectrophotometrically against the prototype RP73 strain and 10 other CF virulent strains, and the toxic potential evaluated toward CF IB3-1 bronchial epithelial cells, five potential hits were selected for further analysis: the anti-inflammatory and antioxidant ebselen, the anticancer drugs tirapazamine, carmofur, and 5-fluorouracil, and the antifungal tavaborole. A time-kill assay showed that ebselen has the potential to cause rapid and dose-dependent bactericidal activity. The antibiofilm activity was evaluated by viable cell count and crystal violet assays, revealing carmofur and 5-fluorouracil as the most active drugs in preventing biofilm formation regardless of the concentration. In contrast, tirapazamine and tavaborole were the only drugs actively dispersing preformed biofilms. Tavaborole was the most active drug against CF pathogens other than P. aeruginosa, especially against Burkholderia cepacia and Acinetobacter baumannii, while carmofur, ebselen, and tirapazamine were particularly active against Staphylococcus aureus and B. cepacia. Electron microscopy and propidium iodide uptake assay revealed that ebselen, carmofur, and tirapazamine significantly damage cell membranes, with leakage and cytoplasm loss, by increasing membrane permeability. IMPORTANCE Antibiotic resistance makes it urgent to design new strategies for treating pulmonary infections in CF patients. The repurposing approach accelerates drug discovery and development, as the drugs' general pharmacological, pharmacokinetic, and toxicological properties are already well known. In the present study, for the first time, a high-throughput compound library screening was performed under experimental conditions relevant to CF-infected lungs. Among 3,386 drugs screened, the clinically used drugs from outside infection treatment ebselen, tirapazamine, carmofur, 5-fluorouracil, and tavaborole showed, although to different extents, anti-P. aeruginosa activity against planktonic and biofilm cells and broad-spectrum activity against other CF pathogens at concentrations not toxic to bronchial epithelial cells. The mode-of-action studies revealed ebselen, carmofur, and tirapazamine targeted the cell membrane, increasing its permeability with subsequent cell lysis. These drugs are strong candidates for repurposing for treating CF lung P. aeruginosa infections.
Asunto(s)
Fibrosis Quística , Infecciones por Pseudomonas , Humanos , Pseudomonas aeruginosa , Fibrosis Quística/microbiología , Ensayos Analíticos de Alto Rendimiento , Reposicionamiento de Medicamentos , Tirapazamina/farmacología , Tirapazamina/uso terapéutico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Fluorouracilo , Biopelículas , Infecciones por Pseudomonas/microbiologíaRESUMEN
Blockage of blood supply while administering chemotherapy to tumors, using trans-arterial chemoembolization (TACE), is the most common treatment for intermediate and advanced-stage unresectable Hepatocellular carcinoma (HCC). However, HCC is characterized by a poor prognosis and high recurrence rates (≈30%), partly due to a hypoxic pro-angiogenic and pro-cancerous microenvironment. This study investigates how modifying tissue stress while improving drug exposure in target organs may maximize the therapeutic outcomes. Porous degradable polymeric microspheres (MS) are designed to obtain a gradual occlusion of the hepatic artery that nourishes the liver, while enabling efficient drug perfusion to the tumor site. The fabricated porous MS are introduced intrahepatically and designed to release a combination therapy of Doxorubicin (DOX) and Tirapazamine (TPZ), which is a hypoxia-activated prodrug. Liver cancer cell lines that are treated with the combination therapy under hypoxia reveal a synergic anti-proliferation effect. An orthotopic liver cancer model, based on N1-S1 hepatoma in rats, is used for the efficacy, biodistribution, and safety studies. Porous DOX-TPZ MS are very effective in suppressing tumor growth in rats, and induction tissue necrosis is associated with high intratumor drug concentrations. Porous particles without drugs show some advantages over nonporous particles, suggesting that morphology may affect the treatment outcomes.
Asunto(s)
Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Ratas , Animales , Neoplasias Hepáticas/tratamiento farmacológico , Carcinoma Hepatocelular/tratamiento farmacológico , Microesferas , Distribución Tisular , Porosidad , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Tirapazamina/farmacología , Tirapazamina/uso terapéutico , Hipoxia/tratamiento farmacológico , Microambiente TumoralRESUMEN
To improve the drug loading, tumor targeting, and delivery simplicity of hydrophilic drugs, we propose a supramolecular assembly strategy that potentially benefits a wide range of hydrophilic drug delivery. Firstly, we choose a hydrophilic drug (tirapazamine) as a model drug to directly co-assemble with chlorin e6 (Ce6) at different molar ratios, and systematically evaluate the resultant Ce6-tirapazamine nanoparticles (CT NPs) in aspects of size distribution, polydispersity, morphology, optical properties and molecular dynamics simulation. Based on the assembling facts between Ce6 and tirapazamine, we summarize a plausible rule of the supramolecular assembly for hydrophilic drugs. To validate our findings, more drugs with increasing hydrophilicity, such as temozolomide, gemcitabine hydrochloride and 5-azacytidine, successfully co-assemble with Ce6 into nanostructures by following similar assembling behaviors, demonstrating that our assembling rule may guide a wide range of hydrophilic drug delivery. Next, the combination of Ce6 and tirapazamine was chosen as the representative to investigate the anti-tumor activities of the supramolecular assemblies. CT NPs showed synergistic anti-tumor efficacy, increased tumor accumulation and significant tumor progression and metastasis inhibition in tumor-bearing mice. We anticipate that the supramolecular assembly mechanism will provide broad guidance for developing easy-to-make but functional nanomedicines. STATEMENT OF SIGNIFICANCE: Although thousands of nanomedicines have been developed, only a few have been approved for clinical use. The manufacturing complexity significantly hinders the "bench-to-bed" translation of nanomedicines. Hence, we need to rethink how to conduct research on translational nanomedicines by avoiding more and more complex chemistry and complicated nanostructures. Here, we summarize a plausible rule according to multiple supramolecular assembly pairs and propose a supramolecular assembly strategy that can improve the drug loading, tumor targeting, and manufacturing simplicity of nanomedicine for hydrophilic drugs. The supramolecular assembly strategy would guide a broader range of drug delivery to provide a new paradigm for developing easy-to-make but multifunctional nanoformulations for synergistic cancer treatment.
Asunto(s)
Nanopartículas , Neoplasias , Fotoquimioterapia , Porfirinas , Animales , Ratones , Tirapazamina/uso terapéutico , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Nanopartículas/química , Fármacos Fotosensibilizantes/química , Porfirinas/químicaRESUMEN
The selective anti-tumor activity and less toxic nature of hypoxia-activated prodrugs including tirapazamine (TPZ) are harbored by hypoxia levels in tumors, the inadequacy of which leads to failure in clinical trials. Thus, the development of effective clinical applications of TPZ requires advanced strategies to intensify hypoxia levels in tumors effectively and safely. In this study, we designed and fabricated a paclitaxel (PTX)-loaded dual-response delivery system with a low dose (e.g., 2 Gy) of X-ray and reactive oxygen species on the basis of diselenide block copolymers. Upon the external X-ray stimulus, the system accurately released encapsulated PTX at tumor sites and remarkably improved tumor hypoxia levels by causing severe damage to tumor blood vessels. Subsequently, these enhanced tumor hypoxia levels effectively activated the reduction of TPZ into benzotriazinyl free radicals, which significantly improved the antitumor efficacy of our system against 4T1 breast cancer cells with an initial tumor volume of 500 mm3. Moreover, the dual-stimulus coordinated and controlled release of PTX was found to largely avoid the off-target effects of PTX on normal cells while exhibiting very limited side effects in experimental mice. The current novel strategy for regulating tumor hypoxia levels offers an effective and safe way to activate TPZ for the treatment of large solid tumors.
Asunto(s)
Antineoplásicos , Neoplasias , Animales , Ratones , Tirapazamina/farmacología , Tirapazamina/uso terapéutico , Especies Reactivas de Oxígeno/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Hipoxia Tumoral , Rayos X , Neoplasias/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Hipoxia/tratamiento farmacológico , Línea Celular TumoralRESUMEN
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 O2 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.
Asunto(s)
Antineoplásicos , Glioma , Neoplasias , Profármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Glioma/tratamiento farmacológico , Humanos , Hipoxia/tratamiento farmacológico , Indoles/uso terapéutico , Isoindoles , Neoplasias/tratamiento farmacológico , Compuestos Organometálicos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Profármacos/farmacología , Profármacos/uso terapéutico , Especies Reactivas de Oxígeno , Tirapazamina/uso terapéutico , Microambiente Tumoral , Compuestos de ZincRESUMEN
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.
Asunto(s)
Nanopartículas , Neoplasias , Profármacos , Línea Celular Tumoral , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Profármacos/farmacología , Profármacos/uso terapéutico , Tirapazamina/metabolismo , Tirapazamina/farmacología , Tirapazamina/uso terapéutico , Microambiente TumoralRESUMEN
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 1O2 generation and photothermal conversion capabilities, good biocompatibility, and tumor microenvironment responsiveness. In vivo and in vitro experiments reveal that S-NSs-TPZ-ICG can be selectively decomposed under acidic and H2O2 conditions to release TPZ and ICG, and significantly inhibit tumor growth under laser irradiation without obvious toxic side effects.
Asunto(s)
Nanopartículas , Neoplasias , Línea Celular Tumoral , Humanos , Peróxido de Hidrógeno/farmacología , Verde de Indocianina/farmacología , Neoplasias/tratamiento farmacológico , Fototerapia , Azufre , Tirapazamina/farmacología , Tirapazamina/uso terapéutico , Microambiente TumoralRESUMEN
The integration of reactive oxygen species (ROS)-based chemodynamic therapy (CDT) and photodynamic therapy (PDT) has attracted enormous attention for synergistic antitumor therapies. However, the strategy is severely hampered by tumor hypoxia and overproduced antioxidant glutathione (GSH) in the tumor microenvironment. Inspired by the concept of metal coordination-based nanomedicines, we proposed an effective strategy for synergistic cancer treatment in response to the special tumor microenvironmental properties. Herein, we present novel metal-coordinated multifunctional nanoparticles (NPs) by the Cu2+-triggered assembly of photosensitizer indocyanine green (ICG) and hypoxia-activated anticancer prodrug tirapazamine (TPZ) (Cu-ICG/TPZ NPs). After accumulating within tumor sites via the enhanced permeability and retention (EPR) effect, the Cu-ICG/TPZ NPs were capable of triggering a cascade of combinational therapeutic reactions, including hyperthermia, GSH elimination, and Cu+-mediated â¢OH generation and the subsequent hypoxia-triggered chemotherapeutic effect of TPZ, thus achieving synergistic tumor therapy. Both in vitro and in vivo evaluations suggested that the multifunctional Cu-ICG/TPZ NPs could realize satisfactory therapeutic efficacy with excellent biosafety. These results thus suggested the great potential of Cu-ICG/TPZ NPs to serve as a metallodrug nanoagent for synergetically enhanced tumor treatment.
Asunto(s)
Nanopartículas Multifuncionales , Neoplasias , Glutatión/uso terapéutico , Humanos , Hipoxia/tratamiento farmacológico , Verde de Indocianina/farmacología , Verde de Indocianina/uso terapéutico , Neoplasias/tratamiento farmacológico , Tirapazamina/uso terapéutico , Microambiente TumoralRESUMEN
Disturbance in redox homeostasis always leads to oxidative damages to cellular components, which inhibits cancer cell proliferation and causes tumor regression. Therefore, synergistic effects arising from cellular redox imbalance together with other treatment modalities are worth further investigation. Herein, a metal-organic framework nanosystem (NMOF) based on coordination between Fe (III) and 4,4,4,4-(porphine-5,10,15,20-tetrayl) tetrakis (benzoic acid) (TCPP) was synthesized through a one-pot method. After surface capping of silk fibroin (SF) to form NMOF@SF nanoparticles (NPs), this nanoplatform can serve as an eligible nanocarrier to deliver tirapazamine (TPZ), a hypoxia-activated precursor. As-developed NS@TPZ (NST) NPs remained inactive in the normal tissue, whereas became highly active upon endocytosis by tumor cells via glutathione (GSH)-mediated reduction of Fe (III) into Fe (II), further enabling Fe (II)-mediated chemodynamic therapy (CDT). Upon optical laser irradiation, TCPP-mediated photodynamic therapy (PDT) coordinated with CDT to aggravate intracellular oxidative stress. Thus, such reactive oxygen species accumulation and GSH deprivation contributed to a deleterious redox dyshomeostasis. On the other hand, local deoxygenation caused by PDT can increase the cytotoxicity of released TPZ, which significantly improved the integral therapeutic effectiveness relying on the combined redox balance disruption and bioreductive chemotherapy. More importantly, severe immunogenic cell death can be triggered by the combinatorial treatment modalities and the presence of SF, which facilitated an almost complete tumor eradication in vivo. Taken together, this paradigm provides an insightful strategy for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy, which can remarkably enhance antitumor efficacy with negligible adverse effects. STATEMENT OF SIGNIFICANCE: Recently, silk fibroin (SF) has been demonstrated to be effective in activating antitumor immune system through polarization tumor-associated macrophages into M1 subtype. However, engineering SF into multifunctional nanocomposites is seldom reported for combination tumor therapy. In another aspect, disruption of redox homeostasis becomes increasingly attractive for tumor suppression with high clinical-relevance. Herein, we established a newfashioned NMOF nanosystem, named as NST, for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy. This platform takes advantages of Fe2+/Fe3+ coupled Fenton-like reaction and GSH depletion, as well as TCPP-mediated photosensitization for admirable redox unbalancing, which further initiates hypoxia-relevant toxin of TPZ for chemotherapy. Finally, combinatorial treatments and the presence of SF could trigger ICD for rendering a complete tumor eradication in vivo.
Asunto(s)
Antineoplásicos , Fibroínas , Estructuras Metalorgánicas , Nanopartículas , Neoplasias , Fotoquimioterapia , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Humanos , Estructuras Metalorgánicas/farmacología , Neoplasias/tratamiento farmacológico , Oxidación-Reducción , Tirapazamina/uso terapéuticoRESUMEN
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 (η = 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.
Asunto(s)
Antineoplásicos/uso terapéutico , Portadores de Fármacos/química , Melaninas/uso terapéutico , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Antineoplásicos/química , Ácidos Borónicos/química , Ácidos Borónicos/efectos de la radiación , Ácidos Borónicos/uso terapéutico , Terapia Combinada , Quimioterapia , Femenino , Humanos , Células MCF-7 , Melaninas/química , Melaninas/efectos de la radiación , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Nanopartículas/efectos de la radiación , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/efectos de la radiación , Terapia Fototérmica , Profármacos/química , Profármacos/uso terapéutico , Tirapazamina/química , Tirapazamina/uso terapéutico , Hipoxia Tumoral/fisiología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Photodynamic therapy (PDT) efficacy has been severely limited by the hypoxia in tumor microenvironment. A multitherapy modality was developed, integrating the advantages of each therapy and a nanocarrier: PDT and PDT-induced hypoxia-activated chemotherapy. Following PDT-induced hypoxia augmented in the periphery of the tumors, chemotherapy was locally activated. To this end, new indocyanine green (IR820) and a hypoxia-activated prodrug tirapazamine (TPZ) were loaded in glutathione (GSH) decomposable mesoporous organic silica nanoparticles (GMONs), tethered by hyaluronic acid (HA). This nanohybrid showed a tendency to accumulate and be retained in tumors, due to passive and active targeting. The IR820 produced singlet oxygen (1O2) under near-infrared (NIR) laser irradiation and concomitantly tumorous abnormality exacerbated hypoxia. TPZ-mediated hypoxia-activated chemotherapy acted to kill more tumor cells. In vivo results indicated that the tumor inhibition rate of dual-loaded nanohybrids was up to 76% under NIR laser irradiation. The immunofluorescence staining of tumor slices demonstrated that the superficial part of tumors experienced exacerbated hypoxia with laser irradiation, resulting in TPZ exerting powerful chemotherapy effects. This nanohybrid is expected to be valuable as spatiotemporally specific therapy for cancer.
Asunto(s)
Nanopartículas , Neoplasias , Fotoquimioterapia , Línea Celular Tumoral , Glutatión , Humanos , Hipoxia , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Tirapazamina/uso terapéutico , Microambiente TumoralRESUMEN
In combination therapy, synergetic effects of drugs and their efficient delivery are essential. Herein, we screened 12 anticancer drugs for combination with photodynamic therapy (PDT) using pheophorbide a (Pba). On the basis of combination index (CI) values in cell viability tests, we selected tirapazamine (TPZ) and developed self-assembled gelatin nanoparticles (NPs) containing both Pba and TPZ. The resulting TPZ-Pba-NPs showed a synergetic effect to kill tumor cells because TPZ was activated under the hypoxic conditions that originated from the PDT with Pba and laser irradiation. After they were injected into tumor-bearing mice via the tail vein, TPZ-Pba-NPs showed 3.17-fold higher blood concentration and 4.12-fold higher accumulation in tumor tissue 3 and 24 h postinjection, respectively. Upon laser irradiation to tumor tissue, TPZ-Pba-NPs successfully suppressed tumor growth by efficient drug delivery and synergetic effects in vivo. These overall results suggest that in vitro screening of drugs based on CI values, mechanism studies in hypoxia, and real-time in vivo imaging are promising strategies in developing NPs for optimized combination therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Clorofila/análogos & derivados , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Tirapazamina/uso terapéutico , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Clorofila/farmacocinética , Clorofila/efectos de la radiación , Clorofila/uso terapéutico , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Quimioterapia , Gelatina/química , Luz , Ratones Endogámicos C3H , Neoplasias/metabolismo , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/efectos de la radiación , Especies Reactivas de Oxígeno/metabolismo , Tirapazamina/farmacocinéticaRESUMEN
A tumor redox-activatable micellar nanoplatform based on the naturally occurring biomacromolecule hyaluronic acid (HA) was developed for complementary photodynamic/chemotherapy against CD44-positive tumors. Here HA was first conjugated with l-carnitine (Lc)-modified zinc phthalocyanine (ZnPc) via disulfide linkage and then co-assembled with tirapazamine (TPZ) to afford the physiologically stable micellar nanostructure. The mitochondria-targeted photodynamic activity of ZnPc-Lc could efficiently activate the mitochondrial apoptosis cascade and deplete the oxygen in the tumor intracellular environment to amplify the hypoxia-dependent cytotoxic effect of TPZ.
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Biopolímeros/química , Micelas , Mitocondrias/metabolismo , Nanoestructuras/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Carnitina/química , Línea Celular Tumoral , Humanos , Ácido Hialurónico/química , Indoles/química , Rayos Infrarrojos , Isoindoles , Ratones , Mitocondrias/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Compuestos Organometálicos/química , Oxidación-Reducción , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Tirapazamina/química , Tirapazamina/farmacología , Tirapazamina/uso terapéutico , Trasplante Heterólogo , Compuestos de ZincRESUMEN
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@MH ) 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 (MH )-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.
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Antineoplásicos/uso terapéutico , Materiales Biomiméticos/química , Neoplasias Pulmonares/tratamiento farmacológico , Terapia por Ultrasonido/métodos , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Clorofilidas , Humanos , Liposomas/química , Neoplasias Pulmonares/secundario , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Porfirinas/química , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Tirapazamina/química , Tirapazamina/farmacología , Tirapazamina/uso terapéutico , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Purpose: To evaluate the usefulness of combined treatment with both continuous administration of a hypoxic cytotoxin, tirapazamine (TPZ) and mild temperature hyperthermia (MTH) in boron neutron capture therapy (BNCT) in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells.Materials and methods: B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumors received reactor thermal neutron beam irradiation following the administration of a 10B-carrier (L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH)) after single intraperitoneal injection of an acute hypoxia-releasing agent (nicotinamide), MTH (40 °C for 60 min), and 24-h continuous subcutaneous infusion of TPZ or combined treatment with both TPZ and MTH. Immediately after irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (=P + Q) tumor cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated.Results: BPA-BNCT increased the sensitivity of the total tumor cell population more than BSH-BNCT. However, the sensitivity of Q cells treated with BPA was lower than that of BSH-treated Q cells. With or without a 10B-carrier, combination with continuously administered TPZ with or without MTH enhanced the sensitivity of the both total and Q cells, especially Q cells. Even without irradiation, nicotinamide treatment decreased the number of lung metastases. With irradiation, BPA-BNCT, especially in combination with combined treatment with both TPZ and MTH as well as nicotinamide treatment, showed the potential to reduce the number more than BSH-BNCT.Conclusion: BSH-BNCT combined with TPZ with or without MTH improved local tumor control, while BPA-BNCT in combination with both TPZ and MTH as well as nicotinamide is thought to reduce the number of lung metastases. It was elucidated that control of the chronic hypoxia-rich Q cell population in the primary solid tumor has the potential to impact the control of local tumors as a whole and that control of the acute hypoxia-rich total tumor cell population in the primary solid tumor has the potential to impact the control of lung metastases.
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Terapia por Captura de Neutrón de Boro , Hipertermia Inducida , Neoplasias Pulmonares/secundario , Melanoma/patología , Tirapazamina/farmacología , Hipoxia Tumoral/efectos de los fármacos , Hipoxia Tumoral/efectos de la radiación , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Terapia Combinada , Melanoma/tratamiento farmacológico , Melanoma/radioterapia , Ratones , Tirapazamina/administración & dosificación , Tirapazamina/uso terapéutico , Resultado del TratamientoRESUMEN
Highly specific and effective cancer phototherapy remains as a great challenge. Herein, a smart nanoplatform (TENAB NP) sequentially responsive to light, low pH and hypoxia is demonstrated for multi-mode imaging guided synergistic cancer therapy with negligible skin phototoxicity. Upon 808-nm laser irradiation, TENAB NPs can generate hyperthermia to melt the phase change material (PCM-LASA) coat and thereafter release chemo-drug tirapazamine (TPZ). Meanwhile, under acidic pH, photosensitizer ENAB would turn "off" its charge-transfer state, generating prominent 1O2 for photodynamic therapy (PDT) and heat for photothermal therapy (PTT), respectively. Accompanied with PDT-induced hypoxia, the released TPZ can be activated into its cytotoxic form for tumor cells killing. Notably, owing to phase change material LASA coat and ENAB's pH sensitivity, TENAB NPs show negligible photosensitization to skin and normal tissues. As the multi-stimuli responsive mechanism, TENAB NPs demonstrate a promising future in cancer photo-chemo theranostics with excellent skin protection.
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Sistemas de Liberación de Medicamentos/métodos , Fotoquimioterapia/métodos , Animales , Alcoholes Grasos/química , Femenino , Células HeLa , Humanos , Ácido Linoleico/química , Ratones , Ratones Desnudos , Microscopía Confocal , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Piel/efectos de los fármacos , Piel/metabolismo , Piel/efectos de la radiación , Tirapazamina/uso terapéuticoRESUMEN
Although photodynamic therapy (PDT) has been an attractive strategy for several cancer treatments in the clinical setting, PDT efficacy is attenuated by consumption of oxygen. To address this photodynamic issue, we adopted a phototherapy-chemotherapy combination strategy based on targeted delivery of the near-infrared photosensitizer indocyanine green (ICG), photothermal conversion agent polydopamine (PDA), and tirapazamine (TPZ), a hypoxia-activated prodrug. Under laser irradiation, ICG consumption of oxygen and aggravated hypoxia in tumor sites can activate TPZ to damage DNA. In parallel, ICG produces reactive oxygen species which work in synergy with PDA to enhance phototherapeutic efficiency. Herein, hybrid CaCO3/TPGS nanoparticles delivering ICG, PDA, and TPZ (ICG-PDA-TPZ NPs) were designed for effective and safe cancer therapy. ICG-PDA-TPZ NPs showed significantly improved cellular uptake and accumulation in tumors. Furthermore, we demonstrated that ICG-PDA-TPZ NPs showed intensive photodynamic and photothermal effects in vitro and in vivo, which synergized with TPZ in subcutaneous U87 malignant glioma growth and orthotopic B16F10 tumor inhibition, with negligible side effects. Thus, ICG-PDA-TPZ NPs could be an effective strategy for improvement of PDT.