RESUMO
A significant amount of progress in nanotechnology has been made due to the development of engineered nanoparticles. The use of metallic nanoparticles for various biomedical applications has been extensively investigated. Biomedical research is highly focused on them because of their inert nature, nanoscale structure, and similar size to many biological molecules. The intrinsic characteristics of these particles, including electronic, optical, physicochemical, and surface plasmon resonance, that can be altered by altering their size, shape, environment, aspect ratio, ease of synthesis, and functionalization properties, have led to numerous biomedical applications. Targeted drug delivery, sensing, photothermal and photodynamic therapy, and imaging are some of these. The promising clinical results of NBTXR3, a high-Z radiosensitizing nanomaterial derived from hafnium, have demonstrated translational potential of this metal. This radiosensitization approach leverages the dependence of energy attenuation on atomic number to enhance energy-matter interactions conducive to radiation therapy. High-Z nanoparticle localization in tumor issue differentially increases the effect of ionizing radiation on cancer cells versus nearby healthy ones and mitigates adverse effects by reducing the overall radiation burden. This principle enables material multifunctionality as contrast agents in X-ray-based imaging. The physiochemical properties of hafnium (Z = 72) are particularly advantageous for these applications. A well-placed K-edge absorption energy and high mass attenuation coefficient compared to elements in human tissue across clinical energy ranges leads to significant attenuation. Chemical reactivity allows for variety in nanoparticle synthesis, composition, and functionalization. Nanoparticles such as hafnium oxide exhibit excellent biocompatibility due to physiochemical inertness prior to incidence with ionizing radiation. Additionally, the optical and electronic properties are applicable in biosensing, optical component coatings, and semiconductors. The wide interest has prompted extensive research in design and synthesis to facilitate property fine-tuning. This review summarizes synthetic methods for hafnium-based nanomaterials and applications in therapy, imaging, and biosensing with a mechanistic focus. A discussion and future perspective section highlights clinical progress and elaborates on current challenges. By focusing on factors impacting applicational effectiveness and examining limitations this review aims to support researchers and expedite clinical translation of future hafnium-based nanomedicine.
Assuntos
Nanopartículas Metálicas , Nanoestruturas , Neoplasias , Humanos , Háfnio/química , Nanoestruturas/uso terapêutico , Nanoestruturas/química , Nanopartículas Metálicas/uso terapêutico , Nanopartículas Metálicas/química , Neoplasias/tratamento farmacológico , MetaisRESUMO
We report on the results of a numerical investigation into a phase transition material and hafnium (IV) oxide-based refractive index sensor with a wide spectral range, including both the visible and infrared regions of the electromagnetic spectrum. The sensor relies on hafnium (IV) oxide and a phase transition material (HfO2). Three layered versions of the proposed structure are studied; each configuration is built from alternating layers of HfO2, silica, Ge2Sb2Te5(GST), and silver. The three different arrangements have all been studied. The reflectance response of such multilayer structures is discussed in this manuscript for refractive indices ranging from 1 to 2.4. In addition, we have investigated how the varying heights of the materials affect the overall performance of the structure. Finally, we have supplied several formulae for resonating traces that may be used to calculate the sensing behaviour across a specific wavelength range and refractive index values. The corresponding equations are shown below. We have computed numerous equation traces throughout this inquiry to calculate the wavelength and refractive index values. Computational methods may be used to analyze the proposed structure, which might aid in creating biosensors for detecting a wide variety of biomolecules and biomarkers, such as saliva-cortisol, urine, glucose, cancerous and cancerous, and hemoglobin.
Assuntos
Técnicas Biossensoriais , Háfnio , Háfnio/química , Óxidos/química , HemoglobinasRESUMO
With the rapid development of nanotechnology and nanomedicine, there are great interests in employing nanomaterials to improve the efficiency of disease diagnosis and treatment. The clinical translation of hafnium oxide (HfO2 ), commercially namedas NBTXR3, as a new kind of nanoradiosensitizer for radiotherapy (RT) of cancers has aroused extensive interest in researches on Hf-based nanomaterials for biomedical application. In the past 20 years, Hf-based nanomaterials have emerged as potential and important nanomedicine for computed tomography (CT)-involved bioimaging and RT-associated cancer treatment due to their excellent electronic structures and intrinsic physiochemical properties. In this review, a bibliometric analysis method is employed to summarize the progress on the synthesis technology of various Hf-based nanomaterials, including HfO2 , HfO2 -based compounds, and Hf-organic ligand coordination hybrids, such as metal-organic frameworks or nanoscaled coordination polymers. Moreover, current states in the application of Hf-based CT-involved contrasts for tissue imaging or cancer diagnosis are reviewed in detail. Importantly, the recent advances in Hf-based nanomaterials-mediated radiosensitization and synergistic RT with other current mainstream treatments are also generalized. Finally, current challenges and future perspectives of Hf-based nanomaterials with a view to maximize their great potential in the research of translational medicine are also discussed.
Assuntos
Antineoplásicos , Nanoestruturas , Neoplasias , Humanos , Háfnio/química , Nanoestruturas/química , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Nanotecnologia/métodosRESUMO
Photothermal therapy (PTT) achieves substantive therapeutic progress in certain tumor types without exogenous agents but is hampered by the over-activated inflammatory response or tumor recurrence in some cases. Herein, we technically developed the metal-polyphenolic nanosystem with precise NIR-II fluorescence-imaging guidance for combining hafnium (Hf)-sensitized radiotherapy with PTT to regress tumor growth.
Assuntos
Antineoplásicos/uso terapêutico , Corantes Fluorescentes/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Compostos Radiofarmacêuticos/uso terapêutico , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Dopamina/análogos & derivados , Feminino , Fluorescência , Corantes Fluorescentes/química , Háfnio/química , Háfnio/uso terapêutico , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Terapia Fototérmica , Poloxâmero/química , Compostos Radiofarmacêuticos/química , RadioterapiaRESUMO
PURPOSE: The side effects of radiotherapy induced on healthy tissue limit its use. To overcome this issue and fully exploit the potential of radiotherapy to treat cancers, the first-in-class radioenhancer NBTXR3 (functionalized hafnium oxide nanoparticles) has been designed to amplify the effects of radiotherapy. PATIENTS AND METHODS: Thanks to its physical mode of action, NBTXR3 has the potential to be used to treat any type of solid tumor. Here we demonstrate that NBTXR3 can be used to treat a wide variety of solid cancers. For this, we evaluated different parameters on a large panel of human cancer models, such as nanoparticle endocytosis, in vitro cell death induction, dispersion, and retention of NBTXR3 in the tumor tissue and tumor growth control. RESULTS: Whatever the model considered, we show that NBTXR3 was internalized by cancer cells and persisted within the tumors throughout radiotherapy treatment. NBTXR3 activated by radiotherapy was also more effective in destroying cancer cells and in controlling tumor growth than radiotherapy alone. Beyond the effects of NBTXR3 as single agent, we show that the antitumor efficacy of cisplatin-based chemoradiotherapy treatment was improved when combined with NBTXR3. CONCLUSION: These data support that NBTXR3 could be universally used to treat solid cancers when radiotherapy is indicated, opening promising new therapeutic perspectives of treatment for the benefit of many patients.
Assuntos
Antineoplásicos/uso terapêutico , Háfnio/química , Nanopartículas/química , Neoplasias/radioterapia , Óxidos/química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Terapia Combinada , Endocitose/efeitos dos fármacos , Humanos , Camundongos Nus , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Distribuição Tecidual/efeitos dos fármacos , Resultado do TratamentoRESUMO
The in situ spectroelectrochemical cyclic voltammetric studies of the antimony-monocapped nickel(II) and iron(II) tris-pyridineoximates with a labile triethylantimony cross-linking group and Zr(IV)/Hf(IV) phthalocyaninate complexes were performed in order to understand the nature of the redox events in the molecules of heterodinuclear zirconium(IV) and hafnium(IV) phthalocyaninate-capped derivatives. Electronic structures of their 1e-oxidized and 1e-electron-reduced forms were experimentally studied by electron paramagnetic resonance (EPR) spectroscopy and UV-vis-near-IR spectroelectrochemical experiments and supported by density functional theory (DFT) calculations. The investigated hybrid molecular systems that combine a transition metal (pseudo)clathrochelate and a Zr/Hf-phthalocyaninate moiety exhibit quite rich redox activity both in the cathodic and in the anodic region. These binuclear compounds and their precursors were tested as potential catalysts in oxidation reactions of cyclohexane and the results are discussed.
Assuntos
Complexos de Coordenação/química , Cicloexanos/química , Háfnio/química , Zircônio/química , Catálise , Teoria da Densidade Funcional , Espectroscopia de Ressonância de Spin Eletrônica , Indóis/química , Ferro/química , Isoindóis , Modelos Moleculares , Níquel/química , Oxirredução , Oximas/química , Piridinas/químicaRESUMO
Radiodynamic therapy (RDT), an emerging therapeutic approach for cancer treatment by employing ionizing irradiation to induce localized photodynamic therapy (PDT) can overcome the drawbacks of the limited penetration depth for traditional PDT and the unconcentrated energy in the tumor for traditional radiotherapy (RT). Taking advantage of aggregation-induced emission (AIE) photosensitizers with bright fluorescence and efficient singlet oxygen production in the aggregate state, Hf-AIE coordination polymer nanoparticles (CPNs), which show both strong RT and RDT effect under X-ray irradiation, are developed. Furthermore, to enhance the tumor accumulation and prolong the tumor retention of the CPNs, bioorthogonal click chemistry is applied in the system through coupling between dibenzocyclooctyne (DBCO)-modified CPNs (Hf-AIE-PEG-DBCO) (PEG: poly(ethylene glycol)) and azide groups on the cell membrane formed by metabolic glycoengineering. Thanks to the high penetration of X-ray irradiation, the bioorthogonal-assisted RT and RDT combination therapy realizes significant killing of cancer cells without showing noticeable biotoxicity after intravenous administration of CPNs.
Assuntos
Antineoplásicos/química , Háfnio/química , Nanopartículas/química , Neoplasias/radioterapia , Fármacos Fotossensibilizantes/química , Animais , Antineoplásicos/uso terapêutico , Transporte Biológico , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Proliferação de Células , Ciclo-Octanos/química , Humanos , Camundongos , Neoplasias Experimentais , Ácidos Fosfatídicos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Polietilenoglicóis/química , Oxigênio Singlete/químicaRESUMO
BACKGROUND: Recent studies have validated and confirmed the great potential of nanoscale metal-organic framework (NMOF) in the biomedical field, especially in improving the efficiency of cancer diagnosis and therapy. However, most previous studies only utilized either the metal cluster or the organic ligand of the NMOF for cancer treatments and merely reported limited theranostic functions, which may not be optimized. As a highly designable and easily functionalized material, prospective rational design offers a powerful way to extract the maximum benefit from NMOF for cancer theranostic applications. MATERIALS AND METHODS: A NMOF based on hafnium (Hf) cluster and Mn(III)-porphyrin ligand was rational designed and synthesized as a high-performance multifunctional theranostic agent. The folic acid (FA) was modified on the NMOF surface to enhance the cancer targeting efficacy. The proposed "all-in-one" FA-Hf-Mn-NMOF (fHMNM) was characterized and identified using various analytical techniques. Then, in vitro and in vivo studies were performed to further explore the effects of fHMNM both as the magnetic resonance imaging (MRI)/computed tomography (CT)/photoacoustic imaging (PAI) contrast agent and as the photothermal therapy (PTT)/radiotherapy (RT) agent. RESULTS: A tumour targeting multifunctional fHMNM was successfully synthesized with high performance for MRI/CT/PAI enhancements and image-guided PTT/RT synergistic therapy properties. Compared with the current clinical CT and MR contrast agents, the X-ray attenuation and T1 relaxation rate of this integrated nanosystem increased 1.7-fold and 3-5-fold, respectively. More importantly, the catalase-like Mn(III)-porphyrin ligand can decompose H2O2 into O2 in tumour microenvironments to improve the synergistic treatment efficiency of PTT and RT. Significant tumour growth inhibition was achieved in mouse cancer models without obvious damage to the other organs. CONCLUSION: This work highlights the potential of fHMNM as an easily designable material for biomedical applications, could be an effective tool for in vivo detection and subsequent treatment of tumour.
Assuntos
Háfnio/química , Hipertermia Induzida , Estruturas Metalorgânicas/química , Metaloporfirinas/química , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Fototerapia , Animais , Meios de Contraste/química , Fluorescência , Ácido Fólico/uso terapêutico , Células HeLa , Humanos , Imageamento por Ressonância Magnética , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Neoplasias/radioterapia , Técnicas Fotoacústicas , Radioterapia Guiada por ImagemRESUMO
BACKGROUND: Due to increasing aging of population prevalence of age-related disorders including osteoporosis is rapidly growing. Due to health and economic impact of the disease, there is an urgent need to develop techniques supporting bone metabolism and bone regeneration after fracture. Due to imbalance between bone forming and bone resorbing cells, the healing process of osteoporotic bone is problematic and prolonged. Thus searching for agents able to restore the homeostasis between these cells is strongly desirable. RESULTS: In the present study, using ALD technology, we obtained homogeneous, amorphous layer of hafnium (IV) oxide (HfO2). Considering the specific growth rate (1.9Å/cycle) for the selected process at the temperature of 90 °C, we performed the 100 nm deposition process, which was confirmed by measuring film thickness using reflectometry. Then biological properties of the layer were investigated with pre-osteoblast (MC3T3), pre-osteoclasts (4B12) and macrophages (RAW 264.7) using immunofluorescence and RT-qPCR. We have shown, that HfO2 (i) enhance osteogenesis, (ii) reduce osteoclastogenesis (iii) do not elicit immune response and (iv) exert anti-inflammatory effects. CONCLUSION: HfO2 layer can be applied to cover the surface of metallic biomaterials in order to enhance the healing process of osteoporotic bone fracture.
Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Háfnio/química , MicroRNAs/metabolismo , Osteoclastos/metabolismo , Óxidos/química , Animais , Materiais Biocompatíveis , Regeneração Óssea , Reabsorção Óssea/metabolismo , Proliferação de Células/efeitos dos fármacos , Homeostase , Macrófagos/metabolismo , Camundongos , Osteoblastos/efeitos dos fármacos , Osteogênese , Osteoporose , Células RAW 264.7RESUMO
The design and synthesis of a novel generation of a nanoscaled platform with imaging-guided therapy remain a real challenge. It can not only improve the imaging sensitivity of tumor tissues for guiding all kinds of treatments but also reduce the harm for healthy tissues. Here, polydopamine (PDA), polyethylene glycol (PEG), and c(RGDyK) peptide (RGD)-modified and cisplatin-loaded Gd2Hf2O7 nanoparticles (Gd2Hf2O7@PDA@PEG-Pt-RGD NPs) are designed for magnetic resonance imaging (MRI)-guided combined chemo-/photothermal-/radiotherapy of resistant tumors. The as-prepared NPs display high relaxivity (r1 = 38.28 mM-1 s-1) as an MRI contrast agent because of their ultrasmall size and surface modification with polyacrylic acid and PDA. Gd2Hf2O7@PDA@PEG-Pt-RGD NPs exhibit pH and NIR dual-stimuli responsiveness for cisplatin release. Based on competent NIR absorption and high X-ray attenuation efficiency, Gd2Hf2O7@PDA@PEG-Pt-RGD NPs show potential photothermal effect by exposing to an 808 nm NIR laser and significantly improve the generation of reactive oxygen species after X-ray radiation. Combined chemo-/photothermal-/radiotherapy can effectively treat the resistant A549R cells, providing the enhanced therapeutic efficiency to cancer tissues and the reduced side effect to healthy tissues. Furthermore, Gd2Hf2O7@PDA@PEG-Pt-RGD NPs present no obvious toxicity during the treatment, which demonstrates the potential as an efficient MRI-guided combined chemo-/photothermal-/radiotherapy nanoplatform for drug-resistant tumors.
Assuntos
Antineoplásicos/química , Meios de Contraste/química , Gadolínio/química , Háfnio/química , Nanopartículas Metálicas/química , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Óxidos/química , Animais , Antineoplásicos/farmacologia , Cisplatino/química , Cisplatino/farmacologia , Terapia Combinada , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Resistencia a Medicamentos Antineoplásicos , Tratamento Farmacológico , Feminino , Humanos , Hipertermia Induzida , Indóis/química , Integrinas/metabolismo , Imageamento por Ressonância Magnética , Camundongos , Camundongos Nus , Oligopeptídeos/química , Terapia Fototérmica , Polietilenoglicóis/química , Polímeros/química , Radioterapia , Espécies Reativas de Oxigênio/metabolismo , Propriedades de SuperfícieRESUMO
PURPOSE: Despite tremendous results achieved by immune checkpoint inhibitors, most patients are not responders, mainly because of the lack of a pre-existing anti-tumor immune response. Thus, solutions to efficiently prime this immune response are currently under intensive investigations. Radiotherapy elicits cancer cell death, generating an antitumor-specific T cell response, turning tumors in personalized in situ vaccines, with potentially systemic effects (abscopal effect). Nonetheless, clinical evidence of sustained anti-tumor immunity as abscopal effect are rare. METHODS: Hafnium oxide nanoparticles (NBTXR3) have been designed to increase energy dose deposit within cancer cells. We examined the effect of radiotherapy-activated NBTXR3 on anti-tumor immune response activation and abscopal effect production using a mouse colorectal cancer model. RESULTS: We demonstrate that radiotherapy-activated NBTXR3 kill more cancer cells than radiotherapy alone, significantly increase immune cell infiltrates both in treated and in untreated distant tumors, generating an abscopal effect dependent on CD8+ lymphocyte T cells. CONCLUSION: These data show that radiotherapy-activated NBTXR3 could increase local and distant tumor control through immune system priming. Our results may have important implications for immunotherapeutic agent combination with radiotherapy.
Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Háfnio/farmacologia , Óxidos/farmacologia , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacocinética , Disponibilidade Biológica , Linfócitos T CD8-Positivos/imunologia , Neoplasias Colorretais/imunologia , Feminino , Háfnio/química , Háfnio/farmacocinética , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/radioterapia , Óxidos/química , Óxidos/farmacocinéticaRESUMO
Saliva has been reported to contain various cytokine biomarkers which are associated with some severe diseases such as cancers. Non-invasive saliva diagnosis using wearable or portable devices may pave a new avenue for monitoring conditions of the high risk population. Here, a graphene-based fully integrated portable nanosensing system, the entire size of which is smaller than a smart-phone and can be handheld, is presented for on-line detection of cytokine biomarkers in saliva. This miniaturized system employs an aptameric graphene-based field effect transistor (GFET) using a buried-gate geometry with HfO2 as the dielectric layer and on-line signal processing circuits to realize the transduction and processing of signals which reflect cytokine concentrations. The signal can be wirelessly transmitted to a smart-phone or cloud sever through the Wi-Fi connection for visualizing the trend of the cytokine concentration change. Interleukin-6 (IL-6) is used as a representative to examine the sensing capability of the system. Experimental results demonstrate that the nanosensing system responds to the change of IL-6 concentration within 400s in saliva with a detection limit down to 12 pM. Therefore, this portable system offers the practicality to be potentially used for non-invasive saliva diagnosis of diseases at early stage.
Assuntos
Aptâmeros de Nucleotídeos/química , Técnicas Biossensoriais/instrumentação , Grafite/química , Interleucina-6/análise , Saliva/química , Tecnologia sem Fio/instrumentação , Biomarcadores/análise , Citocinas/análise , Desenho de Equipamento , Háfnio/química , Humanos , Limite de Detecção , Óxidos/química , Smartphone/instrumentação , Transistores EletrônicosRESUMO
We report here a new bimetallic ZrHf metal-organic framework (ZrHf-MOF) embedded with abundant carbon dots (CDs) (denoted as CDs@ZrHf-MOF), which exhibits strong fluorescence and rich-amino-functionalization. The CDs@ZrHf-MOF can be applied as the scaffold for anchoring aptamer strands to determine human epidermal growth factor receptor-2 (HER2) and living HER2-overexpressed MCF-7 cells. The basic characterizations reveal that the CDs are embedded within the interior cavities of ZrHf-MOF without varying the nanostructure, leading to good biocompatibility, strong fluorescence, and high electrochemical activity of CDs@ZrHf-MOF. As compared with the pristine ZrHf-MOF, the CDs@ZrHf-MOF-based electrochemical aptasensor displays better sensing performances toward both HER-2 and MCF-7 cells, giving an extremely low detection limit of 19â¯fgâ¯mL-1 (HER2 concentration range: 0.001-10â¯ngâ¯mL-1) and 23 cellâ¯mL-1 (cell concentration range: 1â¯×â¯102~1â¯×â¯105 cellâ¯mL-1), with good selectivity, stability, reproducibility, and acceptable applicability. The proposed strategy for developing CDs@ZrHf-MOF-based aptasensor is promising for the early and sensitive detection of cancer markers and living cancer cells.
Assuntos
Aptâmeros de Nucleotídeos/química , Técnicas Biossensoriais/métodos , Neoplasias da Mama/diagnóstico , Háfnio/química , Estruturas Metalorgânicas/química , Receptor ErbB-2/análise , Zircônio/química , Carbono/química , Detecção Precoce de Câncer , Feminino , Humanos , Limite de Detecção , Células MCF-7 , Nanoestruturas/química , Reprodutibilidade dos TestesRESUMO
High-Z metal oxide nanoparticles hold promise as imaging probes and radio-enhancers. Hafnium dioxide nanoparticles have recently entered clinical evaluation. Despite promising early clinical findings, the potential of HfO2 as a matrix for multimodal theranostics is yet to be developed. Here, we investigate the physicochemical properties and the potential of HfO2-based nanoparticles for multimodal theranostic imaging. Undoped and lanthanide (Eu3+, Tb3+, and Gd3+)-doped HfO2 nanoparticles were synthesized and functionalized with various moieties including poly(vinylpyrrolidone) (PVP), (3-aminopropyl)triethoxysilane (APTES), and folic acid (FA). We show that different synthesis routes, including direct precipitation, microwave-assisted synthesis, and sol-gel chemistry, allow preparation of hafnium dioxide particles with distinct physicochemical properties. Sol-gel based synthesis allows preparation of uniform nanoparticles with dopant incorporation efficiencies superior to the other two methods. Both luminescence and contrast properties can be tweaked by lanthanide doping. We show that MRI contrast can be unified with radio-enhancement by incorporating lanthanide dopants in the HfO2 matrix. Importantly, ion leaching from the HfO2 host matrix in lysosomal-like conditions was minimal. For Gd:HfO2 nanoparticles, leaching was reduced >10× compared to Gd2O3, and no relevant cytotoxic effects have been observed in monocyte-derived macrophages for nanoparticle concentrations up to 250 µg/mL. Chemical surface modification allows further tailoring of the cyto- and hemocompatibility and enables functionalization with molecular targeting entities, which lead to enhanced cellular uptake. Taken together, the present study illustrates the manifold properties of HfO2-based nanomaterials with prospective clinical utility beyond radio-enhancement.
Assuntos
Háfnio , Elementos da Série dos Lantanídeos , Luminescência , Macrófagos/metabolismo , Imageamento por Ressonância Magnética , Nanopartículas/química , Óxidos , Células CACO-2 , Háfnio/química , Háfnio/farmacologia , Humanos , Elementos da Série dos Lantanídeos/química , Elementos da Série dos Lantanídeos/farmacologia , Óxidos/química , Óxidos/farmacologiaRESUMO
Nuclear medicine with radioisotopes is extremely useful for clinical cancer diagnosis, prognosis, and treatment. Herein, polyethylene glycol (PEG)-modified nanoscale coordination polymers (NCPs) composed of hafnium (Hf4+) and tetrakis (4-carboxyphenyl) porphyrin (TCPP) are prepared via a one-pot reaction. By chelation with the porphyrin structure of TCPP, such Hf-TCPP-PEG NCPs could be easily labeled with 99mTc4+, an imaging radioisotope widely used for single-photon emission computed tomography (SPECT) in a clinical environment. Interestingly, Hf, as a high- Z element in such 99mTc-Hf-TCPP-PEG NCPs, could endow nontherapeutic 99mTc with the therapeutic function of killing cancer cells, likely owing to the interaction of Hf with γ rays emitted from 99mTc to produce charged particles for radiosensitization. With efficient tumor retention, as revealed by SPECT imaging, our 99mTc-Hf-TCPP-PEG NCPs offer exceptional therapeutic results in eliminating tumors with moderate doses of 99mTc after either local or systemic administration. Importantly, those biodegradable NCPs could be rapidly excreted without much long-term body retention. Our work, showing the success of applying NCPs for radioisotope therapy (RIT), presents a potential concept for the realization of highly effective cancer treatment with 99mTc, a short-half-life (6.0 h) diagnostic radioisotope, which is promising for cancer RIT with enhanced efficacy and reduced side effects.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Háfnio/farmacologia , Polietilenoglicóis/farmacologia , Pertecnetato Tc 99m de Sódio/farmacologia , Pertecnetato Tc 99m de Sódio/uso terapêutico , Animais , Neoplasias da Mama/diagnóstico por imagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Háfnio/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Polietilenoglicóis/química , Pertecnetato Tc 99m de Sódio/química , Propriedades de Superfície , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
We report results of the studies relating to fabrication of nanostructured metal oxide (NMO) based cancer biosensor. With the help of 2D electroactive reduced graphene oxide (RGO), we successfully inhibited the Brownian motion of NMO that led to reduced agglomeration of NMO. The nanostructured hafnium oxide (nHfO2) was used as a model NMO. The reduced agglomeration of nHfO2 was achieved through controlled hydrothermal synthesis and investigated via nanoparticles tracking analysis (NTA). X-ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscope (TEM) techniques were used for phase identification as well as morphological analysis of the synthesized nanohybrid (nHfO2@RGO) material. The 3-aminopropyl triethoxysilane (APTES) was used for the functionalization of nHfO2@RGO and electrophoretic deposition (EPD) technique was used for its deposition onto ITO coated glass electrode. Further, antibodies of cancer biomarker (anti-CYFRA-21-1) were immobilized via EDC-NHS chemistry and Bovine serum albumin (BSA) was used for blocking of the non-specific binding sites. The electrochemical response studies of fabricated immunoelectrode (BSA/anti-CYFRA-21-1/APTES/nHfO2@RGO/ITO) revealed higher sensitivity (18.24µAmLng-1), wide linear detection range (0 to 30ngmL-1), with remarkable lower detection limit (0.16ngmL-1). The obtained results showed good agreement with the concentration of CYFRA-21-1 obtained through enzyme linked immunosorbent assay (ELISA) in saliva samples of oral cancer patients.
Assuntos
Antígenos de Neoplasias/isolamento & purificação , Técnicas Biossensoriais , Técnicas Eletroquímicas , Queratina-19/isolamento & purificação , Neoplasias/diagnóstico , Antígenos de Neoplasias/química , Biomarcadores Tumorais/química , Biomarcadores Tumorais/isolamento & purificação , Grafite/química , Háfnio/química , Humanos , Queratina-19/química , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Nanoestruturas/química , Óxidos/química , Propilaminas/química , Silanos/química , Difração de Raios XRESUMO
PURPOSE: To assess the radiotherapy dose enhancement (RDE) potential of calcium tungstate (CaWO4 ) and hafnium oxide (HfO2 ) nano- and microparticles (NPs). A Monte Carlo simulation study was conducted to gauge their respective RDE potentials relative to that of the broadly studied gold (Au) NP. The study was warranted due to the promising clinical and preclinical studies involving both CaWO4 and HfO2 NPs as RDE agents in the treatment of various types of cancers. The study provides a baseline RDE to which future experimental RDE trends can be compared to. METHODS: All three materials were investigated in silico with the software Penetration and Energy Loss of Positrons and Electrons (PENELOPE 2014) developed by Francesc Salvat and distributed in the United States by the Radiation Safety Information Computational Center (RSICC) at Oak Ridge National Laboratory. The work utilizes the extensively studied Au NP as the "gold standard" for a baseline. The key metric used in the evaluation of the materials was the local dose enhancement factor (DEFloc ). An additional metric used, termed the relative enhancement ratio (RER), evaluates material performance at the same mass concentrations. RESULTS: The results of the study indicate that Au has the strongest RDE potential using the DEFloc metric. HfO2 and CaWO4 both underperformed relative to Au with lower DEFloc of 2-3 × and 4-100 ×, respectively. CONCLUSIONS: The computational investigation predicts the RDE performance ranking to be: Au > HfO2 > CaWO4 .
Assuntos
Compostos de Cálcio/química , Háfnio/química , Microesferas , Método de Monte Carlo , Nanopartículas , Óxidos/química , Doses de Radiação , Compostos de Tungstênio/química , Estudos de Viabilidade , Dosagem RadioterapêuticaRESUMO
The development of a strategy to stabilise the cubic phase of HfO2 at lower temperatures is necessary for the emergence of unique properties that are not realised in the thermodynamically stable monoclinic phase. A very high temperature (>2600 °C) is required to produce the cubic phase of HfO2, whereas the monoclinic phase is stable at low temperature. Here, a novel rapid synthesis strategy was designed to develop highly crystalline, pure cubic-phase HfO2 nanoparticles (size <10 nm) using microwave irradiation. Furthermore, the as-prepared nanoparticles were converted to different morphologies (spherical nanoparticles and nanoplates) without compromising the cubic phase by employing a post-hydrothermal treatment in the presence of surface modifiers. The cytotoxicities and proliferative profiles of the synthesised cubic HfO2 nanostructures were investigated over the MCF-7 breast cancer cell line, along with caspase-3/7 activities. The low-temperature phase stabilisation was significantly attributed to surface imperfections (defects and deformations) induced in the crystal lattice by the desirable presence of Na2S·xH2O and NaOH. Our work provides unprecedented insight into the stabilisation of nanoscale cubic-phase HfO2 in ambient environments; the method could be extended to other challenging phases of nanomaterials.
Assuntos
Háfnio/química , Háfnio/farmacologia , Nanoestruturas/química , Óxidos/química , Óxidos/farmacologia , Micro-Ondas , Modelos Moleculares , Conformação Molecular , Peso Molecular , Nanopartículas/química , Nanopartículas/ultraestrutura , Nanoestruturas/ultraestrutura , Polietilenoglicóis/química , Difração de Raios XRESUMO
Purpose: This phase I study aimed to determine the recommended dose (RD), safety profile, and feasibility of a procedure combining intratumoral injection of hafnium oxide nanoparticles (NBTXR3; a radioenhancer) and external beam radiotherapy (EBRT) for preoperative treatment of adults with locally advanced soft tissue sarcoma (STS).Experimental Design: Patients had a preoperative indication of EBRT for STS of the extremity or trunk. Baseline tumor volume (TV) was calculated by MRI. NBTXR3 was injected percutaneously into tumors at 53.3 g/L. Dose escalation was based on four levels equivalent to 2.5%, 5%, 10%, and 20% of baseline TV. NBTXR3 was visualized in the tumor 24 hours postinjection, and EBRT was initiated (50 Gy over 5 weeks). Surgery was performed 6 to 8 weeks after EBRT completion.Results: Twenty-two patients completed NBTXR3 injection, EBRT, and surgery and were followed for a median 22 months (range, 6-40). At NBTXR3 20% of TV, two dose-limiting toxicities occurred: injection-site pain and postoperative scar necrosis. The RD was defined as 10%. No leakage of NBTXR3 into surrounding tissues occurred; intratumor NBTXR3 levels were maintained during radiotherapy. At the RD, median tumor shrinkage was 40% (range 71% shrinkage, 22% increase); median percentage of residual viable tumor cells was 26% (range, 10%-90%). Patients receiving 20% of TV demonstrated pathologic complete responses. Seven grade 3 adverse events occurred, which were reversible.Conclusions: A single intratumoral injection of NBTXR3 at 10% of TV with preoperative EBRT was technically feasible with manageable toxicity; clinical activity was observed. Clin Cancer Res; 23(4); 908-17. ©2016 AACR.
Assuntos
Nanopartículas/administração & dosagem , Recidiva Local de Neoplasia/radioterapia , Neoplasia Residual/radioterapia , Sarcoma/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Háfnio/administração & dosagem , Háfnio/química , Humanos , Masculino , Pessoa de Meia-Idade , Nanopartículas/química , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/patologia , Óxidos/administração & dosagem , Óxidos/química , Cuidados Pré-Operatórios , Dosagem Radioterapêutica , Radioterapia Adjuvante/efeitos adversos , Sarcoma/tratamento farmacológico , Sarcoma/patologiaRESUMO
Nanoscale metal organic frameworks (NMOFs) have shown great potential in biomedicine owing to their structural/chemical diversities, high molecular loading capacities, and intrinsic biodegradability. Herein, we report the rational design of a NMOF composed by hafnium (Hf(4+)) and tetrakis (4-carboxyphenyl) porphyrin (TCPP). In such Hf-TCPP NMOFs, while TCPP is a photosensitizer to allow photodynamic therapy (PDT), Hf(4+) with strong X-ray attenuation ability could serve as a radio-sensitizer to enhance radiotherapy (RT). Those NMOFs with polyethylene glycol (PEG) coating show efficient tumor homing upon intravenous injection, and thus could be used for in vivo combined RT & PDT, achieving a remarkable anti-tumor effect. Importantly, Hf-TCPP NMOFs show efficient clearance from the mouse body, minimizing concerns regarding their possible long-term toxicity. Our work thus presents a new concept of developing multifunctional NMOFs as a biodegradable carrier-free system, in which both metal ions and organic ligands are fully utilized to exert their therapeutic functions.