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Brachytherapy stands as an essential clinical approach for combating locally advanced tumors. Here, an injectable brachytherapy hydrogel is developed for the treatment of both local and metastatic tumor. Fe-tannins nanoparticles are efficiently and stably radiolabeled with clinical used therapeutic radionuclides (such as 131I, 90Y, 177Lu, and 225Ac) without a chelator, and then chemically cross-linked with 4-armPEG-SH to form brachytherapy hydrogel. Upon intratumoral administration, magnetic resonance imaging (MRI) signal from ferric ions embedded within the hydrogel directly correlates with the retention dosage of radionuclides, which can real-time monitor radionuclides emitting short-range rays in vivo without penetration limitation during brachytherapy. The hydrogel's design ensures the long-term tumor retention of therapeutic radionuclides, leading to the effective eradication of local tumor. Furthermore, the radiolabeled hydrogel is integrated with an adjuvant to synergize with immune checkpoint blocking therapy, thereby activating potent anti-tumor immune responses and inhibiting metastatic tumor growth. Therefore, this work presents an imageable brachytherapy hydrogel for real-time monitoring therapeutic process, and expands the indications of brachytherapy from treatment of localized tumors to metastatic tumors.
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To identify the value of salivary gland ultrasound (SGUS) combined with magnetic resonance imaging (MRI) and magnetic resonance sialography (MRS) in predicting the results of labial salivary gland biopsy (LSGB) in patients with suspected primary Sjögren syndrome (pSS), and construct a nomogram model to predict LSGB results. A total of 181 patients who were admitted with suspected pSS from December 2018 to April 2023 were examined and divided into a training set (n = 120) and a validation set (n = 61). Baseline data of the two groups were examined, and the value of SGUS, MRI, and MRS in predicting LSGB was analyzed. Multivariate logistic analysis was used to screen for risk factors, and nomogram prediction models were constructed using these results. In the training set, the SGUS, MRI, and MRS scores of patients in the LSGB + group were higher than those in the LSGB - group (all P < 0.001). The positive prediction value (PPV) was 91% for an SGUS score of 3, and 82% for MRI and MRS scores of 2 or more. We developed a nomogram prediction model based on SGUS, MRI, and MRS data, and it had a concordance index (C-index) of 0.94. The Hosmer-Lemeshow test (χ2 = 3.17, P = 0.92) also indicated the nomogram prediction model had good accuracy and calibration for prediction of LSGB results. A nomogram model based on SGUS, MRI, and MRS results can help rheumatologists decide whether LSGB should be performed in patients with suspected pSS.
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Síndrome de Sjogren , Humanos , Síndrome de Sjogren/diagnóstico por imagem , Síndrome de Sjogren/patologia , Glândulas Salivares/diagnóstico por imagem , Glândulas Salivares/patologia , Biópsia , Glândulas Salivares Menores/diagnóstico por imagem , Glândulas Salivares Menores/patologia , Ultrassonografia/métodosRESUMO
225Ac is considered as one of the most promising radioisotopes for alpha-therapy because its emitted high-energy α-particles can efficiently damage tumor cells. However, it also represents a significant threat to healthy tissues owing to extremely high radiotoxicity if targeted therapy fails. This calls for a pressing requirement of monitoring the biodistribution of 225Ac in vivo during the treatment of tumors. However, the lack of imageable photons or positrons from therapeutic doses of 225Ac makes this task currently quite challenging. We report here a nanoscale luminescent europium-organic framework (EuMOF) that allows for fast, simple, and efficient labeling of 225Ac in its crystal structure with sufficient 225Ac-retention stability based on similar coordination behaviors between Ac3+ and Eu3+. After labeling, the short distance between 225Ac and Eu3+ in the structure leads to exceedingly efficient energy transduction from225Ac-emitted α-particles to surrounding Eu3+ ions, which emits red luminescence through a scintillation process and produces sufficient photons for clearcut imaging. The in vivo intensity distribution of radioluminescence signal originating from the 225Ac-labeled EuMOF is consistent with the dose of 225Ac dispersed among the various organs determined by the radioanalytical measurement ex vivo, certifying the feasibility of in vivo directly monitoring 225Ac using optical imaging for the first time. In addition, 225Ac-labeled EuMOF displays notable efficiency in treating the tumor. These results provide a general design principle for fabricating 225Ac-labeled radiopharmaceuticals with imaging photons and propose a simple way to in vivo track radionuclides with no imaging photons, including but not limited to 225Ac.
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Estruturas Metalorgânicas , Neoplasias , Humanos , Distribuição Tecidual , Radioisótopos , Compostos Radiofarmacêuticos , Neoplasias/tratamento farmacológicoRESUMO
OBJECTIVES: To determine whether age at menarche (AAM), age at first live birth (AFB), and estradiol levels are causally correlated with the development of systemic lupus erythematosus (SLE). METHODS: A two-sample Mendelian randomization (MR) analysis was performed after data was collected from a dataset of genome-wide association studies (GWASs) related to SLE (as outcome), and from open access databases to find statistics related to AAM, AFB, and estradiol levels (as exposure). RESULT: In our study, a negative causal correlation between AAM and SLE was confirmed by MR analysis (MR egger: beta = 0.116, SE = 0.948, p = 0.909; weighted median: beta = -0.416, SE = 0.192, p = 0.030; and IVW: beta = -0.395, SE = 0.165, p = 0.016). However, there were no genetic causal effects of AFB and the estradiol levels on SLE, based on the results of MR analysis as follows: AFB (MR egger: beta = - 2.815, SE = 1.469, p = 0.065; Weighted median: beta = 0.334, SE = 0.378, p = 0.377; and IVW: beta = 0.188, SE = 0.282, p = 0.505) and the estradiol levels (MR egger: beta = 0.139, SE = 0.294, p = 0.651; weighted median: beta = 0.063, SE = 0.108, p = 0.559; IVW: beta = 0.126, SE = 0.097, p = 0.192). CONCLUSIONS: Our findings revealed that AAM may be associated with increased risk of the development of SLE, while there were no such causal effects from AFB and estradiol levels.
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Lúpus Eritematoso Sistêmico , Análise da Randomização Mendeliana , Feminino , Gravidez , Humanos , Estudo de Associação Genômica Ampla , Menarca/genética , Nascido Vivo , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , EstradiolRESUMO
AIM: To evaluate the utility of magnetic resonance imaging (MRI) and magnetic resonance sialography (MRS) for diagnosis of primary Sjögren syndrome (pSS) singly or integrated with 2016 American College of Rheumatology (ACR)/European League Against Rheumatic Diseases (EULAR) classification criteria. METHODS: The diagnostic efficiencies of MRI, MRS, and labial salivary gland biopsy (LSGB) were evaluated. The prediction model was established by multivariate analysis. Finally, performance of the ACR/EULAR criteria was evaluated after addition of MRI + MRS or replacement of original items by MRI + MRS. RESULTS: The combined use of LSGB + MRI + MRS provided the greatest diagnostic value. MRI and MRS grade had positive correlations with disease duration and pathological grade of the labial gland (both P < 0.001). MRI and MRS grade had positive correlations with xerostomia severity and negative correlations with unstimulated salivary flow rate (both P < 0.001). The consistency of MRI grade and MRS grade in the diagnosis of parotid gland lesions was poor (κ = 0.253, P < 0.001). The diagnostic efficiency of our prediction model (AUC 0.906) was similar to that of criteria from the ACR/EULAR (AUC 0.930). Adding MRI + MRS to the ACR/EULAR criteria improved the sensitivity (92.3% vs 90.8%), whereas the specificity remained the same (88.9% vs 89.1%). Replacing LSGB by MRI + MRS in the ACR/EULAR criteria decreased both sensitivity and specificity (88.1% vs 90.8% and 86.4% vs 89.1%, respectively). CONCLUSION: The combined application of MRI and MRS has ideal clinical application value in the diagnosis of early-stage pSS. Validity of the ACR/EULAR criteria remains high after incorporation of MRI + MRS.
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Reumatologia , Síndrome de Sjogren , Humanos , Estados Unidos , Glândula Parótida/patologia , Síndrome de Sjogren/diagnóstico , Sialografia , Ultrassonografia/métodos , Sensibilidade e Especificidade , Imageamento por Ressonância Magnética/métodosRESUMO
Microwave ablation (MWA) as a local tumor ablation strategy suffers from posttreatment tumor recurrence. Development of adjuvant biomaterials to potentiate MWA is therefore of practical significance. Here, the high concentration of Ca2+ fixed by alginate as Ca2+-surplus alginate hydrogel shows enhanced heating efficiency and restricted heating zone under microwave exposure. The high concentration of extracellular Ca2+ synergizes with mild hyperthermia to induce immunogenic cell death by disrupting intracellular Ca2+ homeostasis. Resultantly, Ca2+-surplus alginate hydrogel plus MWA can ablate different tumors on both mice and rabbits at reduced operation powers. This treatment can also elicit antitumor immunity, especially if synergized with Mn2+, an activator of the stimulation of interferon genes pathway, to suppress the growth of both untreated distant tumors and rechallenged tumors. This work highlights that in situ-formed metallo-alginate hydrogel could act as microwave-susceptible and immunostimulatory biomaterial to reinforce the MWA therapy, promising for clinical translation.
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Neoplasias Hepáticas , Micro-Ondas , Alginatos , Animais , Hidrogéis/farmacologia , Neoplasias Hepáticas/patologia , Camundongos , Micro-Ondas/uso terapêutico , Coelhos , Resultado do TratamentoRESUMO
Platinum complexes, despite being the most successful organometallic anticancer chemotherapy drugs, still suffer from serious side effects and therapy resistance. Inspired by the immunomodulation effect of platinum drugs, an epigenetic platinum(IV) complex was synthesized for enhanced cancer chemoimmunotherapy by conjugating oxidized oxaliplatin (OXA) with 2-bromo-1-(3,3-dinitro-1-azetidinyl)ethenone (RRx-001), the latter of which as a nitric oxide (NO) donor is also an epigenetic agent. The obtained complex (named OXA-NO) could significantly increase the level of "eat me" signal CRT expression and decrease the level of "don't eat me" signal CD47 expression on cancer cell membranes to promote their phagocytosis by macrophages. In addition, OXA-NO could release nitric oxide to trigger the transformation of pro-tumorigenic M2-type macrophages into antitumor M1-type macrophages within the tumor to reverse the immunosuppressive tumor microenvironment. Compared to commercial OXA, OXA-NO exhibited much stronger tumor growth inhibition ability and was much better tolerated, with obviously weakened side effects observed in spleen, lung, and kidneys. Therefore, this epigenetic platinum(IV) complex that exhibits excellent therapeutic efficacy and safety has great potential in the clinic.
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Neoplasias , Platina , Epigênese Genética , Humanos , Neoplasias/tratamento farmacológico , Óxido Nítrico , Fagocitose , Platina/uso terapêutico , Microambiente TumoralRESUMO
Graphene quantum dots (GQD) have attracted much attention due to their unique properties in biomedical application, such as biosensing, imaging, and drug delivering. However, scale preparing red luminescing GQD is still challenging now. Herein, with the help of electron beam irradiation, a simple, rapid, and efficient up-to-down strategy was developed to synthesize GQD with size of 2.75 nm emitting 610 nm luminescence. GQD were further functionalized with polyethylene glycol (PEG) and exhibited good solubility and biocompatibility. The potential in vivo toxicity of PEGylated GQD could completely be eliminated by the clinic cholesterol-lowering drug simvastatin. PEGylated GQD could selectively accumulate in tumor after intravenous injection as a security, reliable and sensitive tumor fluorescence imaging agent. Therefore, this work presented a new method preparing red luminescing GQD for biomedical application.
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Grafite , Neoplasias , Pontos Quânticos , Elétrons , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/radioterapia , Imagem Óptica/métodosRESUMO
BACKGROUND: Currently, there is poor evidence on the effect of radiofrequency ablation (RFA) on pain and knee function in patients with knee osteoarthritis (OA). We performed a meta-analysis on randomized controlled trials (RCTs) to determine the effectiveness and safety of RFA on pain and knee function in individuals with knee OA. METHODS: PubMed, EMBASE, Web of Science, Cochrane, Ovid and MEDLINE were systematically searched (up to March 20, 2021) to obtain literature focusing on the impact of RFA on knee OA, using the following keywords and their synonyms: "radiofrequency ablation", "neurotomy", "knee" and "osteoarthritis". Two authors independently evaluated the quality of the RCTs according to the Cochrane Handbook for Systematic Reviews of Interventions version. Pooled effects of this meta-analysis were calculated using STATA version 13.0. RESULTS: Eight RCTs were included for data extraction and meta-analysis. The present study indicated that there were significant differences between the two groups of patients who were treated or not treated with RFA on the pain intensity at 4 week (WMD = -0.504; 95% CI: 0.708 to -0.300; P < 0.001), 12 week (WMD = -0.280; 95% CI: 0.476 to -0.084; P = 0.005) and 24 week (WMD = -2.437; 95% CI: 4.742 to -0.132; P = 0.038). Furthermore, RFA was associated with improved outcome of the Western Ontario and McMaster Universities Arthritis index at 4 week (WMD = -3.189; 95% CI: 5.996 to -0.382, P = 0.026), 12 week (WMD = -3.706; 95% CI:-6.584 to -0.828, P = 0.012) and 24 week (WMD = -2.437; 95% CI: 4.742 to -0.132). No serious adverse events were observed in all patients who received RFA (RD = -0.019; 95% CI: 0.053 to 0.016; P = 0.294). CONCLUSION: RFA showed better effectiveness in relieving pain and promoting function recovery in patients with knee OA. Considering the small sample size of the included studies, the results should be treated with caution.
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Artralgia/cirurgia , Osteoartrite do Joelho/cirurgia , Manejo da Dor/métodos , Ablação por Radiofrequência/métodos , Idoso , Artralgia/etiologia , Artralgia/fisiopatologia , Feminino , Humanos , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/fisiopatologia , Medição da Dor , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Resultado do TratamentoRESUMO
Certain chemotherapeutics and forms of ionizing radiation can induce immunogenic cell death (ICD). If there simultaneously exist immune adjuvants within the tumor, such antitumor immunity would be further amplified. However, as clinical chemo/radiotherapies are usually repeatedly given at low individual doses, it would be impractical to administrate immune adjuvants into tumors at each dose of chemo/radiotherapies. Thus, a smart hydrogel is developed that releases immune adjuvants in response to repeatedly applied chemo-/radiotherapies. Herein, alginate is conjugated with an adenosine triphosphate (ATP)-specific aptamer, which is hybridized with immunoadjuvant CpG oligonucleotide. Upon intratumoral injection, alginate-based hydrogel is formed in situ. Interestingly, low doses of oxaliplatin or X-rays, while inducing ICD of tumor cells, could trigger release of ATP, which competitively binds with ATP-specific aptamer to trigger CpG release. Therefore, the smart hydrogel could release the immune adjuvant synchronized with low-dose repeated chemo/radiotherapies, achieving remarkable synergistic responses in eliminating established tumors, as well as immune memory to reject re-challenged tumors. Moreover, repeated radiotherapies assisted by the smart hydrogel could inhibit distant tumor metastases, especially in combination with immune checkpoint blockade. The study presents a conceptually new strategy to boost cancer immunotherapy coherent with repeated low-dose chemo-/radiotherapies following a clinically relevant manner.
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Trifosfato de Adenosina/metabolismo , Adjuvantes Imunológicos , Hidrogéis , Animais , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Doxorrubicina/farmacologia , Humanos , ImunoterapiaRESUMO
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.
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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
Due to the negative roles of tumor microenvironment (TME) in compromising therapeutic responses of various cancer therapies, it is expected that modulation of TME may be able to enhance the therapeutic responses during cancer treatment. Herein, we develop a concise strategy to prepare pH-responsive nanoparticles via the CaCO3-assisted double emulsion method, thereby enabling effective co-encapsulation of both doxorubicin (DOX), an immunogenic cell death (ICD) inducer, and alkylated NLG919 (aNLG919), an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1). The obtained DOX/aNLG919-loaded CaCO3 nanoparticles (DNCaNPs) are able to cause effective ICD of cancer cells and at the same time restrict the production of immunosuppressive kynurenine by inhibiting IDO1. Upon intravenous injection, such DNCaNPs show efficient tumor accumulation, improved tumor penetration of therapeutics and neutralization of acidic TME. As a result, those DNCaNPs can elicit effective anti-tumor immune responses featured in increased density of tumor-infiltrating CD8+ cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells (Tregs), thus effectively suppressing the growth of subcutaneous CT26 and orthotopic 4T1 tumors on the Balb/c mice through combined chemotherapy & immunotherapy. This study presents a compendious strategy for construction of pH-responsive nanoparticles, endowing significantly enhanced chemo-immunotherapy of cancer by overcoming the immunosuppressive TME.
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Surgical intervention combined with intravesical instillation of chemotherapeutics to clear residual cancer cells after operation is the current standard treatment method for bladder cancer. However, the poor bioavailability of active pharmaceutical ingredients for bladder cancer cells on account of the biological barriers of bladder mucosa, together with significant side effects of currently used intravesical medicine, have limited the clinical outcomes of localized adjuvant therapy for bladder cancer. Aiming at improved intravesical instillation therapy of bladder cancer, a fluorinated polyethylenimine (F-PEI) is employed here for the transmucosal delivery of an active venom peptide, polybia-mastoparan I (MPI), which shows selective antiproliferative effect against various bladder cancer cell lines. Upon simple mixing, MPI and F-PET would coassemble to form stable nanoparticles, which show greatly improved cross-membrane and transmucosal penetration capacities compared with MPI alone or nonfluorinated MPI/PEI nanoparticles. MPI/F-PEI shows higher in vivo tumor growth inhibition efficacy for local treatment of a subcutaneous tumor model. More excitingly, as further demonstrated in an orthotopic bladder cancer model, MPI/F-PEI offers remarkably improved therapeutic effects compared to those achieved by free MPI or the first-line bladder cancer drug mitomycin C. This work presents a new transmucosal delivery carrier particularly promising for intravesical instillation therapy of bladder cancer.
Assuntos
Sistemas de Liberação de Medicamentos , Polímeros de Fluorcarboneto/química , Mucosa/patologia , Peptídeos/administração & dosagem , Peptídeos/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Endocitose/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/ultraestrutura , Peptídeos/farmacologia , Polietilenoimina/química , Análise de Sobrevida , Venenos de Vespas/químicaRESUMO
The abundant tumor extracellular matrix (ECM) could result in insufficient tumor retention and ineffective intratumor penetration of therapeutic agents as well as an acidic and hypoxic tumor microenvironment (TME), leading to unsatisfactory therapeutic outcomes for many types of therapies. Therefore, developing strategies to modulate the TME by selectively degrading the condensed ECM may be helpful to improve existing cancer therapies. Herein, collagenase (CLG)-encapsulated nanoscale coordination polymers (NCPs) are synthesized based on Mn2+ and an acid-sensitive benzoic-imine organic linker and then modified by polyethylene glycol (PEG). Upon intravenous (iv) injection, these CLG@NCP-PEG nanoparticles show efficient accumulation within the tumor, in which CLG would be released because of the collapse of NCP structures within the acidic TME. The released CLG enzyme could then specifically degrade collagens, the major component of ECM, leading to a loosened ECM structure, enhanced tumor perfusion, and relieved hypoxia. As a result, the second wave of nanoparticles, chlorin e6 (Ce6)-loaded liposomes (liposome@Ce6), would exhibit enhanced retention and penetration within the tumor. Such phenomena together with relieved tumor hypoxia could then lead to greatly enhanced photodynamic therapeutic effect of liposome@Ce6 for mice pretreated with CLG@NCP-PEG. Our work thus presents a unique strategy for TME modulation using pH-responsive NCPs as smart enzyme carriers.
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Colagenases , Enzimas Imobilizadas , Nanopartículas/química , Neoplasias Experimentais , Fotoquimioterapia , Porfirinas , Microambiente Tumoral/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Clorofilídeos , Colagenases/química , Colagenases/farmacocinética , Colagenases/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Enzimas Imobilizadas/química , Enzimas Imobilizadas/farmacocinética , Enzimas Imobilizadas/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Camundongos Nus , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tumor-associated macrophages (TAMs) are often related with poor prognosis after radiotherapy. Depleting TAMs may thus be a promising method to improve the radio-therapeutic efficacy. Herein, we report a biocompatible and biodegradable nanoplatform based on calcium bisphosphonate (CaBP-PEG) nanoparticles for chelator-free radiolabeling chemistry, effective in vivo depletion of TAMs, and imaging-guided enhanced cancer radioisotope therapy (RIT). It is found that CaBP-PEG nanoparticles prepared via a mineralization method with poly(ethylene glycol) (PEG) coating could be labeled with various radioisotopes upon simple mixing, including gamma-emitting 99mTc for single-photon-emission computed tomography (SPECT) imaging, as well as beta-emitting 32P as a therapeutic radioisotope for RIT. Upon intravenous injection, CaBP(99mTc)-PEG nanoparticles exhibit efficient tumor homing, as evidenced by SPECT imaging. Owning to the function of bisphosphonates as clinical drugs to deplete TAMs, suppressed angiogenesis, normalized tumor vasculatures, enhanced intratumoral perfusion, and relieved tumor hypoxia are observed after TAM depletion induced by CaBP-PEG. Such modulated tumor microenvironment appears to be highly favorable for cancer RIT using CaBP(32P)-PEG as the radio-therapeutic agent, which offers excellent synergistic therapeutic effect in inhibiting the tumor growth. With great biocompatibility and multifunctionalities, such CaBP-PEG nanoparticles constituted by Ca2+ and a clinical drug would be rather attractive for clinical translation.
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Antineoplásicos/uso terapêutico , Fosfatos de Cálcio/farmacologia , Marcação por Isótopo , Macrófagos/efeitos dos fármacos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Compostos Radiofarmacêuticos/uso terapêutico , Animais , Antineoplásicos/química , Fosfatos de Cálcio/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Quelantes , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Tamanho da Partícula , Radioisótopos de Fósforo , Compostos Radiofarmacêuticos/química , Propriedades de Superfície , Tomografia Computadorizada de Emissão de Fóton Único , Microambiente Tumoral/efeitos dos fármacosRESUMO
Accurate imaging of glutathione (GSH) in vivo is able to provide real-time visualization of physiological and pathological conditions. Herein, we successfully synthesize bimetallic oxide MnMoOX nanorods as an intelligent nanoprobe for in vivo GSH detection via photoacoustic (PA) imaging. The obtained MnMoOX nanoprobe with no near-infrared (NIR) absorption in the absence of GSH would exhibit strong GSH-responsive NIR absorbance, endowing PA imaging detection of GSH. Due to the up-regulated GSH concentration in the tumor microenvironment, our MnMoOX nanoprobe could be utilized for in vivo tumor-specific PA imaging. Moreover, MnMoOX nanorods with GSH-responsive NIR absorbance could also be employed to achieve tumor-specific photothermal therapy (PTT). Importantly, such MnMoOX nanorods show inherent biodegradability and could be rapidly cleared out from the body, minimizing their long-term body retention and potential toxicity. Our work presents a new type of GSH-responsive nanoprobe based on bimetallic oxide nanostructures, promising for tumor-specific imaging and therapy.
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Glutationa/análise , Compostos de Manganês/química , Molibdênio/química , Nanotubos/química , Neoplasias/diagnóstico , Óxidos/química , Técnicas Fotoacústicas/métodos , Nanomedicina Teranóstica/métodos , Animais , Hipertermia Induzida/métodos , Compostos de Manganês/uso terapêutico , Camundongos , Molibdênio/uso terapêutico , Nanotubos/ultraestrutura , Neoplasias/terapia , Óxidos/uso terapêutico , Fototerapia/métodos , Microambiente TumoralRESUMO
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.
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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
Radiation therapy for cancer can lead to off-target toxicity and can be ineffective against hypoxic solid tumours and distant metastases. Here, we show that intratumoral injection, in mouse and rabbit xenografts and in patient-derived mouse xenografts, of a sodium alginate formulation containing catalase (Cat) labelled with the therapeutic 131I radioisotope enables long-term relief of tumour hypoxia and complete tumour elimination at low radioactivity doses. On injection, the soluble polysaccharide rapidly transforms into a hydrogel in the presence of endogenous Ca2+, fixing 131I-Cat within the tumours. We also show that local radiotherapy with a formulation that includes the immunostimulatory CpG oligonucleotide combined with systemic checkpoint-blockade therapy using an anti-CTLA-4 antibody leads to metastasis inhibition and protection against tumour rechallenge. The local therapy, which uses only biocompatible components, might enable new strategies for local tumour treatments that can be combined with systemic therapeutic responses, for the inhibition of tumour metastasis and the prevention of tumour recurrence in patients with advanced-stage cancer.
Assuntos
Antineoplásicos , Neoplasias/terapia , Radioimunoterapia/métodos , Animais , Antineoplásicos/química , Antineoplásicos/imunologia , Antineoplásicos/farmacologia , Antígeno CTLA-4/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/imunologia , Oligodesoxirribonucleotídeos/imunologia , Coelhos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Graphene oxides (GO) are attracting much attention in the diagnosis and therapy of the subcutaneous tumor as a novel biomaterial, but its diagnosis to tissue dysfunction is yet to be found. Here, a novel application of GO for diagnosis of renal dysfunction via contrast-enhanced computed tomography (CT) is proposed. In order to serve as contrast-enhanced agent, Ag nanoparticles (AgNPs) are composited on the surface of GO to promote its X-ray absorption, and then simvastatin is coinjected for eliminating in vivo toxicity induced by AgNPs. It is found that GO/AgNPs can enhance the imaging of CT into the lung, liver, and kidney of mice for a long circulation time (≈24 h) and a safety profile in vivo in the presence of simvastatin. Interestingly, the lower dose of GO/AgNPs (≈0.5 mg per kg bw) shows an excellent performance for CT imaging of renal perfusion, and visually exhibits the right renal dysfunction in model mice. Hence, this work suggests that graphene nanoparticles will play a vital role for the future medical translational development including drug carrier, biosensing, and disease therapy.
Assuntos
Meios de Contraste/química , Grafite/química , Nefropatias/diagnóstico , Nanopartículas Metálicas/química , Óxidos/química , Prata/química , Sinvastatina/química , Animais , Técnicas Biossensoriais/métodos , Meios de Contraste/administração & dosagem , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Feminino , Grafite/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Camundongos , Óxidos/administração & dosagem , Prata/administração & dosagem , Sinvastatina/administração & dosagem , Tomografia Computadorizada por Raios X/métodosRESUMO
Although nanoparticle-based drug delivery systems have been widely explored for tumor-targeted delivery of radioisotope therapy (RIT), the hypoxia zones of tumors on one hand can hardly be reached by nanoparticles with relatively large sizes due to their limited intratumoral diffusion ability, on the other hand often exhibit hypoxia-associated resistance to radiation-induced cell damage. To improve RIT treatment of solid tumors, herein, radionuclide 131 I labeled human serum albumin (HSA)-bound manganese dioxide nanoparticles (131 I-HSA-MnO2 ) are developed as a novel RIT nanomedicine platform that is responsive to the tumor microenvironment (TME). Such 131 I-HSA-MnO2 nanoparticles with suitable sizes during blood circulation show rather efficient tumor passive uptake owing to the enhanced permeability and retention effect, as well as little retention in other normal organs to minimize radiotoxicity. The acidic TME can trigger gradual degradation of MnO2 and thus decomposition of 131 I-HSA-MnO2 nanoparticles into individual 131 I-HSA with sub-10 nm sizes and greatly improves intratumoral diffusion. Furthermore, oxygen produced by MnO2 -triggered decomposition of tumor endogenous H2 O2 would be helpful to relieve hypoxia-associated RIT resistant for those tumors. As the results, the 131 I-HSA-MnO2 nanoparticles appear to be a highly effective RIT agent showing great efficacy in tumor treatment upon systemic administration.