RESUMO
The spread of multidrug-resistant mycobacterium strains requires the development of new approaches to combat diseases caused by these pathogens. For that, photodynamic inactivation (PDI) is a promising approach. In this study, a tricarbocyanine (TCC) is used for the first time as a near-infrared (740 nm) activatable PDI photosensitizer to kill mycobacteria with deep light penetration. For better targeting, a novel tricarbocyanine dye functionalized with two trehalose units (TCC2Tre) is developed. The photodynamic effect of the conjugates against mycobacteria, including Mycobacterium tuberculosis, is evaluated. Under irradiation, TCC2Tre causes more effective killing of mycobacteria compared to the photosensitizer without trehalose conjugation, with 99.99% dead vegetative cells of M. tuberculosis and M. smegmatis. In addition, effective photoinactivation of dormant forms of M. smegmatis is observed after incubation with TCC2Tre. Mycobacteria treated with TCC2Tre are more sensitive to 740 nm light than the Gram-positive Micrococcus luteus and the Gram-negative Escherichia coli. For the first time, this study demonstrates the proof of principle of in vitro PDI of mycobacteria including the fast-growing M. smegmatis and the slow-growing M. tuberculosis using near-infrared activatable photosensitizers conjugated with trehalose. These findings are useful for the development of new efficient alternatives to antibiotic therapy.
Assuntos
Raios Infravermelhos , Mycobacterium smegmatis , Mycobacterium tuberculosis , Fármacos Fotossensibilizantes , Trealose , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/efeitos da radiação , Trealose/farmacologia , Trealose/química , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos da radiação , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Carbocianinas/química , Carbocianinas/farmacologia , Fotoquimioterapia/métodosRESUMO
NIR-IIa fluorescence imaging (FI) and NIR-II photothermal therapy (PTT) have gained popularity due to the advantages of high temporal and spatial resolution and deep penetration. However, the hyperthermia (>48 °C) of conventional PTT with nonspecific warming and thermal diffusion may inevitably cause damage to healthy tissues or organs surrounding the tumor. Therefore, it is highly desirable to provide effective cancer treatment by implementing mild photothermal therapy (mPTT) at mild temperatures with lower laser power density. Here, the nanotheranostic platform FN@P-GA NPs with NIR-II absorption and NIR-IIa emission was developed by constructing J-aggregates. FN@P-GA possesses good biocompatibility, favorable NIR-IIa FI performance, decent stability, and high photothermal conversion efficiency (57.6 %), which lays a solid foundation for FI-guided mPTT. Due to its ability to effectively down-regulate the expression of HSP90 and reduce cellular thermoresistance to kill cancer cells, FN@P-GA successfully achieved NIR-IIa FI-guided mPTT and demonstrated its potent anti-tumor effect under 1064 nm laser irradiation at mild temperature and low power density (0.3 W/cm2).
Assuntos
Carbocianinas , Corantes Fluorescentes , Raios Infravermelhos , Terapia Fototérmica , Humanos , Carbocianinas/química , Carbocianinas/farmacologia , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Animais , Camundongos , Imagem Óptica , Sobrevivência Celular/efeitos dos fármacos , Tamanho da Partícula , Antineoplásicos/química , Antineoplásicos/farmacologia , Propriedades de Superfície , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Nanopartículas/química , Fluorescência , Linhagem Celular TumoralRESUMO
Photodynamic therapy (PDT) and photothermal therapy (PTT) possess different merits in cancer phototherapy, but the tumor microenvironment becomes unfavorable during the phototheranostic progress. Herein, we report a self-adaptive cyanine derivative Cy5-TPA with the PDT-dominated state to PTT-dominated state autoswitch feature for enhanced photoimmunotherapy. The incorporation of rotatable triphenylamine (TPA) moiety renders Cy5-TPA with the temperature or intramolecular-motion regulated photoactivities, which shows preferable reactive oxygen species (ROS) generation at lower temperature while stronger photothermal conversion at higher ones. Such a promising feature permits the in situ switch from PDT-dominated state to PTT-dominated state along with intratumoral temperature increase during laser irradiation, which also works in line with the concurrently reduced intratumoral oxygen level, exhibiting a self-adaptive phototherapeutic behavior to maximize the phototherapeutic antitumor outcome. Most importantly, the self-adaptive PDT-dominated state to PTT-dominated state switch also facilitates the sequential generation and release of damage-associated molecular patterns during immunogenic cell death (ICD). Hence, Cy5-TPA demonstrates excellent photoimmunotherapy performance in ICD induction, dendritic cell maturation, and T cell activation for tumor eradication and metastasis inhibition.
Assuntos
Imunoterapia , Fotoquimioterapia , Fármacos Fotossensibilizantes , Espécies Reativas de Oxigênio , Animais , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Humanos , Terapia Fototérmica , Camundongos Endogâmicos BALB C , Carbocianinas/química , Carbocianinas/farmacologia , Linhagem Celular Tumoral , Feminino , Microambiente Tumoral/efeitos dos fármacosRESUMO
Reactive oxygen species (ROS) have become an effective tool for tumor treatment. The combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT) takes advantage of various ROS and enhances therapeutic effects. However, the activation of CDT usually occurs before PDT, which hinders the sustained maintenance of hydroxyl radicals (â OH) and reduces the treatment efficiency. Herein, we present a light-triggered nano-system based on molecular aggregation regulation for converting cancer therapy from PDT/photothermal therapy (PTT) to a long-lasting CDT. The ordered J-aggregation enhances the photodynamic properties of the cyanine moiety while simultaneously suppressing the chemodynamic capabilities of the copper-porphyrin moiety. Upon light irradiation, Cu-PCy JNPs demonstrate strong photodynamic and photothermal effects. Meanwhile, light triggers a rapid degradation of the cyanine backbone, leading to the destruction of the J-aggregation. As a result, a long-lasting CDT is sequentially activated, and the sustained generation of â OH is observed for up to 48â hours, causing potent cellular oxidative stress and apoptosis. Due to their excellent tumor accumulation, Cu-PCy JNPs exhibit effective in vivo tumor ablation through the converting therapy. This work provides a new approach for effectively prolonging the chemodynamic activity in ROS-based cancer therapy.
Assuntos
Fotoquimioterapia , Fármacos Fotossensibilizantes , Terapia Fototérmica , Animais , Humanos , Camundongos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Cobre/química , Cobre/farmacologia , Luz , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/terapia , Carbocianinas/química , Carbocianinas/farmacologia , Sobrevivência Celular/efeitos dos fármacosRESUMO
BACKGROUND: Peptidyl (protein) arginine deiminases (PADs) provide the transformation of peptidyl arginine to peptidyl citrulline in the presence of calcium with posttranslational modification. The dysregulated PAD activity plays an important role on too many diseases including also the cancer. In this study, it has been aimed to determine the potential cytotoxic and apoptotic activity of chlorine-amidine (Cl-amidine) which is a PAD inhibitor and whose effectiveness has been shown in vitro and in vivo studies recently on human glioblastoma cell line Uppsala 87 malignant glioma (U-87 MG) forming an in vitro model for the glioblastoma multiforme (GBM) which is the most aggressive and has the highest mortality among the brain tumors. METHODS: In the study, the antiproliferative and apoptotic effects of Cl-amidine on GBM cancer model were investigated. The antiproliferative effects of Cl-amidine on U-87 MG cells were determined by 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate method at the 24th and 48th hours. The apoptotic effects were analyzed by Annexin V and Propidium iodide staining, caspase-3 activation, and mitochondrial membrane polarization (5,5', 6,6'-tetrachloro-1,1', 3,3' tetraethyl benzimidazolyl carbocyanine iodide) methods in the flow cytometry. RESULTS: It has been determined that Cl-amidine exhibits notable antiproliferative properties on U-87 MG cell line in a time and concentration-dependent manner, as determined through the 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate assay. Assessment of apoptotic effects via Annexin V and Propidium iodide staining and 5,5', 6,6'-tetrachloro-1,1', 3,3' tetraethyl benzimidazolyl carbocyanine iodide methods has revealed significant efficacy, particularly following a 24-hour exposure period. It has been observed that Cl-amidine induces apoptosis in cells by enhancing mitochondrial depolarization, independently of caspase-3 activation. Furthermore, regarding its impact on healthy cells, it has been demonstrated that Cl-amidine shows lower cytotoxic effects when compared to carmustine, an important therapeutic agent for glioblastoma. CONCLUSION: The findings of this study have shown that Cl-amidine exhibits significant potential as an anticancer agent in the treatment of GBM. This conclusion is based on its noteworthy antiproliferative and apoptotic effects observed in U-87 MG cells, as well as its reduced cytotoxicity toward healthy cells in comparison to existing treatments. We propose that the antineoplastic properties of Cl-amidine should be further investigated through a broader spectrum of cancer cell types. Moreover, we believe that investigating the synergistic interactions of Cl-amidine with single or combination therapies holds promise for the discovery of novel anticancer agents.
Assuntos
Antineoplásicos , Glioblastoma , Nitrofenóis , Ornitina/análogos & derivados , Humanos , Cloro , Glioblastoma/metabolismo , Anexina A5 , Benzeno , Carbocianinas/farmacologia , Caspase 3/metabolismo , Iodetos/metabolismo , Iodetos/farmacologia , Propídio , Desiminases de Arginina em Proteínas/metabolismo , Desiminases de Arginina em Proteínas/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Amidinas/farmacologia , Arginina/metabolismo , ApoptoseRESUMO
Currently, cisplatin resistance has been recognized as a multistep cascade process for its clinical chemotherapy failure. Hitherto, it remains challenging to develop a feasible and promising strategy to overcome the cascade drug resistance (CDR) issue for achieving fundamentally improved chemotherapeutic efficacy. Herein, a novel self-assembled nanoagent is proposed, which is constructed by Pt(IV) prodrug, cyanine dye (cypate), and gadolinium ion (Gd3+), for systematically conquering the cisplatin resistance by employing near-infrared (NIR) light activated mild-temperature hyperthermia in tumor targets. The proposed nanoagents exhibit high photostability, GSH/H+-responsive dissociation, preferable photothermal conversion, and enhanced cellular uptake performance. In particular, upon 785-nm NIR light irradiation, the generated mild temperature of ≈ 43 °C overtly improves the cell membrane permeability and drug uptake, accelerates the disruption of intracellular redox balance, and apparently enhances the formation of Pt-DNA adducts, thereby effectively overcoming the CDR issue and achieves highly improved therapeutic efficacy for cisplatin-resistant tumor ablation.
Assuntos
Cisplatino , Resistencia a Medicamentos Antineoplásicos , Hipertermia Induzida , Indóis , Propionatos , Cisplatino/farmacologia , Cisplatino/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Animais , Hipertermia Induzida/métodos , Camundongos , Linhagem Celular Tumoral , Raios Infravermelhos , Gadolínio/química , Gadolínio/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Camundongos Endogâmicos BALB C , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Camundongos Nus , Carbocianinas/química , Carbocianinas/farmacologiaRESUMO
We designed and synthesized two heptamethine cyanine-based theranostic probes that aimed to target COX-2 in cancer cells. One is I-IR799-CXB, in which I-IR799 is conjugated to the COX-2-specific inhibitor, celecoxib, and another is I-IR799-IMC, where the non-selective COX inhibitor, indomethacin, was used. I-IR799 is a heptamethine cyanine derivative that can be activated by near-infrared light for photodynamic therapy (PDT) purposes. I-IR799-CXB and I-IR799-IMC were tested for their cancer-targeting capacity and photodynamic efficiency toward hepatocellular carcinoma (HepG2) cells relative to normal liver cells, alpha mouse liver 12 (AML12) cells. Interestingly, after conjugation, I-IR799-IMC exhibited better tumour targetability and PDT efficiency than I-IR799-CXB.
Assuntos
Neoplasias , Fotoquimioterapia , Animais , Carbocianinas/farmacologia , Corantes , Ciclo-Oxigenase 2 , Corantes Fluorescentes/farmacologia , CamundongosRESUMO
The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive, triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative, as well as estrogen receptor-positive, breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells, suggesting its mechanism of action differs from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds, as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case.
Assuntos
Antineoplásicos , Neoplasias da Mama/tratamento farmacológico , Carbocianinas , Citotoxinas , Indóis , Piperazinas , Piridinas , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Células CHO , Carbocianinas/química , Carbocianinas/farmacologia , Cricetulus , Citotoxinas/química , Citotoxinas/farmacologia , Feminino , Células HEK293 , Humanos , Indóis/química , Indóis/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Piridinas/química , Piridinas/farmacologiaRESUMO
Cancer and atherosclerosis are chronic diseases that share common characteristics at both early and advanced stages and can arise from multiple factors. Both diseases are characterized by uncontrolled cell proliferation, inflammation, angiogenesis and apoptosis. Herein we investigated the ability of a peptide (CTHRSSVVC), that was previously reported to bind atherosclerotic lesions to home in the tumor microenvironment. The CTHRSSVVC peptide was synthesized on solid phase and N-terminally labeled with a sulfo-Cy5 dye. The specific binding to macrophage was evaluated in vitro with flow cytometry and immunofluorescence and in vivo for tumor targeting in BALB/c mice bearing a 4T1 tumor using optical imaging. The sulfo-Cy5-CTHRSSVVC peptide was synthesized in greater than 99% purity. No selective binding of the sulfo-Cy5-CTHRSSVVC peptide to macrophages in vitro was observed, however in vivo the sulfo-Cy5-CTHRSSVVC peptide accumulated in the 4T1 tumor, with a tumor-to-normal tissue ratio of 7.21 ± 1.44 at 2 h post injection. Ex vivo analysis of tumor tissue by confocal microscopy suggested that the sulfo-Cy5-CTHRSSVVC peptide had accumulated in the stroma of the tumor specifically, in regions of spindle shaped cells. In conclusion, although the target for the sulfo-Cy5-CTHRSSVVC peptide remains to be identified, the Cy5-CTHRSSVVC peptide warrants further investigation as a tumor imaging agent.
Assuntos
Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Macrófagos/imunologia , Neoplasias/diagnóstico por imagem , Peptídeos , Placa Aterosclerótica/diagnóstico por imagem , Receptores de Superfície Celular/análise , Animais , Carbocianinas/farmacologia , Modelos Animais de Doenças , Imunofluorescência , Corantes Fluorescentes/farmacologia , Humanos , Imuno-Histoquímica , Camundongos , Imagem Óptica/métodos , Peptídeos/síntese química , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/farmacologia , Ligação Proteica , Receptores Depuradores/análise , Células THP-1RESUMO
Ibrutinib is an inhibitor of Bruton's tyrosine kinase that has been approved for the treatment of patients with chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom's macroglobulinemia and is connected with toxicities. To minimize its toxicities, we linked ibrutinib to a cell-targeted, internalizing antibody. To this end, we synthesized a poly-anionic derivate, ibrutinib-Cy3.5, that retains full functionality. This anionic inhibitor is complexed by our anti-CD20-protamine targeting conjugate and free protamine, and thereby spontaneously assembles into an electrostatically stabilized vesicular nanocarrier. The complexation led to an accumulation of the drug driven by the CD20 antigen internalization to the intended cells and an amplification of its pharmacological effectivity. Inâ vivo, we observed a significant enrichment of the drug in xenograft lymphoma tumors in immune-compromised mice and a significantly better response to lower doses compared to the original drug.
Assuntos
Adenina/análogos & derivados , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Carbocianinas/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Adenina/química , Adenina/farmacologia , Animais , Anticorpos Monoclonais/química , Antineoplásicos/química , Carbocianinas/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Piperidinas/química , Engenharia de Proteínas , Inibidores de Proteínas Quinases/química , Eletricidade EstáticaRESUMO
Because of the blood-brain barrier and the high infiltration of glioma cells, the diagnostic accuracy and treatment efficiency of gliomas are still facing challenges. There is an urgent need to explore the integration of diagnostic and therapeutic methods to achieve an accurate diagnosis, guide surgery, and inhibit postoperative recurrence. In this work, we developed a macrophage loaded with a photothermal nanoprobe (MFe3O4-Cy5.5), which is able to cross the blood-brain barrier and accumulate into deep gliomas to achieve multimodal imaging and guided glioma surgery purposes. With desirable probing depth and high signal-to-noise ratio, Fe3O4-Cy5.5 can perform fluorescence, photoacoustic, and magnetic resonance imaging, which can distinguish brain tumors from the surrounding normal tissues and accurately guide glioma resection. Meanwhile, Fe3O4-Cy5.5 can effectively induce local photothermal therapy and inhibit the recurrence of glioma after surgery. These results demonstrate that the macrophage-mediated Fe3O4-Cy5.5, which can achieve a multimodal diagnosis, accurate imaging-guided surgery, and effective photothermal therapy, is a promising nanoplatform for gliomas.
Assuntos
Materiais Biomiméticos/farmacologia , Neoplasias Encefálicas/terapia , Carbocianinas/farmacologia , Glioma/terapia , Nanopartículas de Magnetita/química , Terapia Fototérmica , Animais , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/diagnóstico por imagem , Carbocianinas/química , Glioma/diagnóstico por imagem , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Teste de Materiais , Imagem Multimodal , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/terapia , Tamanho da Partícula , Porosidade , Ratos , Ratos Sprague-Dawley , Células Tumorais CultivadasRESUMO
Lysosomes adopt dynamic, tubular states that regulate antigen presentation, phagosome resolution, and autophagy. Tubular lysosomes are studied either by inducing autophagy or by activating immune cells, both of which lead to cell states where lysosomal gene expression differs from the resting state. Therefore, it has been challenging to pinpoint the biochemical properties lysosomes acquire upon tubulation that could drive their functionality. Here we describe a DNA-based assembly that tubulates lysosomes in macrophages without activating them. Proteolytic activity maps at single-lysosome resolution revealed that tubular lysosomes were less degradative and showed proximal to distal luminal pH and Ca2+ gradients. Such gradients had been predicted but never previously observed. We identify a role for tubular lysosomes in promoting phagocytosis and activating MMP9. The ability to tubulate lysosomes without starving or activating immune cells may help reveal new roles for tubular lysosomes.
Assuntos
DNA/química , Lisossomos/metabolismo , Macrófagos/imunologia , Metaloproteinase 9 da Matriz/metabolismo , Fagocitose/fisiologia , Animais , Aptâmeros de Nucleotídeos/farmacologia , Autofagia/fisiologia , Células COS , Cálcio/metabolismo , Carbocianinas/farmacologia , Linhagem Celular Tumoral , Chlorocebus aethiops , Células Hep G2 , Humanos , Lisossomos/efeitos dos fármacos , Camundongos , Nanocompostos/química , Fagossomos/metabolismo , Células RAW 264.7RESUMO
Herein, an unprecedented synergistic strategy for the development of high-performance NIR-II fluorophore is proposed and validated. Based on an unsymmetrical cyanine dye design strategy, the NIR-II emissive dye NIC was successfully developed by replacing only one of the indoline donors of symmetrical cyanine dye ICG with a fully conjugated benz[c,d]indole donor. This minor structural change maximally maintains the high extinction coefficient advantage of cyanine dyes. NIC-ER with endogenous albumin-hitchhiking capability was constructed to further enhance its in vivo fluorescence brightness. In the presence of HSA (Human serum albumin), NIC-ER spontaneously resides in the albumin pocket, and a brilliant ~89-fold increase in fluorescence was observed. Due to its high molar absorptivity and moderate quantum yield, NIC-ER in HSA exhibits bright NIR-II emission with high photostability and significant Stokes shift (>110 nm). Moreover, NIC-ER was successfully employed for tumor-targeted NIR-II/PA imaging and efficient photothermal tumor elimination. Overall, our strategy may open up a new avenue for designing and constructing high-performance NIR-II fluorophores.
Assuntos
Carbocianinas , Corantes , Técnicas Fotoacústicas/métodos , Terapia Fototérmica/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Albuminas/metabolismo , Animais , Carbocianinas/química , Carbocianinas/metabolismo , Carbocianinas/farmacologia , Linhagem Celular Tumoral , Corantes/química , Corantes/metabolismo , Corantes/farmacologia , Camundongos , Camundongos Nus , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologiaRESUMO
A rigid hemicyanine CSZ-J and a flexible molecule ESZ-J were synthesized. In particular, the conformationally restrained CSZ-J had higher fluorescence quantum yields, longer fluorescence lifetimes and higher triplet state quantum yields. CSZ-J could generate highly cytotoxic ROS simultaneously via type I and type II processes. This will contribute to the design and development of new photosensitizers in the future.
Assuntos
Antineoplásicos/farmacologia , Carbocianinas/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/química , Carbocianinas/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Conformação Molecular , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
Heavy-atom-based photosensitizers usually exhibit shortened triplet-state lifetimes, which is not ideal for hypoxic tumor photodynamic therapy. Although several heavy-atom-free photosensitizers possess long triplet-state lifetimes, the clinical applicability is limited by their short excitation wavelengths, poor photon capture abilities, and intrinsically hydrophobic structures. Herein we developed a novel NIR heavy-atom-free photosensitizer design strategy by introducing sterically bulky and electron-rich moieties at the meso position of the pentamethine cyanine (Cy5) skeleton, which simultaneously enhanced intersystem crossing (ISC) and prolonged excited-state lifetime. We found that the 1O2 generation ability is directly correlated to the electron-donating ability of the meso substituent in cyanine, and the excited-state lifetime was simultaneously much elongated when the substituents were anthracene derivatives substituted at the 9-position. Our star compound, ANOMe-Cy5, exhibits intense NIR absorption, the highest 1O2 quantum yield (4.48-fold higher than Cy5), the longest triplet-state lifetime (9.80-fold longer than Cy5), and lossless emission intensity (nearly no change compared with Cy5). Such excellent photophysical properties coupled with its inherently cationic and hydrophilic nature enable the photosensitizer to realize photoablation of solid tumor and antitumor lung metastasis. This study highlights the design of a new generation of NIR photosensitizers for imaging-guided photodynamic cancer treatment.
Assuntos
Antineoplásicos/farmacologia , Carbocianinas/farmacologia , Corantes Fluorescentes/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbocianinas/síntese química , Carbocianinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/químicaRESUMO
We performed an X-ray crystallographic study of complexes of protein kinase PIM-1 with three inhibitors comprising an adenosine mimetic moiety, a linker, and a peptide-mimetic (d-Arg)6 fragment. Guided by the structural models, simplified chemical structures with a reduced number of polar groups and chiral centers were designed. The developed inhibitors retained low-nanomolar potency and possessed remarkable selectivity toward the PIM kinases. The new inhibitors were derivatized with biotin or fluorescent dye Cy5 and then applied for the detection of PIM kinases in biochemical solutions and in complex biological samples. The sandwich assay utilizing a PIM-2-selective detection antibody featured a low limit of quantification (44 pg of active recombinant PIM-2). Fluorescent probes were efficiently taken up by U2OS cells and showed a high extent of co-localization with PIM-1 fused with a fluorescent protein. Overall, the developed inhibitors and derivatives represent versatile chemical tools for studying PIM function in cellular systems in normal and disease physiology.
Assuntos
Corantes Fluorescentes , Imagem Molecular , Peptidomiméticos , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-pim-1 , Carbocianinas/química , Carbocianinas/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/metabolismoRESUMO
Due to the hydrophobicity of the cyanine dye and the huge conjugated plane, the cyanine dye is prone to H-aggregation in aqueous solution, and the ultraviolet absorption is blue-shifted. Here, a hydrophilic quaternary stereo-specific cyanine (HQS-Cy) dye has been synthesized and polypeptide based nanoparticles have been prepared, which improve the water solubility of the cyanine in two aspects. First, at the molecular level, the sulfonic acid group increases the water solubility of the dye molecule while the dimethyl-ammonium functional group repels the molecule through the charge-charge interaction, destroying the planar characteristics of the cyanine structure, increasing the molecular distance between the dye molecules, and preventing the accumulation of cyanine. Secondly, at the nano-micelle level, the use of amphiphilic polypeptide blocks to encapsulate the dye increases the water solubility of the dye while also increasing its biocompatibility. The HQS-Cy@P NPs prepared by the above methods exhibit the maximum absorption at 985 nm and maximum fluorescence emission at 1050 nm in aqueous solution. HQS-Cy@P exhibits good photothermal stability and significant photothermal conversion efficiency of about 35.5%, and both in vitro and in vivo studies revealed that it is an efficient system for NIR-II imaging-guided photothermal therapy of cancer.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carbocianinas/farmacologia , Corantes/farmacologia , Terapia Fototérmica , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/diagnóstico por imagem , Carbocianinas/síntese química , Carbocianinas/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Corantes/síntese química , Corantes/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Raios Infravermelhos , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Imagem Óptica , Solubilidade , Neoplasias do Colo do Útero/diagnóstico por imagemRESUMO
Nonsmall cell lung cancer (NSCLC) remains an intractable disease, which is primarily due to tumor metastasis and the acquisition of resistance to chemotherapy. Therefore, there is an urgent need for novel therapeutics to overcome these obstacles. It was recently demonstrated that upregulated expression of monoamine oxidase A (MAOA) contributes to the progression of NSCLC. G10, a tumortargeting representative conjugate of heptamethine carbocyanine dye and an inhibitor of MAOA, was shown to exert potent cytotoxic effects, comparable to those of doxorubicin, against prostate cancer cell lines, as well as moderate MAOA inhibitory activity. The research described herein aimed to extend our previous study on the antitumor function of G10 in NSCLC in vitro and in vivo, and to elucidate the mechanisms through which G10 exerts its antineoplastic effects. G10 markedly inhibited the proliferation of paclitaxelresistant NSCLC cells (H460/PTX) and reduced tumor cell migration and invasion. Gene expression profiling of paclitaxelresistant NSCLC cells following treatment with G10 demonstrated that the expression of genes associated with the extracellular matrix was significantly affected, particularly the metastasisrelated genes matrix metallopeptidase (MMP)2, MMP14 and COL6A, which exhibited notably reduced expression. Additionally, the results also demonstrated that MAOArelated pathways, including AKT and hypoxiainducible factor1α, were also inhibited by G10 treatment and, subsequently, the downstream molecules of these pathways, such as p21, MMP2 and vascular endothelial growth factor, were also downregulated, highlighting a possible mechanism through which G10 suppresses tumor cell migration, invasion and proliferation. Importantly, in mouse NSCLC xenografts, combined treatment with G10 and paclitaxel resulted in pronounced inhibition of tumor growth. Taken together, the results of the present study highlight the potential of G10 as a novel therapeutic targeting MAOA in paclitaxelresistant NSCLC.
Assuntos
Antineoplásicos/uso terapêutico , Carbocianinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Inibidores da Monoaminoxidase/uso terapêutico , Paclitaxel/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbocianinas/química , Carbocianinas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Reposicionamento de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Paclitaxel/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Abnormally high levels of class I histone deacetylases (HDACs) are associated with triple-negative breast cancer (TNBC) proliferation, malignant transformation, and poor prognosis of patients. Herein, we report a near-infrared imaging probe for TNBC detection via visualizing class I HDACs. Conjugating Cy5.5 to a cyclic depsipeptide inhibitor, we obtained the probe (20-Cy5.5) that retained desirable class I HDAC affinity and selectivity. Then, this probe could visualize epigenetic changes by class I HDACs in TNBC MDA-MB-231 cells and in xenograft tumor models in real time. Treatment with suberoylanilide hydroxamic acid (SAHA) significantly reduced the uptake of the probe in tumors, suggesting its potential use in evaluation of therapeutic responses of HDACi-mediated therapy. Moreover, 20-Cy5.5 could detect class I HDAC expression in TNBC lung metastasis. This novel NIR probe that achieves tumor class I HDAC imaging not only leads to a better understanding of epigenetic regulation in tumors but also has great potential for improving the TNBC diagnosis and treatment.
Assuntos
Carbocianinas/farmacologia , Depsipeptídeos/farmacologia , Epigênese Genética/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Carbocianinas/síntese química , Linhagem Celular Tumoral , Depsipeptídeos/síntese química , Feminino , Fluorometria , Regulação Neoplásica da Expressão Gênica/fisiologia , Xenoenxertos/metabolismo , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/análise , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos Nus , Neoplasias de Mama Triplo Negativas/patologia , Vorinostat/farmacologiaRESUMO
Dual phototherapy agents have attracted great interest in recent years as they offer enhanced cytotoxicity on cancer cells due to the synergistic effect of photodynamic and photothermal therapies (PDT/PTT). In this study, we demonstrate a brominated hemicyanine (HC-1), which is previously shown as mitochondria targeting PDT agent, can also serve as an effective photosensitizer for PTT for the first time under a single (640 nm or 808 nm) and dual laser (640 nm + 808 nm) irradiation. Generation of reactive oxygen species and photothermal conversion as a function of irradiation wavelength and power were studied. Both single wavelength irradiations caused significant phototoxicity in colon and cervical cancer cells after 5 min of irradiation. However, co-irradiation provided near-complete elimination of cancer cells due to synergistic action. This work introduces an easily accessible small molecule-based synergistic phototherapy agent, which holds a great promise towards the realization of local, rapid and highly efficient treatment modalities against cancer.