RESUMEN
BACKGROUND: The effectiveness of immune checkpoint inhibitors in colorectal cancer (CRC) is limited due to the low tumor neoantigen load and low immune infiltration in most microsatellite-stable (MSS) tumors. This study aimed to develop a mitochondria-targeted photodynamic therapy (PDT) approach to provoke host antitumor immunity of MSS-CRC and elucidate the underlying molecular mechanisms. METHODS: The role and mechanism of mitochondria-targeted PDT in inhibiting CRC progression and inducing pyroptosis were evaluated both in vitro and in vivo. The immune effects of PDT sensitization on PD-1 blockade were also assessed in CT26 and 4T1 tumor-bearing mouse models. RESULTS: Here, we report that PDT using IR700DX-6T, a photosensitizer targeting the mitochondrial translocation protein, may trigger an antitumor immune response initiated by pyroptosis in CRC. Mechanistically, IR700DX-6T-PDT produced reactive oxygen species on light irradiation and promoted downstream p38 phosphorylation and active caspase3 (CASP3)-mediated cleavage of gasdermin E (GSDME), subsequently inducing pyroptosis. Furthermore, IR700DX-6T-PDT enhanced the sensitivity of MSS-CRC cells to PD-1 blockade. Decitabine, a demethylation drug used to treat hematologic neoplasms, disrupted the abnormal methylation pattern of GSDME in tumor cells, enhanced the efficacy of IR700DX-6T-PDT, and elicited a potent antitumor immune response in combination with PD-1 blockade and IR700DX-6T-PDT. CONCLUSION: Our work provides clear a understanding of immunogenic cell death triggered by mitochondria-targeted PDT, offering a new approach for enhancing the efficacy of PD-1 blockade in CRC.
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Neoplasias Colorrectales , Fotoquimioterapia , Animales , Ratones , Línea Celular Tumoral , Neoplasias Colorrectales/terapia , Inmunoterapia , Mitocondrias/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Piroptosis , Gasderminas/efectos de los fármacos , Gasderminas/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéuticoRESUMEN
The WMIS Education Committee (2019-2022) reached a consensus that white papers on molecular imaging could be beneficial for practitioners of molecular imaging at their early career stages and other scientists who are interested in molecular imaging. With this consensus, the committee plans to publish a series of white papers on topics related to the daily practice of molecular imaging. In this white paper, we aim to provide practical guidance that could be helpful for optical molecular imaging, particularly for small molecule probe development and validation in vitro and in vivo. The focus of this paper is preclinical animal studies with small-molecule optical probes. Near-infrared fluorescence imaging, bioluminescence imaging, chemiluminescence imaging, image-guided surgery, and Cerenkov luminescence imaging are discussed in this white paper.
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Imagen Molecular , Imagen Óptica , Animales , Imagen Óptica/métodos , Colorantes FluorescentesRESUMEN
Imaging chromatin organization at the molecular-scale resolution remains an important endeavor in basic and translational research. Stochastic optical reconstruction microscopy (STORM) is a powerful superresolution imaging technique to visualize nanoscale molecular organization down to the resolution of ~20 to 30 nm. Despite the substantial progress in imaging chromatin organization in cells and model systems, its routine application on assessing pathological tissue remains limited. It is, in part, hampered by the lack of simple labels that consistently generates high-quality STORM images on the highly processed clinical tissue. We developed a fast, simple, and robust small-molecule fluorescent probe-cyanine 5-conjugated Hoechst-for routine superresolution imaging of nanoscale nuclear architecture on clinical tissue. We demonstrated the biological and clinical significance of imaging superresolved chromatin structure in cancer development and its potential clinical utility for cancer risk stratification.
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Staphylococcus aureus is a serious threat to public health due to the rise of antibiotic resistance in this organism, which can prolong or exacerbate skin and soft tissue infections (SSTIs). Methicillin-resistant S. aureus is a Gram-positive bacterium and a leading cause of SSTIs. As such, many efforts are under way to develop therapies that target essential biological processes in S. aureus. Antimicrobial photodynamic therapy is an effective alternative to antibiotics; therefore we developed an approach to simultaneously expose S. aureus to intracellular and extracellular photosensitizers. A near infrared photosensitizer was conjugated to human monoclonal antibodies (MAbs) that target the S. aureus iron-regulated surface determinant (Isd) heme acquisition proteins. In addition, the compound VU0038882 was developed to increase photoactivatable porphyrins within the cell. Combinatorial photodynamic treatment of drug-resistant S. aureus exposed to VU0038882 and conjugated anti-Isd MAbs proved to be an effective antibacterial strategy in vitro and in a murine model of SSTIs.
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Staphylococcus aureus Resistente a Meticilina , Infecciones de los Tejidos Blandos , Infecciones Estafilocócicas , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Humanos , Ratones , Fármacos Fotosensibilizantes/farmacología , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureusRESUMEN
BACKGROUND/AIMS: IR700DX-6T and IR700DX-mbc94 are two chemically synthesized photosensitizers (PSs) that target the translocator protein (TSPO) and type 2 cannabinoid receptor (CB2R), respectively, for photodynamic therapy (PDT) of cancer. Recently, we found that IR700DX-6T and IR700DX-mbc94 exhibited high selectivity and efficiency in PDT for breast cancer and malignant astrocytoma. Yet, the phototherapeutic effects of the PSs on pancreatic cancer and underlying mechanisms remain unknown. This study investigated the effect of IR700DX-6T- or IR700DX-mbc94-PDT on pancreatic cancer and whether the treatment involves eliciting anticancer immune responses in support of superior therapeutic efficacy. METHODS: Four pancreatic cancer cell lines were used for in vitro studies. C57BL/6 mice bearing pancreatic cancer cell-derived xenografts were generated for in vivo studies regarding the therapeutic effects of IR700DX-6T-PDT and IR700DX-mbc94-PDT on pancreatic cancer. The immunostimulatory or immunosuppressive effects of IR700DX-6T-PDT and IR700DX-mbc94-PDT were examined by detecting CD8+ T cells, regulatory T cells (Tregs), and dendritic cells (DCs) using flow cytometry and immunohistochemistry (IHC). RESULTS: TSPO and CB2R were markedly upregulated in pancreatic cancer cells and tissues. Both IR700DX-6T-PDT and IR700DX-mbc94-PDT significantly inhibited pancreatic cancer cell growth in a dose- and time-dependent manner. Notably, assessment of anticancer immune responses revealed that both IR700DX-6T-PDT and IR700DX-mbc94-PDT significantly induced CD8+ T cells, promoted maturation of DCs, and suppressed Tregs, with stronger effects exerted by IR700DX-6T-PDT compared to IR700DX-mbc94-PDT. CONCLUSIONS: IR700DX-6T-PDT and IR700DX-mbc94-PDT involves eliciting anticancer immune responses. Our study has also implicated that PDT in combination with immunotherapy holds promise to improve therapeutic efficacy for patients with pancreatic cancer.
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Indoles/uso terapéutico , Compuestos de Organosilicio/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Adenosina Trifosfato/metabolismo , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Humanos , Indoles/farmacología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ratones Endogámicos C57BL , Compuestos de Organosilicio/farmacología , Páncreas/metabolismo , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/metabolismo , Fármacos Fotosensibilizantes/farmacología , Receptor Cannabinoide CB2/metabolismo , Receptores de GABA/metabolismo , Bazo/citología , Bazo/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunologíaRESUMEN
Abscopal effect is an attractive cancer therapeutic effect referring to tumor regression at a location distant from the primary treatment site. Immunogenic cell death (ICD) offers a mechanistic link between the primary and remote therapeutic effects by activating favorable anti-tumor immune responses. In this study, we induced ICD in colorectal cancer (CRC) cell lines in vitro and in vivo by targeting the 18 kDa translocator protein (TSPO), a mitochondrial receptor overexpressed in CRC. Photodynamic therapy (PDT) using a TSPO-targeted photosensitizer, IR700DX-6T, caused effective apoptotic cell death in fourteen CRC cell lines. In a syngeneic immunocompetent CRC mouse model, the growth of tumors subjected to TSPO-PDT was greatly suppressed. Remarkably, untreated tumors in the opposing flank also showed marked growth suppression. Dendritic and CD8+ T cells were activated after TSPO-PDT treatment, accompanied by decreased Treg cells in both treated and non-treated tumors. In addition, a cancer vaccine developed from TSPO-PDT produced a significant tumor inhibition effect. These results indicate that TSPO-PDT could not only directly suppress tumor growth but also dramatically provoke host anti-tumor immunity, highlighting the potential of TSPO-PDT as a successful therapeutic for CRC that exhibits systemic effects. STATEMENT OF SIGNIFICANCE: Abscopal effect is an attractive cancer therapeutic effect referring to tumor regression at a location distant from the primary treatment site. Immunogenic cell death (ICD) offers a mechanistic link between the primary and remote therapeutic effects by activating favorable anti-tumor immune responses. In this study, we report a new therapeutic approach that can reduce the growth of multiple CRC cell lines by inducing ICD. Notably, a direct and abscopal effect was observed in mouse tumor-derived MC38 cells when injected into syngeneic immunocompetent mice. If comparable effects could be achieved in humans, it would establish a novel paradigm for treating micro- and macro-metastasis.
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Neoplasias Colorrectales , Fotoquimioterapia , Animales , Linfocitos T CD8-positivos , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Muerte Celular Inmunogénica , Ratones , Fármacos Fotosensibilizantes/farmacologíaRESUMEN
Photodynamic therapy (PDT) is a clinically approved therapeutic strategy that combines a specific wavelength of light and light-activated photosensitizers (PSs). The usage of PDT for cancer treatment is often hampered by the lack of tumor selectivity of PSs, which may cause photodamage to surrounding normal tissues. Recently, translocator protein (TSPO) has attracted great interest as a tumor biomarker, whose expression correlates with tumor aggressiveness. In this study, we report the development of a series of novel TSPO-PSs based on quinazoline, pyrazolopyrimidine, and tetrahydrocarbazole structures. These TSPO-PSs bind to TSPO with nanomolar affinities and demonstrated efficient and target-specific PDT effect upon light irradiation. Therefore, they may have great potential in the treatment of tumors associated with high-TSPO expression.
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Antineoplásicos , Neoplasias , Fotoquimioterapia , Antineoplásicos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Receptores de GABARESUMEN
BACKGROUND/AIM: 18 kDa Translocator protein (TSPO) is a mitochondrial protein up-regulated in colorectal carcinoma (CRC). Our purpose was to develop a TSPO-targeted doxorubicin prodrug (Dox-TSPO) which can be loaded onto drug-eluting beads for transarterial chemoembolization. Furthermore, we evaluated its loading and release kinetics and effects on cell viability. MATERIALS AND METHODS: N-Fmoc-DOX-14-O-hemiglutarate was coupled with a TSPO ligand, 6-TSPOmbb732, using classical N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate coupling to produce Dox-TSPO. Loading and elution studies were performed using DC beads™. Cell viability studies were performed using CellTiter-Glo® Luminescent Cell Viability Assay. RESULTS: Dox-TSPO was successfully synthesized and readily loaded onto and eluted from DC beads™, albeit at a slower rate than free doxorubicin. CRC cell lines expressing TSPO were 2- to 4- fold more sensitive to Dox-TSPO compared to free doxorubicin at 72 h. CONCLUSION: Dox-TSPO is a promising candidate for targeted and directed cancer treatment of CRC liver metastases.
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Neoplasias Colorrectales/tratamiento farmacológico , Doxorrubicina/farmacología , Profármacos/farmacología , Receptores de GABA/genética , Proteínas Portadoras/química , Proteínas Portadoras/farmacología , Línea Celular Tumoral , Quimioembolización Terapéutica/métodos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Doxorrubicina/química , Sistemas de Liberación de Medicamentos , Humanos , Profármacos/química , Receptores de GABA/químicaRESUMEN
PURPOSE: Pancreatic cancer is among the most aggressive malignancies and is rarely discovered early. However, pancreatic "incidentalomas," particularly cysts, are frequently identified in asymptomatic patients through anatomic imaging for unrelated causes. Accurate determination of the malignant potential of cystic lesions could lead to life-saving surgery or spare patients with indolent disease undue risk. Current risk assessment of pancreatic cysts requires invasive sampling, with attendant morbidity and sampling errors. Here, we sought to identify imaging biomarkers of high-risk pancreatic cancer precursor lesions. EXPERIMENTAL DESIGN: Translocator protein (TSPO) expression, which is associated with cholesterol metabolism, was evaluated in premalignant and pancreatic cancer lesions from human and genetically engineered mouse (GEM) tissues. In vivo imaging was performed with [18F]V-1008, a TSPO-targeted PET agent, in two GEM models. For image-guided surgery (IGS), V-1520, a TSPO ligand for near-IR optical imaging based upon the V-1008 pharmacophore, was developed and evaluated. RESULTS: TSPO was highly expressed in human and murine pancreatic cancer. Notably, TSPO expression was associated with high-grade, premalignant intraductal papillary mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasia (PanIN) lesions. In GEM models, [18F]V-1008 exhibited robust uptake in early pancreatic cancer, detectable by PET. Furthermore, V-1520 localized to premalignant pancreatic lesions and advanced tumors enabling real-time IGS. CONCLUSIONS: We anticipate that combined TSPO PET/IGS represents a translational approach for precision pancreatic cancer care through discrimination of high-risk indeterminate lesions and actionable surgery.
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Carcinoma Ductal Pancreático/genética , Colesterol/genética , Neoplasias Pancreáticas/genética , Lesiones Precancerosas/genética , Receptores de GABA/genética , Animales , Animales Modificados Genéticamente/genética , Carcinoma in Situ/diagnóstico por imagen , Carcinoma in Situ/genética , Carcinoma in Situ/patología , Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/patología , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Ratones , Páncreas/diagnóstico por imagen , Páncreas/patología , Quiste Pancreático/diagnóstico por imagen , Quiste Pancreático/patología , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/patología , Lesiones Precancerosas/diagnóstico por imagen , Lesiones Precancerosas/patologíaRESUMEN
Starting from our previously developed c-KIT kinase inhibitor CHMFL-KIT-8140, through a type II kinase inhibitor binding element hybrid design approach, we discovered a novel c-KIT kinase inhibitor compound 18 (CHMFL-KIT-64), which is potent against c-KIT wt and a broad spectrum of drug-resistant mutants with improved bioavailability. 18 exhibits single-digit nM potency against c-KIT kinase and c-KIT T670I mutants in the biochemical assay and displays great potencies against most of the gain-of-function mutations in the juxtamembrane domain, drug-resistant mutations in the ATP binding pocket (except V654A), and activation loops (except D816V). In addition, 18 exhibits a good in vivo pharmacokinetic (PK) profile in different species including mice, rats, and dogs. It also displays good in vivo antitumor efficacy in the c-KIT T670I, D820G, and Y823D mutant-mediated mice models as well as in the c-KIT wt patient primary cells which are known to be imatinib-resistant. The potent activity against a broad spectrum of clinically important c-KIT mutants combining the good in vivo PK/pharmacodynamic properties of 18 indicates that it might be a new potential therapeutic candidate for gastrointestinal stromal tumors.
Asunto(s)
Antineoplásicos/uso terapéutico , Bencenoacetamidas/uso terapéutico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Quinolinas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Bencenoacetamidas/síntesis química , Bencenoacetamidas/metabolismo , Bencenoacetamidas/farmacocinética , Proliferación Celular/efectos de los fármacos , Perros , Descubrimiento de Drogas , Femenino , Neoplasias Gastrointestinales/tratamiento farmacológico , Humanos , Masculino , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Mutación , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Quinolinas/síntesis química , Quinolinas/metabolismo , Quinolinas/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: cKIT kinase overexpression and gain-of-function mutations are the critical pathogenesis of gastrointestinal stromal tumors (GISTs). Although the multiple kinase inhibitors such as imatinib, sunitinib, and regorafenib have been approved for GISTs, the acquisition of polyclonal secondary resistance mutations in KIT is still a limitation for GIST treatment. Here we explored the KIT inhibitory activity of axitinib in preclinical models and describe initial characterization of its activity in GIST patient-derived primary cells. METHODS: The activities of axitinib against mutant KIT were evaluated using protein-based assay and a panel of engineered and GIST-derived cell lines. The binding modes of axitinib-KIT/KIT mutants were analyzed. Four primary cells derived from GIST patients were also used to assess the drug response of axitinib. RESULTS: Axitinib exhibited potent activities against a variety of cKIT associated primary and secondary mutations. It displayed better activity against cKIT wild-type, cKIT V559D/A/G, and L576P primary gain-of-function mutations than imatinib, sunitinib, and regorafenib. In addition, it could inhibit imatinib resistant cKIT T670I and V654A mutants in vitro and in vivo GIST preclinical models. CONCLUSION: Our results provide the basis for extending the application of axitinib to GISTs patients who are unresponsive or intolerant to the current therapies.
RESUMEN
Gain-of-function mutations of c-KIT kinase play crucial pathological roles for the gastrointestinal stromal tumors (GISTs). Despite the success of imatinib as the first-line treatment of GISTs, dozens of drug-acquired resistant mutations emerge, and c-KIT T670I is one of the most common mutants among them. Although several kinase inhibitors are capable of overcoming the T670I mutant, none of them can achieve the selectivity over the c-KIT wild-type (wt), which also plays important roles in a variety of physiological functions such as hematopoiesis. Starting from axitinib, through fragment hybrid type II kinase inhibitor design approach, we have discovered a novel inhibitor 24, which not only exhibits potent activity to c-KIT T670I mutant but also achieves 12-fold selectivity over c-KIT wt. Compound 24 displays good antiproliferative effects against c-KIT T670I mutant-driven GIST cell lines (GIST-T1/T670I and GIST-5R) and also exhibits suitable in vivo pharmacokinetic profiles as well as dose-dependent antitumor efficacy. This study provides a proof of concept for developing a c-KIT mutant selective inhibitor that theoretically can render a better therapeutic window.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Indazoles/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-kit/genética , Animales , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Resistencia a Antineoplásicos , Femenino , Humanos , Indazoles/síntesis química , Indazoles/farmacocinética , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Mutación , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Despite of the great success of imatinib as the first-line treatment for GISTs, the majority of patients will develop drug-acquired resistance due to secondary mutations in the cKIT kinase. Sunitinib and regorafenib have been approved as the second and third line therapies to overcome some of these drug-resistance mutations; however, their limited clinical response, toxicity and resistance of the activation loop mutants still makes new therapies bearing different cKIT mutants activity spectrum profile highly demanded. Through a drug repositioning approach, we found that cabozantinib exhibited higher potency than imatinib against primary gain-of-function mutations of cKIT. Moreover, cabozantinib was able to overcome cKIT gatekeeper T670I mutation and the activation loop mutations that are resistant to imatinib or sunitinib. Cabozantinib demonstrated good efficacy in vitro and in vivo in the cKIT mutant-driven preclinical models of GISTs while displaying a long-lasting effect after treatment withdrawal. Furthermore, it also exhibited dose-dependent anti-proliferative efficacy in the GIST patient derived primary cells. Considering clinical safety and PK profile of cabozantinib, this report provides the basis for the future clinical applications of cabozantinib as an alternative anti-GISTs therapy in precision medicine.
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Anilidas/farmacología , Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Mesilato de Imatinib/farmacología , Mutación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/genética , Piridinas/farmacología , Línea Celular Tumoral , Reposicionamiento de Medicamentos/métodos , Resistencia a Antineoplásicos/genética , Tumores del Estroma Gastrointestinal/genética , Humanos , Mutación/genéticaRESUMEN
Cannabinoids are emerging as promising antitumor drugs. However, complete tumor eradication solely by cannabinoid therapy remains challenging. In this study, we developed a far-red light activatable cannabinoid prodrug, which allows for tumor-specific and combinatory cannabinoid and photodynamic therapy. This prodrug consists of a phthalocyanine photosensitizer (PS), reactive oxygen species (ROS)-sensitive linker, and cannabinoid. It targets the type-2 cannabinoid receptor (CB2R) overexpressed in various types of cancers. Upon the 690-nm light irradiation, the PS produces cytotoxic ROS, which simultaneously cleaves the ROS-sensitive linker and subsequently releases the cannabinoid drug. We found that this unique multifunctional prodrug design offered dramatically improved therapeutic efficacy, and therefore provided a new strategy for targeted, controlled, and effective antitumor cannabinoid therapy.
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Cannabinoides , Fotoquimioterapia/métodos , Profármacos , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Cannabinoides/química , Cannabinoides/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células HEK293 , Humanos , Indoles/química , Indoles/metabolismo , Isoindoles , Ratones , Compuestos de Organosilicio/química , Compuestos de Organosilicio/metabolismo , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Profármacos/química , Profármacos/metabolismo , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Novel near-infrared contrast agents based on the quaterrylene structure were strategically developed and tested for high photo-stability. Both a dendrimeric quaterrylene molecule, QR-G2-COOH, and a small molecule cationic quaterrylene dye, QR-4PyC4, remain optically stable and continue to generate a competitive photoacoustic response when irradiated by short near-infrared laser pulses for a relatively long time in an in-vitro cell study, unlike indocyanine green that rapidly decreases photoacoustic signal amplitude. The small molecule dye, QR-4PyC4 exhibits not only significantly higher cellular uptake rate than QR-G2-COOH and indocyanine green, but also low toxicity at a concentration of up to 10⯵M. The dendrimeric dye, QR-G2-COOH that has surface functional groups available for conjugation with targeting and therapeutic agents shows the highest photoacoustic amplitude with high optical stability. Therefore, QR-4PyC4 can be a promising universal, sensitive and reliable photoacoustic contrast agent and QR-G2-COOH has great potential as a nano-platform with stable photoacoustic imaging capability.
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Medios de Contraste , Dendrímeros , Colorantes Fluorescentes , Rayos Infrarrojos , Imagen Óptica/métodos , Técnicas Fotoacústicas , Línea Celular Tumoral , Medios de Contraste/química , Medios de Contraste/farmacología , Dendrímeros/química , Dendrímeros/farmacología , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacología , HumanosRESUMEN
Triple negative breast cancer (TNBC) is the deadliest form of breast cancer because it is more aggressive, diagnosed at later stage and more likely to develop local and systemic recurrence. Many patients do not experience adequate tumor control after current clinical treatments involving surgical removal, chemotherapy and/or radiotherapy, leading to disease progression and significantly decreased quality of life. Here we report a new combinatory therapy strategy involving cannabinoid-based medicine and photodynamic therapy (PDT) for the treatment of TNBC. This combinatory therapy targets two proteins upregulated in TNBC: the cannabinoid CB2 receptor (CB2R, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the combined CB2R agonist and TSPO-PDT treatment resulted in synergistic inhibition in TNBC cell and tumor growth. This combinatory therapy approach provides new opportunities to treat TNBC with high efficacy. In addition, this study provides new evidence on the therapeutic potential of CB2R agonists for cancer.
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Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Receptor Cannabinoide CB2/agonistas , Receptores de GABA/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Acetamidas/química , Acetamidas/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Terapia Combinada , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Indoles/química , Indoles/farmacología , Ratones , Recurrencia Local de Neoplasia , Éteres Fenílicos/química , Éteres Fenílicos/farmacología , Calidad de Vida , Oxígeno Singlete/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Imaging probes targeting type 2 cannabinoid receptor (CB2R) overexpressed in pancreatic duct adenocarcinoma (PDAC) tissue have the potential to improve early detection and surgical outcome of PDAC. The aim of our study was to evaluate the molecular imaging potential of a CB2R-targeted near-infrared (NIR) fluorescent probe (NIR760-XLP6) for PDAC. CB2R overexpression was observed in both PDAC patient tissues and various pancreatic cancer cell lines. In vitro fluorescence imaging indicated specific binding of NIR760-XLP6 to CB2R in human PDAC PANC-1 cells. In a xenograft mouse tumor model, NIR760-XLP6 showed remarkable 50- (ex vivo) and 3.2-fold (in vivo) tumor to normal contrast enhancement with minimal liver and kidney uptake. In a PDAC lymph node metastasis model, significant signal contrast was observed in bilateral axillary lymph nodes with PDAC metastasis after injection of the probe. In conclusion, NIR760-XLP6 exhibits promising characteristics for imaging PDAC, and CB2R appears to be an attractive target for PDAC imaging.
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INTRODUCTION: Nanoparticles are increasingly used as drug carriers for oral administration. The delivery of drug molecules is largely dependent on the interaction of nanocarriers and gastrointestinal (GI) mucus, a critical barrier that regulates drug absorption. It is therefore important to understand the effects of physical and chemical properties of nanocarriers on the interaction with GI mucus. Unfortunately, most of the nanoparticles are unable to be prepared with satisfactory structural monodispersity to comprehensively investigate the interaction. With controlled size, shape, and surface chemistry, copolymers are ideal candidates for such purpose. MATERIALS AND METHODS: We synthesized a series of diblock copolymers via the atom transfer radical polymerization method and investigated the GI mucus permeability in vitro and in vivo. RESULTS: Our results indicated that uncharged and hydrophobic copolymers exhibited enhanced GI absorption. CONCLUSION: These results provide insights into developing optimal nanocarriers for oral administration.
Asunto(s)
Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/farmacocinética , Mucosa Intestinal/efectos de los fármacos , Polímeros/química , Administración Oral , Animales , Células CACO-2 , Portadores de Fármacos/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Indoles/administración & dosificación , Indoles/farmacocinética , Absorción Intestinal/efectos de los fármacos , Masculino , Metacrilatos/síntesis química , Metacrilatos/química , Metilmetacrilatos/síntesis química , Metilmetacrilatos/química , Ratones , Nanopartículas/química , Nylons/síntesis química , Nylons/química , Tamaño de la Partícula , Polímeros/síntesis química , Propionatos/administración & dosificación , Propionatos/farmacocinética , Distribución TisularRESUMEN
p21-activated kinase 1 (PAK1) is an evolutionarily conserved serine/threonine protein kinase, which has been considered as one of the key regulatory factors in signaling network of tumor cells. Therefore, inhibition of PAK1 may be a potential approach to treat many types of solid tumors. Several allosteric inhibitors of PAK1 have been identified, and the most well known one is IPA-3. But its biological activity is not satisfied, and the structure activity relationship (SAR) of PAK1 allosteric inhibitors is unclear. In this study, we designed and synthesized 13 potential allosteric inhibitors by using computer-aided drug design based on the structure of the existing PAK1 allosteric inhibitors. All the compounds were characterized by 1H-NMR and 13C-NMR, among which six were not reported previously. SAR was investigated by pharmacological studies and In03 and In06 showed increased PAK1 inhibition than previously reported IPA-3. These findings could guide further structure optimization of PAK1 inhibitors.
RESUMEN
Recent efforts to develop tumor-targeted photodynamic therapy (PDT) photosensitizers (PSs) have greatly advanced the potential of PDT in cancer therapy, although complete eradication of tumor cells by PDT alone remains challenging. As a way to improve PDT efficacy, we report a new combinatory PDT therapy technique that specifically targets multilayers of cells. Simply mixing different PDT PSs, even those that target distinct receptors (this may still lead to similar cell-killing pathways), may not achieve ideal therapeutic outcomes. Instead, significantly improved outcomes likely require synergistic therapies that target various cellular pathways. In this study, we target two proteins upregulated in cancers: the cannabinoid CB2 receptor (CB2R, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the CB2R-targeted PS, IR700DX-mbc94, triggered necrotic cell death upon light irradiation, whereas PDT with the TSPO-targeted IR700DX-6T agent led to apoptotic cell death. Both PSs significantly inhibited tumor growth in vivo in a target-specific manner. As expected, the combined CB2R- and TSPO-PDT resulted in enhanced cell killing efficacy and tumor inhibition with lower drug dose. The median survival time of animals with multilayer PDT treatment was extended by as much as 2.8-fold over single PDT treatment. Overall, multilayer PDT provides new opportunities to treat cancers with high efficacy and low side effects. STATEMENT OF SIGNIFICANCE: Photodynamic therapy (PDT) is increasingly used as a minimally invasive, controllable and effective therapeutic procedure for cancer treatment. However, complete eradication of tumor cells by PDT alone remains challenging. In this study, we investigate the potential of multilayer PDT in cancer treatment with high efficacy and low side effects. Through PDT targeting two cancer biomarkers located at distinct subcellular localizations, remarkable synergistic effects in cancer cell killing and tumor inhibition were observed in both in vitro and in vivo experiments. This strategy may be widely applied to treat various cancer types by using strategically designed PDT photosensitizers that target corresponding upregulated receptors at tactical subcellular localization.