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1.
Molecules ; 28(19)2023 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-37836787

RESUMEN

IR-780 is a fluorescent marker, photostable and non-toxic, and is widely used in tumor targeting; however, studies on the impact of IR-780 in animal models of B16-F10 melanoma are scarce in the literature. Therefore, this study aims to analyze behavior of this marker in melanoma cells using in vitro and in vivo analyses with fluorescence microscopy to conduct an analysis of cell culture, and an in vivo imaging system for an analysis of cell culture, tumor targeting on animals, and organ examination. In vitro analysis showed that B16-F10 cells at a concentration of 2 × 105 cells.plate-1 allowed a better visualization using 20 µM of IR-780. Furthermore, the location of IR-780 accumulation was confirmed by its fluorescence microscopy. Through in vivo studies, fluorescence was not observed in subcutaneous nodules, and it was found that animals that received intraperitoneal injection of B16-F10 cells presented ascites and did not absorb IR-780. Additionally, animals exhibiting lung metastasis showed fluorescence in ex vivo lung images. Therefore, use of the IR-780 marker for evaluating the progression of tumor growth did not demonstrate efficiency; however, it was effective in diagnosing pulmonary metastatic tumors. Although this marker presented limitations, results of evaluating pulmonary involvement through ex vivo fluorescence imaging were determined based on intensity of fluorescence.


Asunto(s)
Neoplasias Pulmonares , Melanoma Experimental , Neoplasias Cutáneas , Animales , Ratones , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/secundario , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/patología , Pulmón/patología , Ratones Endogámicos C57BL
2.
J Pharm Biomed Anal ; 229: 115374, 2023 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-37001274

RESUMEN

Given the rising pervasiveness of melanocortin-1 receptor (MC1-R) positive melanoma malignum (MM) and pertinent metastases, radiolabelled receptor-affine alpha-melanocyte stimulating hormone-analogue (α-MSH analogue) imaging probes would be of crucial importance in timely tumor diagnostic assessment. Herein we aimed at investigating the biodistribution and the MM targeting potential of newly synthesized 213Bi-conjugated MC1-R specific peptide-based radioligands with the establishment of MC1-R overexpressing MM preclinical model. DOTA-conjugated NAP, -HOLD, -FOLD, -and MARSamide were labelled with 213Bi. Ex vivo biodistribution studies were conducted post-administration of 3.81 ± 0.32 MBq [213Bi]Bi-DOTA conjugated deriva-tives into twenty B16-F10 tumor-bearing C57BL/6 J and healthy mice. Organ Level Internal Dose Assessment (OLINDA) and IDAC-Dose were used to calculate translational data-based absorbed radiation dose in human organs. Moderate or low %ID/g uptake of [213Bi]Bi-DOTA conjugated NAP, -HOLD, -and MARSamide and significantly increased [213Bi]Bi-DOTA-FOLDamide accumulation was observed in the thoracic and abdominal organs (p ≤ 0.01). High [213Bi]Bi-DOTA-NAP (%ID/g:3.76 ± 0.96), -and FOLDamide (%ID/g:3.28 ± 0.95) tumor tracer activity confirmed their MC1-R-affinity. The bladder wall received the highest radiation absorbed dose followed by the kidneys (bladder wall: 1.95·10-2 and 8.97·10-2 mSv/MBq; kidneys: 7.47·10-3 vs. 5.88·10-2 mSv/MBq measured by IDAC and OLINDA; respectively) indicating the suitability of the NAPamide derivative for clinical use. These novel [213Bi]Bi-DOTA-linked peptide probes displaying meaningful MC1-R affinity could be promising molecular probes in MM imaging.


Asunto(s)
Melanoma Experimental , Humanos , Animales , Ratones , Melanoma Experimental/diagnóstico por imagen , alfa-MSH , Receptor de Melanocortina Tipo 1/metabolismo , Distribución Tisular , Radiofármacos/química , Ratones Endogámicos C57BL , Hormonas Estimuladoras de los Melanocitos
3.
Mol Pharm ; 20(2): 1015-1024, 2023 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-36562303

RESUMEN

Benzamide (BZA), a small molecule that can freely cross cell membranes and bind to melanin, has served as an effective targeting group for melanoma theranostics. In this study, a novel pyridine-based BZA dimer (denoted as H-2) was labeled with 68Ga ([68Ga]Ga-H-2) for positron emission tomography (PET) imaging of malignant melanomas. [68Ga]Ga-H-2 was obtained with high radiochemical yield (98.0 ± 2.0%) and satisfactory radiochemical purity (>95.0%). The specificity and affinity of [68Ga]Ga-H-2 were confirmed in melanoma B16F10 cells and in vivo PET imaging of multiple tumor models (B16F10 tumors, A375 melanoma, and lung metastases). Monomeric [68Ga]Ga-H-1 was prepared as a control radiotracer to verify the effects of the molecular structure on pharmacokinetics. The values of the lipid-water partition coefficient of [68Ga]Ga-H-2 and [68Ga]Ga-H-1 demonstrated hydrophilicity with log P = -2.37 ± 0.07 and -2.02 ± 0.09, respectively. PET imaging and biodistribution showed a higher uptake of [68Ga]Ga-H-2 in B16F10 primary and metastatic melanomas than that in A375 melanomas. However, the relatively low uptake of monomeric [68Ga]Ga-H-1 in B16F10 tumors and high accumulation in nontarget organs resulted in poor PET imaging quality. This study demonstrates the synthesis and preclinical evaluation of the novel pyridine-based BZA dimer [68Ga]Ga-H-2 and indicates that the dimer tracer has promising applications in malignant melanoma-specific PET imaging because of its high uptake and long-time retention in malignant melanoma.


Asunto(s)
Radioisótopos de Galio , Melanoma Experimental , Animales , Radioisótopos de Galio/química , Distribución Tisular , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/metabolismo , Benzamidas/química , Tomografía de Emisión de Positrones/métodos , Piridinas , Línea Celular Tumoral , Melanoma Cutáneo Maligno
4.
Int J Pharm ; 632: 122527, 2023 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-36566825

RESUMEN

Malignant melanoma is a major public health problem with an increasing incidence and mortality in the Caucasian population due to its significant metastatic potential. The early detection of this cancer type by imaging techniques like positron emission tomography acts as an important contributor to the long-term survival. Based on literature data, the radio labelled alpha-MSH analog NAPamide molecule is an appropriate diagnostic tool for the detection of melanoma tumors. Inspired by these facts, a new radiotracer, the [61Cu]Cu-KFTG-NAPamide has been synthesized to exploit the beneficial features of the positron emitter 61Cu and the melanoma specificity of the NAPamide molecule. In this work, we report a new member of the CB-15aneN5 ligand family (KFTG) as the chelator for 61Cu(II) complexation. On the basis of the thorough physico-chemical characterization, the rigid [Cu(KFTG)]+ complex exhibits fast complex formation (t1/2 = 155 s at pH 5.0 and 25 °C) and high inertness (t1/2 = 2.0 h in 5.0 M HCl at 50 °C) as well as moderate superoxide dismutase activity (IC50 = 2.3 µM). Furthermore, the [61Cu]Cu-KFTG-NAPamide possesses outstanding features in the diagnostics of B16-F10 melanoma tumors by PET imaging: (T/M(SUVs) (in vivo): appr. 14, %ID/g: 7 ± 1 and T/M (ex vivo): 315 ± 24 at 180 min).


Asunto(s)
Melanoma Experimental , Radiofármacos , Animales , Humanos , Radiofármacos/química , alfa-MSH/química , Fragmentos de Péptidos , Tomografía de Emisión de Positrones/métodos , Melanoma Experimental/diagnóstico por imagen , Línea Celular Tumoral
5.
Dokl Biochem Biophys ; 504(1): 115-117, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35759138

RESUMEN

The development of effective biomedical technologies using magnetic nanoparticles (MNPs) for the tasks of oncotherapy and nanodiagnostics requires the development and implementation of new methods for the analysis of micro- and nanoscale distributions of MNPs in the volume of cells and tissues. The paper presents a new approach to three-dimensional analysis of MNP distributions - scanning magnetic force nanotomography as applied to the study of tumor tissues. Correlative reconstruction of MNP distributions and nanostructure features of the studied tissues made it possible to quantitatively estimate the parameters of three-dimensional distributions of composite nanoparticles based on silicon and iron oxide obtained by femtosecond laser ablation and injected intravenously and intratumorally into tumor tissue samples of B16/F1 mouse melanoma. The developed technology based on the principles of scanning probe nanotomography is applicable for studying the features of three-dimensional micro- and nanoscale distributions of magnetic nanoparticles in biomaterials, cells and tissues of various types.


Asunto(s)
Nanopartículas de Magnetita , Melanoma Experimental , Nanopartículas , Animales , Materiales Biocompatibles , Fenómenos Magnéticos , Melanoma Experimental/diagnóstico por imagen , Ratones , Nanopartículas/química
6.
Nat Commun ; 13(1): 109, 2022 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-35013154

RESUMEN

Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under development as local immunotherapies. However, due to the relatively recent adoption of intratumoral administration, the pharmacokinetics of locally-injected biologics remains poorly defined, limiting rational design of tumor-localized immunotherapies. Here we define a pharmacokinetic framework for biologics injected intratumorally that can predict tumor exposure and effectiveness. We find empirically and computationally that extending the tumor exposure of locally-injected interleukin-2 by increasing molecular size and/or improving matrix-targeting affinity improves therapeutic efficacy in mice. By tracking the distribution of intratumorally-injected proteins using positron emission tomography, we observe size-dependent enhancement in tumor exposure occurs by slowing the rate of diffusive escape from the tumor and by increasing partitioning to an apparent viscous region of the tumor. In elucidating how molecular weight and matrix binding interplay to determine tumor exposure, our model can aid in the design of intratumoral therapies to exert maximal therapeutic effect.


Asunto(s)
Colágeno/genética , Inmunoterapia/métodos , Interleucina-2/farmacología , Melanoma Experimental/terapia , Receptores Inmunológicos/genética , Neoplasias Cutáneas/terapia , Aloinjertos , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Línea Celular Tumoral , Colágeno/inmunología , Femenino , Biblioteca de Genes , Inyecciones Intralesiones , Interleucina-2/genética , Interleucina-2/inmunología , Interleucina-2/farmacocinética , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/genética , Melanoma Experimental/mortalidad , Ratones , Ratones Endogámicos C57BL , Péptidos/genética , Péptidos/inmunología , Tomografía de Emisión de Positrones , Unión Proteica , Ingeniería de Proteínas/métodos , Receptores Inmunológicos/inmunología , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Albúmina Sérica/genética , Albúmina Sérica/inmunología , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/mortalidad , Análisis de Supervivencia , Carga Tumoral/efectos de los fármacos
7.
J Am Chem Soc ; 144(2): 787-797, 2022 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-34985903

RESUMEN

Tumor-derived exosome can suppress dendritic cells (DCs) and T cells functions. Excessive secretion of exosomal programmed death-ligand 1 (PD-L1) results in therapeutic resistance to PD-1/PD-L1 immunotherapy and clinical failure. Restored T cells by antiexosomal PD-L1 tactic can intensify ferroptosis of tumor cells and vice versa. Diminishing exosomal suppression and establishing a nexus of antiexosomal PD-L1 and ferroptosis may rescue the discouraging antitumor immunity. Here, we engineered phototheranostic metal-phenolic networks (PFG MPNs) by an assembly of semiconductor polymers encapsulating ferroptosis inducer (Fe3+) and exosome inhibitor (GW4869). The PFG MPNs elicited superior near-infrared II fluorescence/photoacoustic imaging tracking performance for a precise photothermal therapy (PTT). PTT-augmented immunogenic cell death relieved exosomal silencing on DC maturation. GW4869 mediated PD-L1 based exosomal inhibition revitalized T cells and enhanced the ferroptosis. This novel synergy of PTT with antiexosomal PD-L1 enhanced ferroptosis evoked potent antitumor immunity in B16F10 tumors and immunological memory against metastatic tumors in lymph nodes.


Asunto(s)
Compuestos de Anilina/química , Antígeno B7-H1/metabolismo , Compuestos de Bencilideno/química , Compuestos Férricos/química , Ferroptosis , Estructuras Metalorgánicas/química , Animales , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Exosomas/metabolismo , Ferroptosis/efectos de los fármacos , Muerte Celular Inmunogénica/efectos de los fármacos , Inmunoterapia , Interferón gamma/metabolismo , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/terapia , Estructuras Metalorgánicas/farmacología , Estructuras Metalorgánicas/uso terapéutico , Ratones , Fenol/química , Técnicas Fotoacústicas , Polietilenglicoles/química , Polímeros/química , Receptor de Muerte Celular Programada 1/metabolismo , Nanomedicina Teranóstica
8.
Cancer Biother Radiopharm ; 37(1): 47-55, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34762521

RESUMEN

Background: The purpose of this study was to examine the effect of 4-p-(tolyl)butyric acid as an albumin-binding (ALB) moiety on tumor targeting and biodistribution properties of 67Ga-labeled albumin binder-conjugated alpha-melanocyte-stimulating hormone peptides. Materials and Methods: DOTA-Lys(ALB)-G/GG/GGG-Nle-CycMSHhex {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Lys(ALB)-Gly/GlyGly/GlyGlyGly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2} were synthesized with 4-p-(tolyl)butyric acid serving as an ALB moiety. The melanocortin-1 receptor (MC1R)-binding affinities of the peptides were determined on B16/F10 melanoma cells. The biodistribution of 67Ga-DOTA-Lys(ALB)-G/GG/GGG-Nle-CycMSHhex was examined on B16/F10 melanoma-bearing C57 mice at 2 h postinjection to select a lead peptide for further evaluation. The melanoma targeting and imaging properties of 67Ga-DOTA-Lys(ALB)-GGNle-CycMSHhex {67Ga-ALB-G2} were determined on B16/F10 melanoma-bearing C57 mice. Results: The IC50 value of DOTA-Lys(ALB)-G/GG/GGG-Nle-CycMSHhex {ALB-G1, ALB-G2, ALB-G3} was 0.67 ± 0.07, 0.5 ± 0.09 and 0.51 ± 0.03 nM on B16/F10 cells, respectively. 67Ga-ALB-G2 was further evaluated as a lead peptide because of its higher tumor uptake (30.25 ± 3.24%ID/g) and lower kidney uptake (7.09 ± 2.22%ID/g) than 67Ga-ALB-G1 and 67Ga-ALB-G3 at 2 h postinjection. The B16/F10 melanoma uptake of 67Ga-ALB-G2 was 15.64 ± 4.55, 30.25 ± 3.24, 26.76 ± 3.23, and 10.71 ± 1.21%ID/g at 0.5, 2, 4, and 24 h postinjection, respectively. The B16/F10 melanoma lesions were clearly visualized by SPECT/CT using 67Ga-ALB-G2 as an imaging probe at 2 h postinjection. Conclusions: The introduction of 4-p-(tolyl)butyric acid as an ALB moiety increased the blood retention, and resulted in higher tumor/kidney ratio of 67Ga-ALB-G2 as compared with its counterpart without an albumin binder. However, the resulting high uptake of 67Ga-ALB-G2 in blood and liver need to be further reduced to facilitate its therapeutic application when replacing 67Ga with therapeutic radionuclides.


Asunto(s)
Melanoma Experimental , alfa-MSH , Albúminas , Animales , Línea Celular Tumoral , Lactamas/química , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Radiofármacos/química , Radiofármacos/farmacología , Distribución Tisular , alfa-MSH/química
9.
Appl Opt ; 60(31): 9651-9658, 2021 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-34807146

RESUMEN

A supercontinuum (SC) light source enables multispectral photoacoustic imaging at excitation wavelengths in the visible-to-near-infrared range. However, for such a broad optical wavelength range, chromatic aberration is non-negligible. We developed a multispectral optical-resolution photoacoustic microscopy (MS-OR-PAM) setup with a nanosecond pulsed SC light source and a reflective objective lens to avoid chromatic aberration. Chromatic aberrations generated by reflective and conventional objective lenses were compared, and the images acquired using the reflective objective were not affected by chromatic aberration. Hence, MS-OR-PAM with the reflective objective was used to distinguish red blood cells from melanoma cells via spectral subtraction processing.


Asunto(s)
Eritrocitos/citología , Procesamiento de Imagen Asistido por Computador/métodos , Luz , Melanoma Experimental/diagnóstico por imagen , Técnicas Fotoacústicas/instrumentación , Animales , Diseño de Equipo , Ratones , Dispositivos Ópticos , Análisis Espectral
10.
Bull Exp Biol Med ; 171(4): 468-471, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34542759

RESUMEN

The efficacy of a new photosensitizer of chlorin E6 conjugated with a prostate-specific membrane antigen (PSMA) in photodynamic therapy of murine melanoma B16 was studied in in vivo experiments. The dynamics of photosensitizer accumulation in the tumor and surrounding tissues was evaluated and antitumor efficacy of photodynamic therapy was assessed by parameters of regression and morphological characteristics of experimental transplanted melanoma B16. The inhibitory effect of photodynamic therapy on melanoma was evaluated by complete regression of the tumor, absolute tumor growth coefficient in animals with continuation of tumor growth, and the increase in life span in comparison with the control; the criterion of cure was the absence of signs of tumor recurrence in mice within 90 days after therapy. The therapeutic potential of photodynamic therapy was determined by devitalization of tumor cells (histological examination of the zones of laser exposure on day 21 after treatment). The photosensitizer with PSMA-ligand exhibited high antitumor activity in photodynamic therapy for melanoma B16. Photodynamic therapy carried out at the optimum time after photosensitizer injection with experimentally determined parameters of laser exposure allows achieving the maximum inhibitory effect on melanoma. Pathomorphological study in the zones of exposure detected no survived tumor cells.


Asunto(s)
Clorofilidas/uso terapéutico , Melanoma Experimental/tratamiento farmacológico , Fotoquimioterapia/métodos , Neoplasias Cutáneas/tratamiento farmacológico , Urea/análogos & derivados , Animales , Línea Celular Tumoral , Clorofilidas/química , Clorofilidas/farmacocinética , Femenino , Ligandos , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/uso terapéutico , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Urea/química , Urea/farmacocinética , Urea/uso terapéutico
11.
NMR Biomed ; 34(12): e4602, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34423470

RESUMEN

D-Glucose and 3-O-Methyl-D-glucose (3OMG) have been shown to provide contrast in magnetic resonance imaging-chemical exchange saturation transfer (MRI-CEST) images. However, a systematic comparison between these two molecules has yet to be performed. The current study deals with the assessment of the effect of pH, saturation power level (B1 ) and magnetic field strength (B0 ) on the MRI-CEST contrast with the aim of comparing the in vivo CEST contrast detectability of these two agents in the glucoCEST procedure. Phosphate-buffered solutions of D-Glucose or 3OMG (20 mM) were prepared at different pH values and Z-spectra were acquired at several B1 levels at 37°C. In vivo glucoCEST images were obtained at 3 and 7 T over a period of 30 min after injection of D-Glucose or 3OMG (at doses of 1.5 or 3 g/kg) in a murine melanoma tumor model (n = 3-5 mice for each molecule, dose and B0 field). A markedly different pH dependence of CEST response was observed in vitro for D-Glucose and 3OMG. The glucoCEST contrast enhancement in the tumor region following intravenous administration (at the 3 g/kg dose) was comparable for both molecules: 1%-2% at 3 T and 2%-3% at 7 T. The percentage change in saturation transfer that resulted was almost constant for 3OMG over the 30-min period, whereas a significant increase was detected for D-Glucose. Our results show similar CEST contrast efficiency but different temporal kinetics for the metabolizable and the nonmetabolizable glucose derivatives in a tumor murine model when administered at the same doses.


Asunto(s)
3-O-Metilglucosa/química , Glucosa/química , Imagen por Resonancia Magnética/métodos , Melanoma Experimental/diagnóstico por imagen , Animales , Línea Celular Tumoral , Concentración de Iones de Hidrógeno , Campos Magnéticos , Masculino , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos C57BL
12.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-34208566

RESUMEN

Regarding the increased incidence and high mortality rate of malignant melanoma, practical early-detection methods are essential to improve patients' clinical outcomes. In this study, we successfully prepared novel picolinamide-benzamide (18F-FPABZA) and nicotinamide-benzamide (18F-FNABZA) conjugates and determined their biological characteristics. The radiochemical yields of 18F-FPABZA and 18F-FNABZA were 26 ± 5% and 1 ± 0.5%, respectively. 18F-FPABZA was more lipophilic (log P = 1.48) than 18F-FNABZA (log P = 0.68). The cellular uptake of 18F-FPABZA in melanotic B16F10 cells was relatively higher than that of 18F-FNABZA at 15 min post-incubation. However, both radiotracers did not retain in amelanotic A375 cells. The tumor-to-muscle ratios of 18F-FPABZA-injected B16F10 tumor-bearing mice increased from 7.6 ± 0.4 at 15 min post-injection (p.i.) to 27.5 ± 16.6 at 3 h p.i., while those administered with 18F-FNABZA did not show a similarly dramatic increase throughout the experimental period. The results obtained from biodistribution studies were consistent with those derived from microPET imaging. This study demonstrated that 18F-FPABZA is a promising melanin-targeting positron emission tomography (PET) probe for melanotic melanoma.


Asunto(s)
Radioisótopos de Flúor , Melanoma Experimental/diagnóstico por imagen , Niacinamida , Ácidos Picolínicos , Radiofármacos , Animales , Línea Celular Tumoral , Radioisótopos de Flúor/química , Melaninas/metabolismo , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Niacinamida/química , Ácidos Picolínicos/química , Tomografía de Emisión de Positrones , Unión Proteica , Radiofármacos/química , Distribución Tisular
13.
Sci Rep ; 11(1): 13446, 2021 06 29.
Artículo en Inglés | MEDLINE | ID: mdl-34188103

RESUMEN

Electrochemotherapy with bleomycin (ECT BLM) is an effective antitumor treatment already used in clinical oncology. However, ECT alone is still considered a local antitumor therapy because it cannot induce systemic immunity. When combined with adjuvant gene electrotransfer of plasmid DNA encoding IL-12 (GET pIL-12), the combined therapy leads to a systemic effect on untreated tumors and distant metastases. Although the antitumor efficacy of both therapies alone or in combination has been demonstrated at both preclinical and clinical levels, data on the predictors of efficacy of the treatments are still lacking. Herein, we evaluated the results of dynamic contrast-enhanced ultrasound (DCE-US) as a predictive factor for ECT BLM and GET pIL-12 in murine melanoma. Melanoma B16F10 tumors grown in female C57Bl/6NCrl mice were treated with GET pIL-12 and ECT BLM. Immediately after therapy, 6 h and 1, 3, 7 and 10 days later, tumors were examined by DCE-US. Statistical analysis was performed to inspect the correlation between tumor doubling time (DT) and DCE-US measurements using semilinear regression models and Bland-Altman plots. Therapeutic groups in which DCE-US showed reduced tumor perfusion had longer tumor DTs. It was confirmed that the DCE-US parameter peak enhancement (PE), reflecting relative blood volume, had predictive value for the outcome of therapy: larger PE correlated with shorter DT. In addition, perfusion heterogeneity was also associated with outcome: tumors that had more heterogeneous perfusion had faster growth, i.e., shorter DTs. This study demonstrates that DCE-US can be used as a method to predict the efficacy of electroporation-based treatment.


Asunto(s)
Medios de Contraste/farmacología , Electroquimioterapia , Técnicas de Transferencia de Gen , Interleucina-12 , Melanoma Experimental , Plásmidos , Animales , Femenino , Interleucina-12/genética , Interleucina-12/inmunología , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Ratones , Perfusión , Plásmidos/genética , Plásmidos/inmunología , Ultrasonografía
14.
ACS Appl Mater Interfaces ; 13(22): 25599-25610, 2021 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-34028266

RESUMEN

Actinium-225 (225Ac) radiolabeled submicrometric core-shell particles (SPs) made of calcium carbonate (CaCO3) coated with biocompatible polymers [tannic acid-human serum albumin (TA/HSA)] have been developed to improve the efficiency of local α-radionuclide therapy in melanoma models (B16-F10 tumor-bearing mice). The developed 225Ac-SPs possess radiochemical stability and demonstrate effective retention of 225Ac and its daughter isotopes. The SPs have been additionally labeled with zirconium-89 (89Zr) to perform the biodistribution studies using positron emission tomography-computerized tomography (PET/CT) imaging for 14 days after intratumoral injection. According to the PET/CT analysis, a significant accumulation of 89Zr-SPs in the tumor area is revealed for the whole investigation period, which correlates with the direct radiometry analysis after intratumoral administration of 225Ac-SPs. The histological analysis has revealed no abnormal changes in healthy tissue organs after treatment with 225Ac-SPs (e.g., no acute pathologic findings are detected in the liver and kidneys). At the same time, the inhibition of tumor growth has been observed as compared with control samples [nonradiolabeled SPs and phosphate-buffered saline (PBS)]. The treatment of mice with 225Ac-SPs has resulted in prolonged survival compared to the control samples. Thus, our study validates the application of 225Ac-doped core-shell submicron CaCO3 particles for local α-radionuclide therapy.


Asunto(s)
Actinio/uso terapéutico , Carbonato de Calcio/química , Melanoma Experimental/radioterapia , Radioisótopos/uso terapéutico , Radiofármacos/uso terapéutico , Circonio/uso terapéutico , Actinio/farmacocinética , Animales , Masculino , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Radioisótopos/farmacocinética , Radiofármacos/farmacocinética , Distribución Tisular , Circonio/farmacocinética
15.
Molecules ; 26(6)2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33808910

RESUMEN

It is known that phenylboronic acid (PBA) can target tumor tissues by binding to sialic acid, a substrate overexpressed by cancer cells. This capability has previously been explored in the design of targeting diagnostic probes such as Gd- and 68Ga-DOTA-EN-PBA, two contrast agents for magnetic resonance imaging (MRI) and positron emission tomography (PET), respectively, whose potential has already been demonstrated through in vivo experiments. In addition to its high resolution, the intrinsic low sensitivity of MRI stimulates the search for more effective contrast agents, which, in the case of small-molecular probes, basically narrows down to either increased tumbling time of the entire molecule or elevated local concentration of the paramagnetic ions, both strategies resulting in enhanced relaxivity, and consequently, a higher MRI contrast. The latter strategy can be achieved by the design of multimeric GdIII complexes. Based on the monomeric PBA-containing probes described recently, herein, we report the synthesis and characterization of the dimeric analogues (GdIII-DOTA-EN)2-PBA and (GdIII-DOTA-EN)2F2PBA. The presence of two Gd ions in one molecule clearly contributes to the improved biological performance, as demonstrated by the relaxometric study and cell-binding investigations.


Asunto(s)
Ácidos Borónicos , Medios de Contraste , Imagen por Resonancia Magnética , Melanoma Experimental , Animales , Ácidos Borónicos/síntesis química , Ácidos Borónicos/química , Ácidos Borónicos/farmacología , Línea Celular Tumoral , Medios de Contraste/síntesis química , Medios de Contraste/química , Medios de Contraste/farmacología , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/metabolismo , Ratones
16.
Biomed Res Int ; 2021: 6642973, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33778075

RESUMEN

INTRODUCTION: The aminopeptidase N (APN/CD13) receptor plays an important role in the neoangiogenic process and metastatic tumor cell invasion. Clinical and preclinical studies reported that bestatin and actinonin are cytotoxic to APN/CD13-positive tumors and metastases due to their APN/CD13-specific inhibitor properties. Our previous studies have already shown that 68Ga-labeled NGR peptides bind specifically to APN/CD13 expressing tumor cells. The APN/CD13 specificity of 68Ga-NGR radiopharmaceuticals enables the following of the efficacy of antiangiogenic therapy with APN/CD13-specific inhibitors using positron emission tomography (PET). The aim of this in vivo study was to assess the antitumor effect of bestatin and actinonin treatment in subcutaneous transplanted HT1080 and B16-F10 tumor-bearing animal models using 68Ga-NODAGA-c(NGR). MATERIALS AND METHODS: Three days after the inoculation of HT1080 and B16-F10 cells, mice were treated with intraperitoneal injection of bestatin (15 mg/kg) or actinonin (5 mg/kg) for 7 days. On the 5th and 10th day, in vivo PET scans and ex vivo biodistribution studies were performed 90 min after intravenous injection of 5.5 ± 0.2 MBq68Ga-NODAGA-c(NGR). RESULTS: Control-untreated HT1080 and B16-F10 tumors were clearly visualized by the APN/CD13-specific 68Ga-NODAGA-c(NGR) radiopharmaceutical. The western blot analysis also confirmed the strong APN/CD13 positivity in the investigated tumors. We found significantly (p ≤ 0.05) lower radiopharmaceutical uptake after bestatin treatment and higher radiotracer accumulation in the actinonin-treated HT1080 tumors. In contrast, significantly lower (p ≤ 0.01) 68Ga-NODAGA-c(NGR) accumulation was observed in both bestatin- and actinonin-treated B16-F10 melanoma tumors compared to the untreated-control tumors. Bestatin inhibited tumor growth and 68Ga-NODAGA-c(NGR) uptake in both tumor models. CONCLUSION: The bestatin treatment is suitable for suppressing the neoangiogenic process and APN/CD13 expression of experimental HT1080 and B16-F10 tumors; furthermore, 68Ga-NODAGA-c(NGR) is an applicable radiotracer for the in vivo monitoring of the efficacy of the APN/CD13 inhibition-based anticancer therapies.


Asunto(s)
Acetatos , Antígenos CD13 , Radioisótopos de Galio , Compuestos Heterocíclicos con 1 Anillo , Melanoma Experimental , Imagen Molecular , Proteínas de Neoplasias , Oligopéptidos , Radiofármacos , Acetatos/farmacocinética , Acetatos/farmacología , Animales , Antígenos CD13/antagonistas & inhibidores , Antígenos CD13/metabolismo , Radioisótopos de Galio/farmacocinética , Radioisótopos de Galio/farmacología , Compuestos Heterocíclicos con 1 Anillo/farmacocinética , Compuestos Heterocíclicos con 1 Anillo/farmacología , Humanos , Masculino , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/enzimología , Ratones , Ratones SCID , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Oligopéptidos/farmacocinética , Oligopéptidos/farmacología , Radiofármacos/farmacocinética , Radiofármacos/farmacología
18.
Bioconjug Chem ; 32(3): 497-501, 2021 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-33576604

RESUMEN

A new fluorescent biarsenical peptide labeling probe was synthesized and labeled with the radioactive isotopes 11C and 18F. The utility of this probe was demonstrated by installing each of these isotopes into a melanocortin 1 receptor (MC1R) binding peptide, which targets melanoma tumors. Its applicability was further showcased by subsequent in vitro imaging in cells as well as in vivo imaging in melanoma xenograft mice by fluorescence and positron emission tomography.


Asunto(s)
Arsenicales/química , Colorantes Fluorescentes/química , Melanoma Experimental/diagnóstico por imagen , Tomografía de Emisión de Positrones , Animales , Línea Celular Tumoral , Xenoinjertos , Melanoma Experimental/metabolismo , Ratones , Péptidos/metabolismo , Receptor de Melanocortina Tipo 1/metabolismo
19.
Biomed Res Int ; 2020: 6863231, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33015175

RESUMEN

Gold nanorods exhibit a wide variety of applications such as tumor molecular imaging and photothermal therapy (PTT) due to their tunable optical properties. Several studies have demonstrated that the combination of other therapeutic strategies may improve PTT efficiency. A method called optical droplet vaporization (ODV) was considered as another noninvasive imaging and therapy strategy. Via the ODV method, superheated perfluorocarbon droplets can be vaporized to a gas phase for enhancing ultrasound imaging; meanwhile, this violent process can cause damage to cells and tissue. In addition, active targeting through the functionalization with targeting ligands can effectively increase nanoprobe accumulation in the tumor area, improving the sensitivity and specificity of imaging and therapy. Our study prepared a nanoparticle loaded with gold nanorods and perfluorinated hexane and conjugated to a monoclonal antibody (MAGE-1 antibody) to melanoma-associated antigens (MAGE) targeting melanoma, investigated the synergistic effect of PTT/ODV therapy, and monitored the therapeutic effect using ultrasound. The prepared MAGE-Au-PFH-NPs achieved complete eradication of tumors. Meanwhile, the MAGE-Au-PFH-NPs also possess significant ultrasound imaging signal enhancement, which shows the potential for imaging-guided tumor therapy in the future.


Asunto(s)
Antígenos de Neoplasias/metabolismo , Oro/química , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/terapia , Nanopartículas del Metal/química , Fototerapia , Neoplasias Cutáneas/terapia , Ultrasonografía , Animales , Materiales Biocompatibles , Proteínas de Choque Térmico/metabolismo , Hipertermia Inducida , Masculino , Nanopartículas del Metal/ultraestructura , Ratones Endogámicos BALB C , Ratones Desnudos , Imagen Óptica , Neoplasias Cutáneas/diagnóstico por imagen , Pruebas de Toxicidad
20.
Eur J Pharm Biopharm ; 157: 85-96, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33039547

RESUMEN

Bone-drug targeting therapies using nanoparticles based on targeting ligands remain challenging due to their uptake clearance at non-target sites such as the liver, kidney, and spleen. Furthermore, the distribution sites of nanoparticles in bones have not been fully investigated, thus halting the development of more effective bone metastasis treatment strategies. In this study, we developed nanoparticles self-assembled from cholesterol-terminated, polyethylene glycol-conjugated, aspartic acid (Asp)-modified polyamidoamine dendrimer (Asp-PAMAM-Micelles) with targeting to active bone turnover sites associated with bone metastasis pathogenesis. On analysis through whole-body single photon emission computed tomography/computed tomography (SPECT/CT) imaging, 111In-Asp-PAMAM-Micelles showed high specificity to active bone turnover sites (especially the joints in the lower limbs, shoulder, and pelvis) after intravenous injection in mice. The lower limb bone uptake clearance for 111In-Asp-PAMAM-Micelles encapsulating paclitaxel (PTX) was 3.5-fold higher than that for 111In-unmodified PAMAM-Micelles (PTX). 3H-PTX encapsulated Asp-PAMAM-Micelles effectively accumulated in the lower limb bones in a similar manner as the 111In-Asp-PAMAM-Micelles (PTX). In a bone metastatic tumor mouse model, the tumor growth in the lower limb bones was significantly inhibited by injection of Asp-PAMAM-Micelles (PTX) compared to unmodified PAMAM-Micelles (PTX). Our results demonstrate that Asp-PAMAM-Micelles are sophisticated drug delivery systems for highly potent targeting to active bone turnover sites.


Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Dendrímeros/química , Portadores de Fármacos , Melanoma Experimental/tratamiento farmacológico , Paclitaxel/administración & dosificación , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacocinética , Ácido Aspártico/química , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/secundario , Línea Celular Tumoral , Colesterol/química , Composición de Medicamentos , Femenino , Inyecciones Intravenosas , Masculino , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/secundario , Ratones Endogámicos C57BL , Micelas , Nanopartículas , Paclitaxel/química , Paclitaxel/farmacocinética , Polietilenglicoles/química , Ratas Wistar , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Distribución Tisular
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