Highly emissive hybrid mesoporous organometallo-silica nanoparticles for bioimaging

Production of mesoporous silica nanoparticles (MSNs) with uniform textural characteristics and imaging properties on a large scale is still a challenge. Thus, the design of simple and scalable methods to obtain reproducible functionalized MSNs has become even more relevant. Herein, we describe an in situ strategy for the synthesis and surface functionalization of highly luminescent mesoporous organometallo-silica nanoparticles. Using the [Ir(dfppy)2(dasipy)]PF6 chromophore and TEOS as sol–gel precursors and different capping agents, such as DMDES or APTES, three different emissive MSNs were prepared (NPOH_IS, NPMe_IS and NPNH2_IS), each containing hydroxyl, methyl and amine groups on their surfaces, respectively. All three were tested on human tumor A549 (lung carcinoma) and HeLa (cervix carcinoma) cell lines, showing intense and stable yellow phosphorescence, biocompatibility and efficient internalization. Moreover, NPMe_IS nanoparticles showed excellent colloidal stability, both in water and biological media, and a BET area of 1120 m2 g−1, making them not only luminescent biomarkers, but potentially also controlled delivery vectors.This work was supported by the Spanish MCIN/AIE/10.13039/501100011033 and by “ERDF A way of making Europe”, by the “European Union” (projects CTQ2015-74494-JIN, RTI2018-099504-B-C21 and PID2019-109742GB-I00) and the Agencia de Desarrollo Económico de La Rioja (Gobierno de la Rioja. Project 2017-I-IDD-00031). E.S. also thanks the University of Alicante through the “Programa de Retención de Talento” (ref. UATALENTO16-03). E.A.-A. is grateful to the Spanish Association Against Cancer (AECC) for her Ph.D. fellowship

Correction: Alfaro-Arnedo et al. IGF1R as a Potential Pharmacological Target in Allergic Asthma. Biomedicines 2021, 9, 912

Correction to Biomedicines 2021, 9(8), 912.Depto. de FisiologíaFac. de MedicinaTRUEpu

IGF1R as a pharmacological target in allergic asthma and cancer-promoting factor in the lung tumor microenvironment

IGF1R (receptor del factor de crecimiento similar a la insulina tipo 1) es una tirosina quinasa ubicua que modula múltiples funciones celulares, como la proliferación, el crecimiento, la diferenciación y la supervivencia. El asma es una enfermedad pulmonar crónica caracterizada por obstrucción reversible del flujo de aire, hiperreactividad de las vías respiratorias, sobreproducción de moco e inflamación. El cáncer de pulmón es la causa principal de enfermedades malignas, dada la ineficacia de las terapias actuales a largo plazo y debido a los diagnósticos en etapa tardía. La progresión del tumor está influenciada por las interacciones de las células cancerosas con el microambiente tumoral (MAT). Aunque se sabe que IGF1R está involucrado en el asma y que afecta al MAT, la inhibición farmacológica de IGF1R en asma y su papel en el MAT pulmonar no se ha investigado previamente. Para ello, los ratones C57BL/6J fueron inoculados intranasalmente con extracto de ácaros del polvo doméstico o PBS durante cuatro semanas y tratados terapéuticamente con el inhibidor de la tirosina quinasa IGF1R NVP-ADW742 (NVP) una vez que se estableció el fenotipo alérgico. También se estudió la correlación de IGF1R con marcadores clínicos establecidos para el asma alérgica. Por otro lado, se evaluaron las alteraciones genómicas y la expresión de IGF1R en muestras de tejido de pacientes con cáncer de pulmón no microcítico (CPNM), así como los niveles séricos de IGF1R. Además, usando ratones deficientes de IGF1R se realizaron modelos de trasplante heterotópico de tumores y metástasis pulmonares utilizando células de melanoma y carcinoma de pulmón de Lewis. Los pulmones de los ratones inoculados con ácaros del polvo doméstico exhibieron un aumento significativo en los niveles de fosfo-IGF1R, aumento de hiperreactividad pulmonar, remodelación de las vías respiratorias, eosinofilia e inflamación alérgica, así como expresión alterada de la surfactante pulmonar, estando todos estos parámetros contrarrestados por el tratamiento con NVP. Los pulmones de los ratones inoculados con ácaros del polvo doméstico también mostraron un aumento de la expresión de fosfo-ERK1/2 (mediador de señalización de IGF1R) que se redujo tras el tratamiento con NVP. Además, los niveles séricos de IGF1R en pacientes con asma alérgica aumentaron significativamente en comparación con los sujetos sanos y se encontraron correlacionados con los niveles de IgE y eosinófilos circulantes. Por otro lado, se observó una mayor amplificación y expresión de ARNm, así como una mayor expresión de proteínas (IGF1R /p-IGF1R) y niveles de IGF1R en muestras tumorales y sueros de pacientes con CPNM, respectivamente. Además, la deficiencia de IGF1R en ratones redujo el crecimiento, la proliferación, la inflamación y la vascularización del tumor, y aumentó la apoptosis después del trasplante heterotópico. Tras la inducción de metástasis pulmonar, los ratones deficientes en IGF1R mostraron menor presencia de leucocitos en la médula ósea y lavado bronquioalveolar, y niveles séricos atenuados de IL6 y TNF. Los pulmones deficientes de IGF1R también mostraron una carga tumoral reducida y una disminución de la expresión de los marcadores de progresión tumoral, fosfo-IGF1R y fosfo-ERK1/2. Además, los pulmones deficientes de IGF1R mostraron un aumento de la apoptosis y una disminución de la proliferación, la senescencia, la vascularización, la transición epitelio-mesénquima y la fibrosis, además de una inflamación e inmunosupresión atenuada tras la inducción de metástasis pulmonar. Estos hallazgos demuestran que IGF1R podría considerarse una diana farmacológica potencial en el asma inducida con ácaros del polvo doméstico en ratones y que IGF1R promueve la iniciación y progresión de la metastásis pulmonar en el MAT. Además, se sugiere que IGF1R es un biomarcador candidato en el asma alérgica y en la predicción temprana de la respuesta famacológica y evolución clínica en pacientes con NSCLC.Background: IGF1R (Insulin-like Growth Factor 1 Receptor) is a ubiquitous tyrosine kinase that modulates multiple cellular functions including proliferation, growth, differentiation and survival. Asthma is a chronic lung disease characterized by reversible airflow obstruction, airway hyperresponsiveness (AHR), mucus overproduction and inflammation. Lung cancer is a leading cause of malignant diseases, given the long-term ineffectiveness of current therapies and late-stage diagnoses, and tumor progression is influenced by cancer cell interactions with the tumor microenvironment (TME). Although IGF1R was found to be involved in asthma and reported to affect the TME, pharmacological inhibition of IGF1R in asthma and its role in the lung TME have not previously been investigated. Methods: C57BL/6J mice were challenged by house dust mite (HDM) extract or PBS for four weeks and therapeutically treated with the IGF1R tyrosine kinase inhibitor (TKI) NVP-ADW742 (NVP) once allergic phenotype was established. The correlation of IGF1R with established clinical biomarkers of allergic asthma was also studied. On the other hand, we assessed IGF1R genomic alterations and expression in non-small-cell lung cancer (NSCLC) patient tissue samples as well as IGF1R serum levels. Moreover, we performed tumor heterotopic transplantation and pulmonary metastases in IGF1R-deficient mice using melanoma and Lewis lung carcinoma (LLC) cells. Results: Lungs of HDM-challenged mice exhibited a significant increase in phospho-IGF1R levels, incremented AHR, airway remodeling, eosinophilia and allergic inflammation, as well as altered pulmonary surfactant expression, being all of these parameters counteracted by NVP treatment. HDM-challenged lungs also displayed augmented expression of the IGF1R signaling mediator p-ERK1/2, which was greatly reduced upon treatment with NVP. Furthermore, serum IGF1R levels in patients with allergic asthma were significantly increased as compared to healthy subjects and correlated with IgE levels and circulating eosinophils. On the other hand, increased amplification and mRNA expression, as well as increased protein expression (IGF1R /p-IGF1R) and IGF1R levels were found in tumor samples and serum from NSCLC patients, respectively. Moreover, IGF1R deficiency in mice reduced tumor growth, proliferation, inflammation and vascularization, and increased apoptosis after tumor heterotopic transplantation. Following induction of lung metastasis, IGF1R-deficient mice exhibited a decreased presence of leukocytes in bone marrow and BALF, and attenuated IL6 and TNF serum levels. IGF1R-deficient lungs also demonstrated a reduced tumor burden, and decreased expression of tumor progression markers, p-IGF1R and p-ERK1/2. Additionally, IGF1R-deficient lungs showed increased apoptosis and diminished proliferation, senescence, vascularization, epithelial-mesenchymal transition (EMT) and fibrosis, along with attenuated inflammation and immunosuppression upon induction of lung metastasis. Conclusions: These findings demonstrate that IGF1R could be considered a potential pharmacological target in murine HDM-induced asthma and that IGF1R promotes metastatic tumor initiation and progression in the lung TME. In addition, IGF1R is suggested to be a candidate biomarker in allergic asthma and in early prediction of drug response and clinical evolution in NSCLC patients

IGF1R as a Potential Pharmacological Target in Allergic Asthma

Background: Asthma is a chronic lung disease characterized by reversible airflow obstruction, airway hyperresponsiveness (AHR), mucus overproduction and inflammation. Although Insulin-like growth factor 1 receptor (IGF1R) was found to be involved in asthma, its pharmacological inhibition has not previously been investigated in this pathology. We aimed to determine if therapeutic targeting of IGF1R ameliorates allergic airway inflammation in a murine model of asthma. Methods: C57BL/6J mice were challenged by house dust mite (HDM) extract or PBS for four weeks and therapeutically treated with the IGF1R tyrosine kinase inhibitor (TKI) NVP-ADW742 (NVP) once allergic phenotype was established. Results: Lungs of HDM-challenged mice exhibited a significant increase in phospho-IGF1R levels, incremented AHR, airway remodeling, eosinophilia and allergic inflammation, as well as altered pulmonary surfactant expression, all of being these parameters counteracted by NVP treatment. HDM-challenged lungs also displayed augmented expression of the IGF1R signaling mediator p-ERK1/2, which was greatly reduced upon treatment with NVP. Conclusions: Our results demonstrate that IGF1R could be considered a potential pharmacological target in murine HDM-induced asthma and a candidate biomarker in allergic asthma

Investigation on Optical and Biological Properties of 2-(4-Dimethylaminophenyl)benzothiazole Based Cycloplatinated Complexes

The optical and biological properties of 2‐(4‐dimethylaminophenyl)benzothiazole cycloplatinated complexes featuring bioactive ligands ([{Pt(Me(2)N‐pbt)(C(6)F(5))}L] [L=Me(2)N‐pbtH 1, p‐dpbH (4‐(diphenylphosphino)benzoic acid) 2, o‐dpbH (2‐(diphenylphosphino)benzoic acid) 3), [Pt(Me(2)N‐pbt)(o‐dpb)] 4, [{Pt(Me(2)N‐pbt)(C(6)F(5))}(2)(μ‐PR( n )P)] [PR(4)P=O(CH(2)CH(2)OC(O)C(6)H(4)PPh(2))(2) 5, PR(12)P=O{(CH(2)CH(2)O)(3)C(O)C(6)H(4)PPh(2)}(2) 6] are presented. Complexes 1–6 display (1)ILCT and metal‐perturbed (3)ILCT dual emissions. The ratio between both bands is excitation dependent, accomplishing warm‐white emissions for 2, 5 and 6. The phosphorescent emission is lost in aerated solutions owing to photoinduced electron transfer to (3)O(2) and the formation of (1)O(2), as confirmed in complexes 2 and 4. They also exhibit photoinduced phosphorescence enhancement in non‐degassed DMSO due to local oxidation of DMSO by sensitized (1)O(2), which causes a local degassing. Me(2)N‐pbtH and the complexes specifically accumulate in the Golgi apparatus, although only 2, 3 and 6 were active against A549 and HeLa cancer cell lines, 6 being highly selective in respect to nontumoral cells. The potential photodynamic property of these complexes was demonstrated with complex 4

Correction: Alfaro-Arnedo et al. IGF1R as a Potential Pharmacological Target in Allergic Asthma. Biomedicines 2021, 9, 912

In the original article [...

Characterization of the acute inflammatory profile and resolution of airway inflammation after Igf1r-gene targeting in a murine model of HDM-induced asthma.

Asthma is a chronic inflammatory disease characterized by bronchial hyperresponsiveness, mucus overproduction and airway remodeling. Notably, we have recently demonstrated that insulin-like growth factor 1 receptor (IGF1R) deficiency in mice attenuates airway hyperresponsiveness and mucus secretion after chronic house dust mite (HDM) exposure. On this basis, inbred C57BL/6 and Igf1r-deficient mice were given HDM extract to study the acute inflammatory profile and implication of Igf1r in acute asthma pathobiology. Additionally, Igf1r-deficiency was therapeutically induced in mice to evaluate the resolution of HDM-induced inflammation. Acute HDM exposure in inbred C57BL/6 mice led to a progressive increase in inflammation, airway remodeling and associated molecular indicators. Preventively-induced Igf1r-deficiency showed reduced neutrophil and eosinophil numbers in BALF and bone marrow, a significant reduction of airway remodeling and decreased levels of related markers. In addition, therapeutic targeting of Igf1r promoted the resolution of HDM-induced-inflammation. Our results demonstrate for the first time that Igf1r is important in acute asthma pathobiology and resolution of HDM-induced inflammation. Thus, IGF1R is suggested to be a promising candidate for future therapeutic approaches for the treatment and prevention of asthma

Cytolocalyzation and cytotoxicity of new luminescent cyclometalated platinum(II) complexes: use as organelle biomarkers and antitumoral drugs with potential in photodynamic therapy

Two series of luminescent cyclometalated Pt(II) com-plexes were synthesized a nd their biological activitywas assessed. One was based on the deprotonated do-nor-acceptor 2-(4-dimethylaminephenyl)benzothiazoleligand (NMe 2 -pbt) and includes four mononuclear com-plexes [Pt(Me2N-pbt)(C6F5 )L] (L = Me2N-pbtH) 1, p-dpbH(4-diphenylphosphino)benzoic acid) 2, o-dpbH (2-diphe-nylphosphino)benzoic acid) [Pt(Me2N-pbt)(C6F5 )(o-dpbH)]3 (unstable), and [Pt(Me2N-pbt)(o-dpb)] 4, as well as oftwo binuclear derivatives [{Pt(Me2N-pbt)(C6F5 )}2(m-PRnP)][PR4 P = O(CH2CH2OC(O)C6H 4PPh 2)2 5; PR12P = O{(CH-2CH2O)3C(O)C6H 4PPh 2}2 6]. The second includes 2,6-di-fluorophenylpyridine (dfppy) and phenylquinoline (pq) aschromophores and acyclic diaminocarbene (ADC) ligandsas auxiliary ligands [Pt(C^N)Cl{C(NHXyl)(NHR)}] [C^N =dfppy (a), pq (b); R = Pr 7a, 8a, CH2 Ph 7b, 8b]. In theNMe2-pbt based complexes the phosphorescent emissionis lost in aerated solutions, owing to photoinduced electrontransfer to 3 O2 and formation 1 O2 singlet, as confirmed incomplexes 2 and 4. Here we report some of their biological activity. Cytotoxicity studies in the human cancer celllines A549 (lung carcinoma) and HeLa (cervix carcinoma)showed good activity for the ADC complexes 7 and 8. Tothe best of our knowledge, these compounds representthe first examples of cycloplatinated complexes bearingacyclic diamino carbenes with antiproliferative properties(Ref.). Accordingly, 7a, 7b and 8a altered DNA electropho-retic mobility pointing as a possible cytotoxic mechanism.NMe2-pbt complexes 2, 3 and 6 were also active againstA549 and HeLa cancer cells, with higher efficiency in A549,in contrast to 1, 4, and 5. Cytolocalization studies revealedthat the no cytotoxic ligand Me 2 N-pbtH and their deriva-tive complexes 1-6 exhibit specific accumulation in theGolgi apparatus. Furthermore, the potential photodynamicproperty of this type of complexes was demonstrated withthe non-cytotoxic complex 4, which demonstrated efficientphotoinduced cytotoxicity after irradiation