Effect of the Size and Shape of Dendronized Iron Oxide Nanoparticles Bearing a Targeting Ligand on MRI, Magnetic Hyperthermia, and Photothermia Properties-From Suspension to In Vitro Studies.

Functionalized iron oxide nanoparticles (IONPs) are increasingly being designed as a theranostic nanoplatform combining specific targeting, diagnosis by magnetic resonance imaging (MRI), and multimodal therapy by hyperthermia. The effect of the size and the shape of IONPs is of tremendous importance to develop theranostic nanoobjects displaying efficient MRI contrast agents and hyperthermia agent via the combination of magnetic hyperthermia (MH) and/or photothermia (PTT). Another key parameter is that the amount of accumulation of IONPs in cancerous cells is sufficiently high, which often requires the grafting of specific targeting ligands (TLs). Herein, IONPs with nanoplate and nanocube shapes, which are promising to combine magnetic hyperthermia (MH) and photothermia (PTT), were synthesized by the thermal decomposition method and coated with a designed dendron molecule to ensure their biocompatibility and colloidal stability in suspension. Then, the efficiency of these dendronized IONPs as contrast agents (CAs) for MRI and their ability to heat via MH or PTT were investigated. The 22 nm nanospheres and the 19 nm nanocubes presented the most promising theranostic properties (respectively, r2 = 416 s-1·mM-1, SARMH = 580 W·g-1, SARPTT = 800 W·g-1; and r2 = 407 s-1·mM-1, SARMH = 899 W·g-1, SARPTT = 300 W·g-1). MH experiments have proven that the heating power mainly originates from Brownian relaxation and that SAR values can remain high if IONPs are prealigned with a magnet. This raises hope that heating will maintain efficient even in a confined environment, such as in cells or in tumors. Preliminary in vitro MH and PTT experiments have shown the promising effect of the cubic shaped IONPs, even though the experiments should be repeated with an improved set-up. Finally, the grafting of a specific peptide (P22) as a TL for head and neck cancers (HNCs) has shown the positive impact of the TL to enhance IONP accumulation in cells.

Bioconjugation studies of an EGF-R targeting ligand on dendronized iron oxide nanoparticles to target head and neck cancer cells.

A major challenge in nanomedicine is designing nanoplatforms (NPFs) to selectively target abnormal cells to ensure early diagnosis and targeted therapy. Among developed NPFs, iron oxide nanoparticles (IONPs) are good MRI contrast agents and can be used for therapy by hyperthermia and as radio-sensitizing agents. Active targeting is a promising method for selective IONPs accumulation in cancer tissues and is generally performed by using targeting ligands (TL). Here, a TL specific for the epidermal growth factor receptor (EGFR) is bound to the surface of dendronized IONPs to produce nanostructures able to specifically recognize EGFR-positive FaDu and 93-Vu head and neck cancer cell lines. Several parameters were optimized to ensure a high coupling yield and to adequately quantify the amount of TL per nanoparticle. Nanostructures with variable amounts of TL on the surface were produced and evaluated for their potential to specifically target and be thereafter internalized by cells. Compared to the bare NPs, the presence of the TL at the surface was shown to be effective to enhance their internalization and to play a role in the total amount of iron present per cell.

Impact of PEGylation on the degradation and pore organization in mesoporous silica nanoparticles: A study of the inner mesoporous structure in physiologically relevant ionic conditions.

The degradation of mesoporous silica nanoparticles (MSNs) in the biological milieu due to silica hydrolysis plays a fundamental role for the delivery of encapsulated drugs and therapeutics. However, little is known on the evolution of the pore arrangement in the MSNs in biologically relevant conditions. Small Angle X-ray scattering (SAXS) studies were performed on unmodified and PEGylated MSNs with a MCM-48 pore structure and average sizes of 140 nm, exposed to simulated body fluid solution (SBF) at pH 7.4 for different time intervals from 30 min to 24 h. Experiments were performed with silica concentrations below, at and over 0.14 mg/mL, the saturation concentration of silica in water at physiological temperature. At silica concentrations of 1 mg/mL (oversaturation), unmodified MSNs show variation in interpore distances over 6 h exposure to SBF, remaining constant thereafter. A decrease in radius of gyration is observed over the same time. Mesoporosity and radius of gyration of unmodified MSNs remain then unchanged up to 24 h. PEGylated MSNs at 1 mg/mL concentration show a broader diffraction peak but no change in the position of the peak is observed following 24 h exposure to SBF. PEGylated MSNs at 0.01 mg/mL show no diffraction peaks already after 30 min exposure to SBF, while at 0.14 mg/mL a small diffraction peak is present after 30 min exposure but disappears after 1 h.

Core vs. surface labelling of mesoporous silica nanoparticles: advancing the understanding of nanoparticle fate and design of labelling strategies.

Despite great interest in the use of silica mesoporous nanoparticles (MSNs) in drug delivery little is known on their biological fate. Positron emission tomography (PET) studies of radiolabelled MSNs face a major difficulty due to the degradation of the MSNs during circulation as it is difficult to assign activity values to either the MSNs or their degradation products. Here, a PET study is conducted using two strategies of labelling. MSNs are either radiolabelled in the core by complexation with silanols from the MSNs with 89Zr, or on the MSN coating through attachment of 131I radiolabelled Lin-TT1 (AKRGARSTA), a homing peptide for targeting cancer tissue. Results from the biodistribution of MSNs with the two labels are compared, obtaining meanful information on the fate of MSNs. While MSNs accumulate in liver and spleen, MSN degradation products 89Zr or silicate bearing the radioisotope, are found in the bones and probably in lungs. A partial detachment of the peptide from the surface of the MSN is also observed. This work highlights the importance of choosing an appropriate labelling strategy for nanoparticles since core or surface labelling may result in different particle biodistribution if the labelled component degrades or the label detaches.

Hybrid Multivalent Jack Bean α-Mannosidase Inhibitors: The First Example of Gold Nanoparticles Decorated with Deoxynojirimycin Inhitopes.

Among carbohydrate-processing enzymes, Jack bean α-mannosidase (JBα-man) is the glycosidase with the best responsiveness to the multivalent presentation of iminosugar inhitopes. We report, in this work, the preparation of water dispersible gold nanoparticles simultaneously coated with the iminosugar deoxynojirimycin (DNJ) inhitope and simple monosaccharides (ß-d-gluco- or α-d-mannosides). The display of DNJ at the gold surface has been modulated (i) by using an amphiphilic linker longer than the aliphatic chain used for the monosaccharides and (ii) by presenting the inhitope, not only in monomeric form, but also in a trimeric fashion through combination of a dendron approach with glyconanotechnology. The latter strategy resulted in a strong enhancement of the inhibitory activity towards JBα-man, with a Ki in the nanomolar range (Ki = 84 nM), i.e., more than three orders of magnitude higher than the monovalent reference compound.

Novel Core-Shell Polyamine Phosphate Nanoparticles Self-Assembled from PEGylated Poly(allylamine hydrochloride) with Low Toxicity and Increased In Vivo Circulation Time.

An approach for reducing toxicity and enhancing therapeutic potential of supramolecular polyamine phosphate nanoparticles (PANs) through PEGylation of polyamines before their assembly into nanoparticles is presented here. It is shown that the number of polyethylene glycol (PEG) chains for polyamine largely influence physico-chemical properties of PANs and their biological endpoints. Poly(allylamine hydrochloride) (PAH) are functionalized through carbodiimide chemistry with three ratios of PEG molecules per PAH chain: 0.1, 1, and 10. PEGylated PAH is then assembled into PANs by exposing the polymer to phosphate buffer solution. PANs decrease size and surface charge with increasing PEG ratios as evidenced by dynamic light scattering and zeta potential measurements, with the ten PEG/PAH ratio PANs having practically zero charge. Small angle X-ray scattering (SAXS) proves that PEG chains form a shell around a polyamine core, which is responsible for the screening of positive charges. MTT experiments show that the screening of amine groups decreases nanoparticle toxicity, with the lowest toxicity for the 10 PEG/PAH ratio. Fluorescence correlation spectroscopy (FCS) proves less interaction with proteins for PEGylated PANs. Positron emission tomography (PET) imaging of 18 F labelled PANs shows longer circulation time in healthy mice for PEGylated PANs than non-PEGylated ones.

In Vivo Tracking of the Degradation of Mesoporous Silica through 89 Zr Radio-Labeled Core-Shell Nanoparticles.

While mesoporous silica nanoparticles (MSNs) are extensively studied as high-potential drug delivery platforms, the successful clinical translation of these nanocarriers strongly depends on their biodistribution, biodegradation, and elimination patterns in vivo. Here, a novel method is reported to follow the in vivo degradation of MSNs by tracking a radioactive label embedded in the silica structure. Core-shell silica nanoparticles (NPs) with a dense core and a mesoporous shell are labeled with low quantities of the positron emitter 89 Zr, either in the dense core or in the mesoporous shell. In vivo positron emission tomography imaging and ex vivo organ measurements reveal a remarkable difference in the 89 Zr biodistribution between the shell-labeled and the core-labeled NPs. Release of the radiotracer from shell-labeled NPs is used as a probe of the extent of silica dissolution, and a prompt release of the radioisotope is observed, with partial excretion already in the first 2 h post injection, and a slower accumulation in bones over time. On the other hand, when 89 Zr is embedded in the nanoparticle core, the biodistribution remains largely unchanged during the first 6 h. These findings indicate that MSNs have fast, hour-scale, degradation kinetics in vivo.

Visible-Light Acceleration of H2 Evolution from Aqueous Solutions of Inorganic Hydrides Catalyzed by Gold-Transition-Metal Nanoalloys.

Production of hydrogen (H2) upon hydrolysis of inorganic hydrides potentially is a key step in green energy production. We find that visible-light irradiation of aqueous solutions of ammonia-borane (AB) or NaBH4 containing "click"-dendrimer-stabilized alloyed nanocatalysts composed of nanogold and another late transition-metal nanoparticle (LTMNP) highly enhances catalytic activity for H2 generation while also inducing alloy to Au core@M shell nanocatalyst restructuration. In terms of visible-light-induced acceleration of H2 production from both AB and NaBH4, the Au1Ru1 alloy catalysts show the most significant light-boosting effect. Au-Rh and Au-PtNPs are also remarkable with total H2 release time from AB and NaBH4 down to 1.3 min at 25 °C (AuRh), 3 times less than in the dark, and Co is the best earth-abundant metal alloyed with nanogold. This boosting effect is explained by the transfer of plasmon-induced hot electron from the Au atoms to the LTMNP atoms facilitating water O-H oxidative addition on the LTMNP surface, as shown by the large primary kinetic isotope effect kH/kD upon using D2O obtained for both AB and NaBH4. The second simultaneous and progressive effect of visible-light irradiation during these reactions, alloy to Au core@M shell restructuration, enhances the catalytic activity in the recycling, because, in the resulting Au core@M shell, the surface metal (such as Ru) is much more active than the original Au-containing alloy surface in dark reactions. There is no light effect on the rate of hydrogen production for the recycled nanocatalyst because of the absence of Au on the NP surface, but it is still very efficient in hydrogen release during four cycles because of the initial light-induced restructuration, although it is slightly less efficient than the original nanoalloy in the presence of light. The dendritic triazole coordination on each LTMNP surface appears to play a key role in these remarkable light-induced processes.

Poloxamer/sodium cholate co-formulation for micellar encapsulation of doxorubicin with high efficiency for intracellular delivery: An in-vitro bioavailability study.

HYPOTHESIS: Doxorubicin hydrochloride (DX) is widely used as a chemotherapeutic agent, though its severe side-effects limit its clinical use. A way to overcome these limitations is to increase DX latency through encapsulation in suitable carriers. However, DX has a high solubility in water, hindering encapsulation. The formulation of DX with sodium cholate (NaC) will reduce aqueous solubility through charge neutralization and hydrophobic interactions thus facilitating DX encapsulation into poloxamer (F127) micelles, increasing drug latency. EXPERIMENTS: DX/NaC/PEO-PPO-PEO triblock copolymer (F127) formulations with high DX content (DX-PMs) have been prepared and characterized by scattering techniques, transmission electron microscopy and fluorescence spectroscopy. Cell proliferation has been evaluated after DX-PMs uptake in three cell lines (A549, Hela, 4T1). Cell uptake of DX has been studied by means of confocal laser scanning microscopy and flow cytometry. FINDINGS: DX-PMs formulations result in small and stable pluronic micelles, with the drug located in the apolar core of the polymeric micelles. Cell proliferation assays show a delayed cell toxicity for the encapsulated DX compared with the free drug. Data show a good correlation between cytotoxic response and slow DX delivery to nuclei. DX-PMs offer the means to restrict DX delivery to the cell interior in a highly stable and biocompatible formulation, suitable for cancer therapy.

iRGD-guided tamoxifen polymersomes inhibit estrogen receptor transcriptional activity and decrease the number of breast cancer cells with self-renewing capacity.

BACKGROUND: Tamoxifen (Tam) is the most frequent treatment for estrogen receptor (ER) positive breast cancer. We recently showed that fibronectin (FN) leads to Tam resistance and selection of breast cancer stem cells. With the aim of developing a nanoformulation that would simultaneously tackle ER and FN/ß1 integrin interactions, we designed polyethylene glycol-polycaprolactone polymersomes polymersomes (PS) that carry Tam and are functionalized with the tumor-penetrating iRGD peptide (iRGD-PS-Tam). RESULTS: Polyethylene glycol-polycaprolactone PS were assembled and loaded with Tam using the hydration film method. The loading of encapsulated Tam, measured by UPLC, was 2.4 ± 0.5 mol Tam/mol polymer. Physicochemical characterization of the PS demonstrated that iRGD functionalization had no effect on morphology, and a minimal effect on the PS size and polydispersity (176 nm and Pdi 0.37 for iRGD-TAM-PS and 171 nm and Pdi 0.36 for TAM-PS). iRGD-PS-Tam were taken up by ER+ breast carcinoma cells in 2D-culture and exhibited increased penetration of 3D-spheroids. Treatment with iRGD-PS-Tam inhibited proliferation and sensitized cells cultured on FN to Tam. Mechanistically, treatment with iRGD-PS-Tam resulted in inhibition ER transcriptional activity as evaluated by a luciferase reporter assay. iRGD-PS-Tam reduced the number of cells with self-renewing capacity, a characteristic of breast cancer stem cells. In vivo, systemic iRGD-PS-Tam showed selective accumulation at the tumor site. CONCLUSIONS: Our study suggests iRGD-guided delivery of PS-Tam as a potential novel therapeutic strategy for the management of breast tumors that express high levels of FN. Future studies in pre-clinical in vivo models are warranted.

Polyphosphate Poly(amine) Nanoparticles: Self-Assembly, Thermodynamics, and Stability Studies.

The interaction of polyamine poly(allylamine hydrochloride) with Na3PO4, Na4P2O7, Na5P3O10, Na6P6O18, and (NaPO3)26 salts and the formation of polyamine phosphate nanoparticles (PANs) are studied here. Dynamic light scattering, isothermal titration calorimetry (ITC), electrophoretical mobility measurements, atomic force microscopy, and transmission electron microscopy are used to explore the formation, stability, and pH sensitivity of PANs. An optimal concentration for PAN formation is found for each phosphate salt in terms of the most stable size and lowest polydispersity index of the nanoparticles. The minimal concentration of phosphate ions for PAN formation decreases with the increasing number of phosphate groups per phosphate salt. ITC measurements show that all polyphosphates display a characteristic endothermic peak, which is not present when monophosphates are used for PAN formation. pH stability of PANs depends on the type of phosphate salt. PANs formed with small phosphates show a small window of stability with pH from 8 to 9, while those formed with long phosphates are stable in more acidic pH environments. Our findings open multiple possibilities for fine-tuning the pH sensitivity of PANs by varying phosphate salts for potential applications in drug delivery.

[Efficiency of laparoscopic vs endoscopic management in cholelithiasis and choledocholithiasis. Is there any difference?] / Eficiencia del manejo laparoscópico vs. endoscópico en colelitiasis y coledocolitiasis. ¿Existe diferencia?

BACKGROUND: Concomitant cholelithiasis and choledocholithiasis is a disease where incidence increases with age and can have serious complications such as pancreatitis, cholangitis and liver abscesses, but its management is controversial, because there are minimally invasive laparoscopic and endoscopic surgical procedures. OBJECTIVE: To compare the efficiency in the management of cholelithiasis and choledocholithiasis with laparoscopic cholecystectomy with common bile duct exploration vs cholangiopancreatography endoscopic retrograde+laparoscopic cholecystectomy. MATERIAL AND METHOD: Retrospective analysis of a five year observational, cross sectional multicenter study of patients with cholelithiasis and concomitant high risk of choledocholithiasis who were divided into two groups and the efficiency of both procedures was compared. Group 1 underwent laparoscopic cholecystectomy with common bile duct exploration and group 2 underwent cholangiopancreatography endoscopic retrograde+laparoscopic cholecystectomy. RESULTS: 40 patients, 20 were included in each group, we found p=0.10 in terms of operating time; when we compared hospital days we found p=0.63; the success of stone extraction by study group we obtained was p=0.15; the complications presented by group was p=0.1 and the number of hospitalizations by group was p ≤ 0.05 demonstrating statistical significance. CONCLUSIONS: Both approaches have the same efficiency in the management of cholelithiasis and choledocholithiasis in terms of operating time, success in extracting stone, days of hospitalization, postoperative complications and conversion to open surgery. However the laparoscopic approach is favourable because it reduces the number of surgical anaesthetic events and the number of hospital admissions.

Componentes culturales que influyen en la salud bucal / Cultural components that influence oral health

El propósito de este trabajo es realizar una revisión bibliográfica acerca de los conocimientos, las actitudesy las prácticas en salud bucal (CAPSB), tres componentes culturales que influyen en la incidencia de afecciones de la cavidad oral. La cultura y sus componentes han pasado por tres fases en su conceptualización: la concreta, la abstracta y la simbólica; esta última es la que se encuentra vigente y sobre la cual otras áreas del conocimiento han trabajado, entre ellas, las ciencias de la salud. La cultura es aprendida, estandarizada y compartida. Los componentes culturales son transmitidos mediante los procesos de socialización (primaria y secundaria) que determinan la manera en la que la salud, y por lo tanto el proceso salud-enfermedad, son comprendidos por los individuos. Los conocimientos son resultado deprocesos sociales y cognitivos que están determinados por las características aceptadas y representativas del grupo social en el que se desarrollan, son la parte cognitiva de la cultura. La concepción que cada ser humano tenga acerca de la salud bucal determinará su actitud. La actitud representa una forma de ser, una posición, inclinación o tendencia, es la variable intermedia entre una situación y la manera encómo se responde a ella. Las prácticas ante el proceso salud-enfermedad son acciones observables en los individuos y están presentes en los niveles individual, familiar y comunitario e impactan en la saludgeneral de las poblaciones. Este trabajo es una aproximación al tema, haciendo un acercamiento al casode la población mexicana.

The aim of this work is to review the literature about the knowledge, attitudes and practices (KAP) about oral health, the three cultural components influencing the incidence of diseases at the oral cavity. The concept of culture and its components has undergone three phases: the concrete phase, the abstract phase and the symbolic phase; the latter is the current one, and the one over which other areas of knowledge have worked, including the health sciences. Culture can be learned, standardized and sha-red. Cultural components are transmitted through the processes of socialization (primary and secondary socialization) and they help determine the way in which health, and therefore the health-disease pro-cess, is understood by individuals. Knowledge is the result of social and cognitive processes determined by the characteristics accepted by and representative of the social group where they develop; they are the cognitive part of culture. The notion that every human being has about oral health will determine his/her attitude towards it. Attitude shows a way of being, a position, an inclination or tendency, it is a variable between situations and how people respond to them. Practices to face the health-disease process are actions that can be observed in individuals. They are present at the individual, family and community levels, and they impact on the overall health of the population. This work is an approach to the theme, while we discuss the Mexican population case.

[Hysteroscopy used in infertility. Diagnosis and therapy]. / Histeroscopia en infertilidad. Diagnóstico y tratamiento.

The purpose of this study is to review the prevalence of different uterine defects associated with infertility, recurrent pregnancy loss, and preterm pregnancies. Various infertility etiologies are analyzed, mainly that of uterine basis (adhesions, septa, myomas, polyps, pelvic inflammations or infection, and endometriosis). Importance of surgical techniques with minimal invasion is studied, basically hysteroscopy as a diagnosis and therapeutic method, which is compared with the rest of techniques.

Interrupción de la vena cava inferior / Inferior vena cava interruption: US, CT and MR features

La interrupción de la vena cava inferior (VCI), con continuación con el sistema ácigos-hemiácigos, es una entidad poco común, con una incidencia de presentación del 0,6 por ciento. La más frecuente es la ausencia del segmento suprarrenal, que constituye el 90 por ciento de estas anomalías y sólo un 6 por ciento compromete el segmento renal e infrarrenal. Esta entidad puede asociarse a poliesplenia o asplenia y a situs inversus, aunque también puede presentarse aisladamente. Presentamos un paciente de sexo masculino, de 51 años, que presenta interrupción del segmento intrahepático de la VCI, con continuación de las venas ácigos y hemiácigos asociada a poliesplenia

Interrupción de la vena cava inferior / Inferior vena cava interruption: US, CT and MR features

La interrupción de la vena cava inferior (VCI), con continuación con el sistema ácigos-hemiácigos, es una entidad poco común, con una incidencia de presentación del 0,6 por ciento. La más frecuente es la ausencia del segmento suprarrenal, que constituye el 90 por ciento de estas anomalías y sólo un 6 por ciento compromete el segmento renal e infrarrenal. Esta entidad puede asociarse a poliesplenia o asplenia y a situs inversus, aunque también puede presentarse aisladamente. Presentamos un paciente de sexo masculino, de 51 años, que presenta interrupción del segmento intrahepático de la VCI, con continuación de las venas ácigos y hemiácigos asociada a poliesplenia (AU)

Enfermedad de Crohn: a propósito de un caso / Duodenal Crohn's disease

La enfermedad de Crohn es un proceso inflamatorio crónico de causa desconocida, que puede comprometer cualquier zona del tubo digestivo, desde la cavidad oral hasta el ano. Presentamos una paciente de 22 años con enfermedad de Crohn, patología poco frecuente en nuestro medio, con una forma de presentación atípica, donde los métodos de diagnóstico por imágenes asumieron un rol preponderante para arribar al diagnóstico definitivo. Los estudios realizados fueron: ecografía abdominal, TC de abdomen con contraste oral y endovenoso con cortes finos para páncreas, tránsito convencional de intestino delgado, esófago-gastroduodenoscopia y colonoscopia con toma de biopsia

Enfermedad de Crohn: a propósito de un caso / Duodenal Crohns disease

La enfermedad de Crohn es un proceso inflamatorio crónico de causa desconocida, que puede comprometer cualquier zona del tubo digestivo, desde la cavidad oral hasta el ano. Presentamos una paciente de 22 años con enfermedad de Crohn, patología poco frecuente en nuestro medio, con una forma de presentación atípica, donde los métodos de diagnóstico por imágenes asumieron un rol preponderante para arribar al diagnóstico definitivo. Los estudios realizados fueron: ecografía abdominal, TC de abdomen con contraste oral y endovenoso con cortes finos para páncreas, tránsito convencional de intestino delgado, esófago-gastroduodenoscopia y colonoscopia con toma de biopsia (AU)