Glycopolymer-Functionalized MOF-808 Nanoparticles as a Cancer-Targeted Dual Drug Delivery System for Carboplatin and Floxuridine.

Codelivery of chemotherapeutics via nanomaterials has attracted much attention over the last decades due to improved drug delivery to tumor tissues, decreased systemic effects, and increased therapeutic efficacies. High porosities, large pore volumes and surface areas, and tunable structures have positioned metal-organic frameworks (MOFs) as promising drug delivery systems (DDSs). In particular, nanoscale Zr-linked MOFs such as MOF-808 offer notable advantages for biomedical applications such as high porosity, good stability, and biocompatibility. In this study, we report efficient dual drug delivery of floxuridine (FUDR) and carboplatin (CARB) loaded in MOF-808 nanoparticles to cancer cells. The nanoparticles were further functionalized by a poly(acrylic acid-mannose acrylamide) (PAAMAM) glycopolymer coating to obtain a highly selective DDS in cancer cells and enhance the therapeutic efficacy of chemotherapy. While MOF-808 was found to enhance the individual therapeutic effects of FUDR and CARB toward cancerous cells, combining FUDR and CARB was seen to cause a synergistic effect, further enhancing the cytotoxicity of the free drugs. Enhancement of CARB loading and therefore cytotoxicity of the CARB-loaded MOFs could be induced through a modified activation protocol, while coating of MOF-808 with the PAAMAM glycopolymer increased the uptake of the nanoparticles in cancer cells used in the study and offered a particularly significant selective drug delivery with high cytotoxicity in HepG2 human hepatocellular carcinoma cells. These results show how the enhancement of cytotoxicity is possible through both nanovector delivery and synergistic treatment, and that MOF-808 is a viable candidate for future drug delivery studies.

Applications of nanoscale metal-organic frameworks as imaging agents in biology and medicine.

Nanoscale metal-organic frameworks (NMOFs) are an interesting and unique class of hybrid porous materials constructed by the self-assembly of metal ions/clusters with organic linkers. The high storage capacities, facile synthesis, easy surface functionalization, diverse compositions and excellent biocompatibilities of NMOFs have made them promising agents for theranostic applications. By combination of a large variety of metal ions and organic ligands, and incorporation of desired molecular functionalities including imaging modalities and therapeutic molecules, diverse MOF structures with versatile functionalities can be obtained and utilized in biomedical imaging and drug delivery. In recent years, NMOFs have attracted great interest as imaging agents in optical imaging (OI), magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET) and photoacoustic imaging (PAI). Furthermore, the significant porosity of MOFs allows them to be loaded with multiple imaging agents and therapeutics simultaneously and applied for multimodal imaging and therapy as a single entity. In this review, which is intended as an introduction to the use of MOFs in biomedical imaging for a reader entering the subject, we summarize the up-to-date progress of NMOFs as bioimaging agents, giving (i) a broad perspective of the varying imaging techniques that MOFs can enable, (ii) the different routes to manufacturing functionalised MOF nanoparticles and hybrids, and (iii) the integration of imaging with differing therapeutic techniques. The current challenges and perspectives of NMOFs for their further clinical translation are also highlighted and discussed.

Change in the dimensions of the lumbar area muscles after surgery: MRI analysis.

OBJECTIVE: This study aims to assess the change in the dimensions of the lumbar muscles in patients with chronic lower back pain using Magnetic Resonance Imaging (MRI) and to determine pre/post effects of surgery. METHODS: We enrolled 28 individuals (13F/15M; age: 45.39±11.56 years) whose L2-S1 muscle measurements were obtained using MRI, before and at follow-up 6-12 months after surgery. The control group comprising 37 individuals (18F/19M; age: 34.41±10.72 years) who had no lumbar pathology but for whom retrospective archive images were available. In the axial MRI analysis, the cross-sections of m.multifidus, mm.erector spinae and m.psoas major on both sides were measured with the 'closed polygon' technique. RESULTS: The L2-3 and L4-5 levels of the m.multifidus on the right side, the L2-3, L4-5 and L5-S1 levels of the m.multifidus and the L5-S1 levels of the mm. erector spinae on the left side cross-sectional areas were significantly lower than the control group (p<0.05). The right-side m.multifidus and the left-side mm.erector spinae sectional areas were significantly lower than the pre-surgery values at the L5-S1 levels (p<0.05). CONCLUSION: This study demonstrated that chronic lower back pain causes atrophy in the lumbar muscles and established the existence and continuity of atrophy after surgery.

Enhanced photodynamic therapy and fluorescence imaging using gold nanorods for porphyrin delivery in a novel in vitro squamous cell carcinoma 3D model.

Nanocomposites of gold nanorods (Au NRs) with the cationic porphyrin TMPyP (5,10,15,20-tetrakis(1- methyl 4-pyridinio)porphyrin tetra(p-toluenesulfonate)) were investigated as a nanocarrier system for photodynamic therapy (PDT) and fluorescence imaging. To confer biocompatibility and facilitate the cellular uptake, the NRs were encapsulated with polyacrylic acid (PAA) and efficiently loaded with the cationic porphyrin by electrostatic interaction. The nanocomposites were tested with and without light exposure following incubation in 2D monolayer cultures and a 3D compressed collagen construct of head and neck squamous cell carcinoma (HNSCC). The results showed that Au NRs enhance the absorption and emission intensity of TMPyP and improve its photodynamic efficiency and fluorescence imaging capability in both 2D cultures and 3D cancer constructs. Au NRs are promising theranostic agents for delivery of photosensitisers for HNSCC treatment and imaging.

Bypassing pro-survival and resistance mechanisms of autophagy in EGFR-positive lung cancer cells by targeted delivery of 5FU using theranostic Ag2S quantum dots.

Targeted drug delivery systems that combine imaging and therapeutic functions in a single structure have become very popular in nanomedicine. Near-infrared (NIR) emitting Ag2S quantum dots (QDs) are excellent candidates for this task. Here, we have developed PEGylated Ag2S QDs functionalized with Cetuximab (Cet) antibody and loaded with an anticancer drug, 5-fluorouracil (5FU). These theranostic QDs were used for targeted NIR imaging and treatment of lung cancer using low (H1299) and high (A549) Epidermal Growth Factor Receptor (EGFR) overexpressing cell lines. The Cet conjugated QDs effectively and selectively delivered 5FU to A549 cells and provided significantly enhanced cell death associated with apoptosis. Interestingly, while treatment of cells with free 5FU activated autophagy, a cellular mechanism conferring resistance to cell death, these EGFR targeting multimodal QDs significantly overcame drug resistance compared to 5FU treatment alone. The improved therapeutic outcome of 5FU delivered to A549 cells by Cet conjugated Ag2S QDs is suggested as the synergistic outcome of enhanced receptor mediated uptake of nanoparticles, and hence the drug, coupled with suppressed autophagy even in the absence of addition of an autophagy suppressor.

Development of near-infrared region luminescent N-acetyl-L-cysteine-coated Ag2S quantum dots with differential therapeutic effect.

AIM: N-acetyl-L-cysteine (NAC) is a free radical scavenger. We developed NAC-coated Ag2S (NAC-Ag2S) quantum dot (QD) as an optical imaging and therapeutic agent. MATERIALS & METHODS: QDs were synthesized in water. Their optical imaging potential and toxicity were studied in vitro. RESULTS: NAC-Ag2S QDs have strong emission, that is tunable between 748 and 840 nm, and are stable in biologically relevant media. QDs showed significant differences both in cell internalization and toxicity in vitro. QDs were quite toxic to breast and cervical cancer cells but not to lung derived cells despite the higher uptake. NAC-Ag2S reduces reactive oxygen species (ROS) but causes cell death via DNA damage and apoptosis. CONCLUSION: NAC-Ag2S QDs are stable and strong signal-generating theranostic agents offering selective therapeutic effects.

Phosphonate-functionalized poly(ß-amino ester) macromers as potential biomaterials.

Biodegradability, hemocompatibility, resistance to protein adsorption, and strong interactions with hydroxyapatite (HAP)-based tissues such as dentin, enamel, and bone are important properties of phosphorus-containing biomaterials. Here, novel phosphonate-functionalized poly(ß-amino ester) (PBAE) macromers are synthesized through aza-Michael addition of various diacrylates [1,6-hexanediol diacrylate (HDDA), poly(ethylene glycol) diacrylate (PEGDA, Mn = 575), 1,4-butanediol diacrylate (BDDA), 1,6-hexanediol ethoxylate diacrylate (HDEDA) and triethylene glycol diacrylate (TEGDA)] and a phosphonate-containing primary amine (diethyl 2-aminoethylphosphonate, A1) efficiently without any catalyst; where replacement of A1 with propyl amine (PA) served as control. The macromers, whose molecular weight is ca. 1000-4000 Da as confirmed by both GPC and 1 H-NMR spectroscopy, are photopolymerized to give biodegradable gels. The degradation behavior and cell interaction of these gels are studied. The degradation rates of the gels can be varied by choice of starting acrylates and the acrylate:amine ratio. Furthermore, the gels showed slightly higher degradability than PA-based analogs (controls). Except TEGDA and PEGDA-based ones, all phosphonate-functionalized PBAE gels supported the attachment of larger number of SaOS-2 cells than nonphosphonated ones and the best film was found to be the one based on HDEDA-A1 with balanced hydrophilicity. Degradation products of these films have no significant cytotoxicity except HDDA-PA. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1390-1399, 2018.

3D Micropatterned All-Flexible Microfluidic Platform for Microwave-Assisted Flow Organic Synthesis.

A large-area, all-flexible, microwaveable polydimethoxysilane microfluidic reactor was fabricated by using a 3D printing system. The sacrificial microchannels were printed on polydimethoxysilane substrates by a direct ink writing method using water-soluble Pluronic F-127 ink and then encapsulated between polydimethoxysilane layers. The structure of micron-sized channels was analyzed by optical and electron microscopy techniques. The fabricated flexible microfluidic reactors were utilized for the acetylation of different amines under microwave irradiation to obtain acetamides in shorter reaction times and good yields by flow organic synthesis.

Folic acid-conjugated cationic Ag2S quantum dots for optical imaging and selective doxorubicin delivery to HeLa cells.

AIM: We aim to develop folic acid (FA)-conjugated cationic Ag2S near-infrared quantum dots (NIRQDs) for the delivery of doxorubicin (DOX) selectively to folate receptor (FR)-positive cancer cells to achieve enhanced drug efficacy and optical tracking in the NIR region. MATERIALS & METHODS: Cationic Ag2S NIRQDs were decorated with FA using a PEG bridge and loaded with DOX. In vitro studies were performed on FR-positive human cervical carcinoma cells and FR-negative A549 cells. RESULTS: Significantly higher uptake of DOX by human cervical carcinoma cells cells and a greater therapeutic effect along with a strong intracellular optical signal were obtained with DOX-loaded FA-conjugated Ag2S NIRQDs. CONCLUSION: These Ag2S NIRQDs are promising theranostic nanoparticles for receptor-mediated delivery of DOX with enhanced drug efficacy combined with optical imaging.

Bisphosphonate-functionalized poly(ß-amino ester) network polymers.

Three novel bisphosphonate-functionalized secondary diamines are synthesized and incorporated into poly(ß-amino ester)s (PBAEs) to investigate the effects of bisphosphonates on biodegradation and toxicity of PBAE polymer networks. These three novel amines, BPA1, BPA2, and BPA3, were prepared from the reactions of 1,4-butanediamine, 1,6-hexanediamine, or 4,9-dioxa-1,12-dodecanediamine with tetraethyl vinylidene bisphosphonate, respectively. The PBAE macromers were obtained from the aza-Michael addition reaction of these amines to 1,6-hexane diol diacrylate (HDDA) and poly(ethylene glycol) diacrylate (PEGDA, Mn = 575) and photopolymerized to produce biodegradable gels. These gels with different chemistries exhibited similar degradation behavior with mass loss of 53-73% within 24 h, indicating that degradation is mostly governed by the bisphosphonate group. Based on the in vitro cytotoxicity evaluation against NIH 3T3 mouse embryonic fibroblast cells, the degradation products do not exhibit significant toxicity in most cases. It was also shown that PBAE macromers can be used as cross-linkers for the synthesis of 2-hydroxyethyl methacrylate hydrogels, conferring small and customizable degradation rates upon them. The materials reported have potential to be used as nontoxic degradable biomaterials. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1412-1421, 2017.

The Role of Active Video-Accompanied Exercises in Improvement of the Obese State in Children: A Prospective Study from Turkey.

OBJECTIVE: The aim of this study was to determine the effects of active video games and music-accompanied aerobic and callisthenic exercises on body mass index (BMI), body fat ratio, physical performance tests, psychosocial status, and self-respect in overweight and obese adolescents. METHODS: Fifty (21 males and 29 females) slightly overweight and obese participants with no chronic disorder and of an average age of 12.16±0.99 years were included in the study. The percentile values for BMI, triceps skinfold thickness, waist circumference measurements, and physical performance tests were evaluated. The effects of obesity on psychological wellness were evaluated using the depression scale for children (DSC) and the Piers-Harris Children's Self-Concept Scale for self-esteem. Following these evaluations, the participants were subjected to an exercise program in five groups of 10 people, 3 days a week for a duration of 8 weeks. Each exercise session lasted 45 minutes. Participants were re-evaluated at the end of the exercise program. The data collected both before and after the exercise program were analyzed using the SPSS 18.0 program. RESULTS: According to BMI reference values, 28% of the 50 participants (n=14; 6 males and 8 females) were assessed to be overweight and 72% to be obese (n=36; 15 males and 21 females). Following the exercise program, 14% of the participants (n=7; 3 males and 4 females) were assessed as normal, 46% (n=23; 14 males and 9 female) as slightly overweight, and 40% (n=20; 4 male and 16 female) as obese. It was determined that the decrease in BMI values (p<0.05) was higher in male participants than in female participants and that the frequency of obesity was higher in the females. A statistically significant decrease in BMI values was found after the exercise program (p<0.01). Following the exercise program, statistically significant differences have also been observed in the self-esteem (p<0.01), psychological wellness (p=0.025), triceps skinfold thickness, as well as in waist circumference and BMI values of the participants compared to the pre-exercise phase (p<0.01). CONCLUSION: An exercise program applied with active video games was found to have positive effects on the obese state as well as on the psychosocial status and self-esteem of obese individuals, indicating that exercise and physical activity have an important role in improvement of the obese state in childhood as well as having positive contributions to self-esteem and psychological wellness state.

Highly luminescent and cytocompatible cationic Ag2S NIR-emitting quantum dots for optical imaging and gene transfection.

The development of non-toxic theranostic nanoparticles capable of delivering a therapeutic cargo and providing a means for diagnosis is one of the most challenging tasks in nano-biotechnology. Gene therapy is a very important mode of therapy and polyethyleneimine (PEI) is one of the most successful vehicles for gene transfection, yet poses significant toxicity. Optical imaging utilizing quantum dots is one of the newer but fast growing diagnostic modalities, which requires non-toxic, highly luminescent materials, preferentially active in the near infrared region. Ag2S NIRQDs fit to this profile perfectly. Here, we demonstrate the aqueous synthesis of cationic Ag2S NIRQDs with a mixed coating of 2-mercaptopropionic acid (2MPA) and PEI (branched, 25 kDa), which are highly luminescent in the NIR-I window (λem = 810-840 nm) as new theranostic nanoparticles. Synergistic stabilization of the QD surface via the simultaneous use of a small molecule and a polymeric material provided the highest quantum yield, 150% (with respect to LDS 798 at pH 7.4), reported in the literature for Ag2S. These cationic particles show a dramatic improvement in cytocompatibility even without PEGylation, a strong optical signal easily detected by confocal laser microscopy and effective conjugation and transfection of the green fluorescence protein plasmid (pGFP) to HeLa and MCF-7 cell lines (40% efficiency). Overall, these Ag2S NIRQDs show great potential as new theranostics.

A comparative analysis of surface areas and ratio of the cervical spinal cord and the vertebral canal at the same levels via MRI on healthy individuals / Análisis comparativo de las áreas de superficie y proporción de la médula espinal cervical y el canal vertebral en los mismos niveles via resonancia magnética en individuos sanos

The determination of the normal values of the cross-sectional surface areas and ratios of the vertebral canal and the spinal cord on the healthy individuals is of great importance with regards to the fact that it provides convenience for the doctors to make correct pathological diagnosis because of the most suitable treatment. In this study, it has been aimed to determine the respective ratios between the vertebral canal and the spinal cord via measuring their cross-sectional surface areas at the C3­C6 vertebra levels. The study has been implemented on the Magnetic Resonance Images (MRI) of the cervical vertebral column from healthy individuals at the Department of Radiology, Meram Faculty of Medicine, Necmettin Erbakan University. The study has been applied to 67 (50 female-17 male) individuals whose ages varied between 14 and 59 and these individuals have been divided into two groups as below and over 40 years of age. During the cervical MRI examination, axial and sagittal images have been evaluated and measurements have been made on the non-pathological axial images. The vertebral canal and the spinal cord surface areas have been calculated in square millimeters at the C3­C6 levels. Also, we calculated the ratio between the spinal cord surface area and the vertebral canal surface area. The obtained data has been transferred on the computer and statistical analysis has been implemented via SPSS package program (for Windows, 15.0). The summary of the data has been stated as Mean±SD. It has also been compared with regard to sex and age groups (below and over 40 years of age) using the Student t-test. The relationship between parameters has been evaluated by means of Pearson correlation test. No significant discrepancy (P>0.05) has been determined between the male and the female subjects in terms of the vertebral canal and spinal cord surface area values. On the other hand, at the C4, C5 and C6 levels, a significant discrepancy (P<0.05) has been observed between male and female subjects in terms of the ratio of spinal cord surface to the vertebral canal surface, stating that the male have it larger than the female. A positive correlation (P<0.01) between the surface area and ratio data of both sexes has been determined. We believe that the results of this study will be useful for the fields of neurology, neurosurgery and physical therapy and rehabilitation, particularly in evaluating spinal atrophy.

La determinación de los valores normales de las áreas de superficie de la sección transversal y las proporciones del canal vertebral de la médula espinal en los individuos sanos es de gran importancia para los médicos, para realizar un diagnóstico patológico correcto y un tratamiento más adecuado. Este estudio se llevó a cabo para determinar las respectivas proporciones entre el canal vertebral y la médula espinal a través de la medición transversal de áreas de superficie, entre los niveles de las vértebras C3­C6. El estudio se realizó através de imágenes de resonancia magnética (IRM) de la columna vertebral cervical de individuos sanos en el Departamento de Radiología, de la Facultad de Medicina de Meram, Universidad de Necmettin Erbakan. En el estudio participaron 67 sujetos (50 mujeres, 17 hombres) entre 14 y 59 años de edad. Los sujetos fueron divididos en dos grupos, menores y mayores de 40 años de edad. Durante el examen de IRM cervical, se evaluaron imágenes axiales y sagitales, estas mediciones se realizaron en las imágenes axiales no patológicas. El canal vertebral y las áreas de superficie de la médula espinal fueron calculados en milímetros cuadrados entre los niveles C3­C6. Además, se calculó el cociente entre el área de superficie de la médula espinal y la superficie del canal vertebral. Los datos obtenidos de superficie del canal vertebral, fueron transferidos al equipo y el análisis estadístico se implementó a través del programa SPSS (para Windows, 15.0). El resumen de los datos fue declarado como Media±DE. También fueron comparados grupos entre ambos sexos y por edad (menores y mayores de 40 años de edad) através de la prueba t de Student. La relación entre los parámetros fue evaluada mediante la prueba de correlación de Pearson. No se observó discrepancia significativa (P>0,05) entre hombres y mujeres en términos del canal vertebral, y los valores de la columna vertebral de la zona de superficie dorsal. Por otro lado, a nivel C4, C5 y C6, se observó una discrepancia significativa (P<0,05) entre hombres y mujeres, en términos de la proporción de la superficie de la médula espinal y la superficie del canal vertebral, indicando que fue mayor en los hombres. Se determinó una correlación positiva (P<0,01) entre el área de superficie y los datos de proporción de ambos sexos. Creemos que los resultados de este estudio serán de utilidad en las áreas de la neurología, neurocirugía, como también en terapia física y rehabilitación, en particular en la evaluación de la atrofia espinal.