Enzyme-responsive mannose-grafted magnetic nanoparticles for breast and liver cancer therapy and tumor-associated macrophage immunomodulation.

BACKGROUND: Chemo-immunotherapy modifies the tumor microenvironment to enhance the immune response and improve chemotherapy. This study introduces a dual-armed chemo-immunotherapy strategy combating breast tumor progression while re-polarizing Tumor-Associated Macrophage (TAM) using prodigiosin-loaded mannan-coated magnetic nanoparticles (PG@M-MNPs). METHODS: The physicochemical properties of one-step synthetized M-MNPs were analyzed, including X-ray diffraction, FTIR, DLS, VSM, TEM, zeta potential analysis, and drug loading content were carried out. Biocompatibility, cancer specificity, cellular uptake, and distribution of PG@M-MNPs were investigated using fluorescence and confocal laser scanning microscopy, and flow cytometry. Furthermore, the expression levels of IL-6 and ARG-1 after treatment with PG and PG@M-MNPs on M1 and M2 macrophage subsets were studied. RESULTS: The M-MNPs were successfully synthesized and characterized, demonstrating a size below 100 nm. The release kinetics of PG from M-MNPs showed sustained and controlled patterns, with enzyme-triggered release. Cytotoxicity assessments revealed an enhanced selectivity of PG@M-MNPs against cancer cells and minimal effects on normal cells. Additionally, immuno-modulatory activity demonstrates the potential of PG@M-MNPs to change the polarization dynamics of macrophages. CONCLUSION: These findings highlight the potential of a targeted approach to breast cancer treatment, offering new avenues for improved therapeutic outcomes and patient survival.

In vitro siRNA-mediated GPX4 and AKT1 silencing in oxaliplatin resistance cancer cells induces ferroptosis and apoptosis.

Oxaliplatin is a member of platinum-based chemotherapy drugs frequently used in colorectal cancer (CRC). However, resistance to oxaliplatin causes tumor progression and metastasis. Akt1 and Gpx4 are essential regulator genes of apoptosis and ferroptosis pathways. Inhibition of these genes might eradicate oxaliplatin resistance in resistant CRC cells. We compared two cell death strategies to reverse drug resistance in Caco-2 and HT-29 oxaliplatin-resistant cell lines. We used the AKT1-specific siRNA to induce apoptosis. Also, GPX4-specific siRNA and FIN56 were utilized to generate ferroptosis. The effect of these treatments was assessed by reactive oxygen species (ROS) formation, cell viability, and protein expression level assays. Besides, the expression of GPX4, CoQ10, and NRF2 was assessed in both cell lines after treatments. Correctly measuring the expression of these responsible genes and proteins confirms the occurrence of different types of cell death. In addition, the ability of Akt1/ GPX4 siRNA in resensitizing HT-29 and Caco-2 oxaliplatin resistance cells was evaluated. Our finding showed that the upregulation of GPX4/siRNA caused a reduction in GPX4 and CoQ10 expressions in both cell lines. However, the expression level of NRF2 showed the same level in our cell lines, so we observed a downregulation of NRF2 in resistant CRC cell lines. Cell viability assay indicated that induction of ferroptosis by GPX4/siRNA or FIN56 and apoptosis by Akt1/siRNA in resistant cell lines could reverse the oxaliplatin resistance. We concluded that downregulation of Akt1 or Gpx4 could increase the efficacy of oxaliplatin to overcome the resistance compared to FIN56.

Ferroptosis as a Potential Cell Death Mechanism Against Cisplatin-Resistant Lung Cancer Cell Line.

Purpose: Drug resistance is a challenging issue in cancer chemotherapy. Cell death induction is one of the main strategies to overcome chemotherapy resistance. Notably, ferroptosis has been considered a critical cell death mechanism in recent years. Accordingly, in this study, the different cell death strategies focused on ferroptosis have been utilized to overcome cisplatin resistance in an in vitro lung cancer model. Methods: The physiological functions of Akt1 and GPX4, as critical targets for ferroptosis and apoptosis induction, were suppressed by siRNA or antagonistic agents in resistant A549 cells. Afterward, the interventions' impacts on cell viability and reactive oxygen species (ROS) amount were analyzed by flow cytometry. Moreover, the alteration in the relevant gene and protein expression levels were quantified using Real-time PCR and western blot methods. Results: The result showed that the treatment with Akt1 siRNA reversed the cisplatin resistance in the A549 cell line through the induction of apoptosis. Likewise, the combination treatment of the GPX4 siRNA or FIN56 as ferroptosis inducers alongside cisplatin elevated ROS's cellular level, reduced the cellular antioxidant genes level and increased the cisplatin cytotoxic effect. Conclusion: In conclusion, our study indicated that ferroptosis induction can be considered a promising cell death strategy in cisplatin-resistant cancer cells.

Targeted Codelivery of Prodigiosin and Simvastatin Using Smart BioMOF: Functionalization by Recombinant Anti-VEGFR1 scFv.

Biological metal-organic frameworks (BioMOFs) are hybrid compounds in which metal nodes are linked to biocompatible organic ligands and have potential for medical application. Herein, we developed a novel BioMOF modified with an anti-VEGFR1 scFv antibody (D16F7 scFv). Our BioMOF is co-loaded with a combination of an anticancer compound and a lipid-lowering drug to simultaneously suppress the proliferation, growth rate and metastases of cancer cells in cell culture model system. In particular, Prodigiosin (PG) and Simvastatin (SIM) were co-loaded into the newly synthesized Ca-Gly BioMOF nanoparticles coated with maltose and functionalized with a recombinant maltose binding protein-scFv fragment of anti-VEGFR1 (Ca-Gly-Maltose-D16F7). The nanoformulation, termed PG + SIM-NP-D16F7, has been shown to have strong active targeting behavior towards VEGFR1-overexpresing cancer cells. Moreover, the co-delivery of PG and SIM not only effectively inhibits the proliferation of cancer cells, but also prevents their invasion and metastasis. The PG + SIM-NP-D16F7 nanocarrier exhibited stronger cytotoxic and anti-metastatic effects compared to mono-treatment of free drugs and drug-loaded nanoparticles. Smart co-delivery of PG and SIM on BioMOF nanoparticles had synergistic effects on growth inhibition and prevented cancer cell metastasis. The present nanoplatform can be introduced as a promising tool for chemotherapy compared with mono-treatment and/or non-targeted formulations.

Mesenchymal Stem Cells and Cancer Stem Cells: An Overview of Tumor- Mesenchymal Stem Cell Interaction for Therapeutic Interventions.

Tumors are made up of different types of cancer cells that contribute to tumor heterogeneity. Among these cells, cancer stem cells (CSCs) have a significant role in the onset of cancer and development. Like other stem cells, CSCs are characterized by the capacity for differentiation and self-renewal. A specific population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into mesoderm-specific cells. The pro-or anti-tumorigenic potential of MSCs on the proliferation and development of tumor cells has been reported as contradictory results. Also, tumor progression is specified by the corresponding tumor cells like the tumor microenvironment. The tumor microenvironment consists of a network of reciprocal cell types such as endothelial cells, immune cells, MSCs, and fibroblasts as well as growth factors, chemokines, and cytokines. In this review, recent findings related to the tumor microenvironment and associated cell populations, homing of MSCs to tumor sites, and interaction of MSCs with tumor cells will be discussed.

Mesenchymal Stem Cells cause Telomere Length Reduction of Molt-4 Cells via Caspase-3, BAD and P53 Apoptotic Pathway.

Mesenchymal stem cells (MSCs) as undifferentiated cells are specially considered in cell-based cancer therapy due to unique features such as multi-potency, pluripotency, and self-renewal. A multitude of cytokines secreted from MSCs are known to give such multifunctional attributes, but details of their role are yet to be unknown. In the present study, MSCs were cultured, characterized and co-cultured with Molt-4 cells as acute lymphoblastic leukemia cell line in a trans-well plate. Then, cultured Molt-4 alone and Molt-4 co-cultured with MSCs (10:1) were collected on day 7 and subjected to real time-PCR and Western blotting for gene and protein expression assessment, respectively. Ki-67/caspase-3 as well as telomere length were investigated by flow cytometry and real time-PCR, respectively. The results showed that MSCs caused significant decrease in telomere length as well as hTERT gene expression of Molt-4 cells. Also, gene and protein expression of BAD and P53 were significantly increased. Furthermore, the flow cytometry analysis indicated the decrease and increase of the Ki-67 and caspaspase-3 expression, respectively. It was concluded that MSCs co-cultured with Molt-4 cells could be involved in the promotion of Molt-4 cell apoptosis via caspase-3, BAD, and P53 expression. In addition, the decrease of telomere length is another effect of MSCs on Molt-4 leukemic cells.

In vitro evaluation of cytotoxic effects of di (2-ethylhexyl) phthalate (DEHP) produced by Bacillus velezensis strain RP137 isolated from Persian Gulf.

Phthalates are widely used in polymer science and have potential toxicity related to their chemical structures. However, lots of evidence indicate that phthalate derivatives are undoubtedly produced as secondary metabolites by organisms, including plants, animals, and microorganisms. In the present study, Bacillus velezensis strain RP137 was cultured under optimized conditions. Its biomass was extracted with ethyl acetate with one fraction showing cytotoxic properties. A pure compound was isolated from the active fraction using combined silica gel and LH20 size exclusion column chromatography. Structural evaluation including FT-IR, 1H NMR, 13C NMR, HR-MS and CHN analysis identified the purified compound as di(2-ethylhexyl)phthalate (DEHP) with the formula C24H38O4 and the molecular weight of 389.29 Da. The microorganism-derived (stereospecific) DEHP was strongly reduced the proliferation and induced cytotoxic effects on various eukaryotic cell lines in compare to the synthetic racemic mixture of the compound when assessed by MTT assay. Furthermore, crystal violet assay and morphological changes confirmed the cytotoxic effect of DEHP. Interestingly, non-malignant SV40-immortalized fibroblast cells were less affected by the purified DEHP. Further evaluation on the antibacterial activity of DEHP documented no effect toward Gram-positive (S. aureus) and Gram-negative (E. coli and P. aeruginosa) pathogens even at a high concentration of 100 µM. In conclusion, existence of DEHP as byproduct of microorganism's metabolism can seriously be considered as a warning to human health.

Optimization of Fermentation Conditions to Enhance Cytotoxic Metabolites Production by Bacillus velezensis Strain RP137 from the Persian Gulf.

BACKGROUND: Isolation, introduction and producing bioactive compounds from bacteria, especially marine bacteria, is an attractive research area. One of the main challenges of using these metabolites as drug and their industrialization is the optimization of production conditions. METHODS: In the present study, the response surface methodology was applied to optimize the production of a cytotoxic extract (C-137-R) by Bacillus velezensis (B. velezensis) strain RP137. Initially, among the three carbon and three nitrogen sources, rice starch and potassium nitrate were selected as the best, with cell toxicity equal to IC50=54.4 and 45.1 µg/ml in human lung and liver cancer cell lines, respectively (A549 and HepG2). In the next step, fractional factorial design was performed to survey effect of seven physical and chemical factors on the amount of production, and the most important factors including carbon and nitrogen sources with the positive effect and the sea salt with negative effect were determined. Finally, using the central composite design with 20 experiments, the best concentrations of rice starch and potassium nitrate (1.5%) and sea salt (1%) were obtained. RESULTS: The average amount of dried extract produced in the optimum conditions was 131.1 mg/L and the best response was 71.45%, which is more than 28-fold better than the pre-optimized conditions. CONCLUSION: In general, it can be suggested that the use of modern statistical methods to optimize environmental conditions affecting the growth and metabolism of bacteria can be a highly valuable tool in industrializing the production of bioactive compounds.

Microindoline 581, an Indole Derivative from Microbacterium Sp. RP581 as A Novel Selective Antineoplastic Agent to Combat Hepatic Cancer Cells: Production, Optimization and Structural Elucidation.

Screening of bioactive compounds with potential binding affinity to DNA as one of the target molecules in fighting against cancer cells has gained the attention of many scientists. Finding such compounds in the cellular content of microorganisms, especially marine bacteria as valuable and rich natural resources, is of great importance. Microbacterium sp. RP581, as a member of Actinobacteria phylum, was isolated from the Persian Gulf coastal area and the production of the target compound was optimized using statistical methods in cheap culture ingredients. The purification of the target compound was performed by flash chromatography and preparative HPLC. Both molecular and structural analyses indicated that the compound was an indole derivate which was tentatively named as Microindoline 581. Interaction of Microindoline 581 with genomic and circular DNA revealed that this compound can cause double- strand breaks through binding to the DNA. The analysis of cellular growth and proliferation of various cancer cell lines suggested proper and specific effect of the Microindoline 581 towards HepG2 cells with an IC50 of 172.2 ± 1.7 µM. Additional studies on cell migration inhibition and cell-death induction indicated a concentration-dependent inhibitory effect on proliferation and induction of death of HepG2 cells. The selective action of Microindoline 581 which was isolated from the Microbacterium sp. RP581 in killing HepG2 cells might be due to its specific metabolism in those cells as a precursor.

A gene-based anti-angiogenesis therapy as a novel strategy for cancer treatment.

Angiogenesis-targeted therapy of cancer is considered a promising strategy for therapeutic management of cancer progression. Over the last two decades, a few anti-angiogenesis monoclonal antibodies (mAbs) blocking VEGF signaling have been developed and approved by the FDA. The most widely used anti-angiogenesis drug is bevacizumab which binds VEGFA and prevents its interaction with VEGF receptor leading to suppression of angiogenesis. Despite the remarkable success in development of angiogenesis inhibitory mAbs, their clinical application is limited by the high-cost of mAbs-based regimen which includes multiple doses of mAbs due to their short biological half-life. Antibody gene therapy is an alternative system of antibody production. In this study, we have developed a gene-based anti-VEGF mAb system which is expected to produce a high concentration of anti-VEGFA mAb upon a single administration in cancer patients. The full-length cDNA bevacizumab light and heavy chains joint with T2A sequence were cloned in pCDH lentivirus vector. The lentiviral particles expressing bevacizumab was produced in HEK-293T cells. Recombinant lentiviral particles containing bevacizumab (rLV-bev) efficiently transduced HEK-293cells and produced functional bevacizumab mAb. Bevacizumab expression in the transduced cell was assessed by qRT-PCR and western blot at both the mRNA and protein level, respectively. The functionality of the recombinant bevacizumab was confirmed using the tube formation assay in the co-culture system of endothelial cells and HT-29cells transduced with rLV-bev viral particles. Our results show that rLV-bev gene therapy can be useful for angiogenesis-targeted therapy of cancer.

An Aminoglycoside Antibacterial Substance, S-137-R, Produced by Newly Isolated Bacillus velezensis Strain RP137 from the Persian Gulf.

Given antibiotic resistance in pathogens, finding antibiotics from new sources is always a topic of interest to scientists. In the present study, among various isolates from the Persian Gulf coastal area, the strain RP137 was selected as producer of antibacterial compound. Morphological and biochemical studies along with 16S rDNA sequencing showed that strain RP137 belongs to Bacillus genus and was tentatively named Bacillus velezensis strain RP137. The effect of various carbon and nitrogen sources on optimizing the production of antibacterial compound showed that the low-cost rice starch and potassium nitrate supply to the strain RP137 caused producing of 86.0 ± 8.7 µg/mL extract having the antibacterial activity. The fractionation of the primary methanol extract in different solvents followed by reversed-phase HPLC obtained a pure antibacterial-active sample, S-137-R. Structural analysis of the purified S-137-R with the help of FTIR, HR-MS, 1H-NMR, and 13C-NMR showed that the S-137-R compound is classified as aminoglycoside. Minimum inhibition concentration (MIC) of the pure compound for Gram-positive bacteria, Staphylococcus aureus and methicillin resistant Staphylococcus aureus, showed an average antibacterial effect of about 80 µg/mL and 150 µg/mL, respectively and for Pseudomonas aeruginosa (100 µg/mL), while having very little toxic effect on E. coli. Moreover, low cytotoxicity effect of the S-137-R on cancerous and normal cells as well as the low intensity of the hemolysis of red blood cells in higher concentrations of S-137-R make it an ideal candidate for further structure-activity relationship assessments towards its medical applications.

Drug Targeting Strategies Based on Charge Dependent Uptake of Nanoparticles into Cancer Cells.

The aim of this review was to describe the preferred charged nano-particles (CNPs) for targeted delivery in tumor cells. Zeta Potential (ZP), which represents the surface charge of NPs was highlighted in cell entrance and interactions. In this regard, various types of endocytosis pathways which are involved in NPs' uptake were first introduced. Then, significance of positively charged NPs (PCNPs) in proton sponge effect corresponding to lysosomal escape was discussed. Cells prefer to endocyte the NPs with positive charge in passive targeting and gene delivery, while in active targeting; the charge of receptors' ligand binding site determines the NPs cellular uptake. Moreover, pH-sensitive NPs represent charge reversible behavior depending on pH changes which leads to longer blood circulation residence and higher uptake at acidic microenvironment of the cancer media. Role of the CNPs in overcoming multidrug resistance (MDR) and bypassing p-glycoprotein was further investigated.

Substituted effect on some water-soluble Mn(II) salen complexes: DNA binding, cytotoxicity, molecular docking, DFT studies and theoretical IR & UV studies.

Based on the importance of central metal complexes to interact with DNA, in this research focused on synthesis of some new water soluble Mn(II) complexes 1-4 which modified substituted in ligand at the same position with N, Me, H, and Cl. These complexes were isolated and characterized by elemental analyses, FT-IR, electrospray ionization mass spectrometry (ESI-MS) and UV-vis spectroscopy. DNA binding studies had been studied by using circular dichroism (CD) spectroscopy, UV-vis absorption spectroscopy, cyclic voltammetry (CV), viscosity measurements, emission spectroscopy and gel electrophoresis which proposed the metal buildings go about as effective DNA binders were studied in the presence of Fish-DNA (FS-DNA) which showed the highest binding affinity to DNA with hydrophobic and electron donating substituent. Cell toxicity assays against two human leukemia (Jurkat) and breast cancer (MCF-7) cell lines showed that the complex 3 exhibited a remarkable effects equal to a famous anticancer drug, cisplatin that high cytotoxic activity strongly depend on the hydrophobic substituted ligand. In the theoretical part, density functional theory (DFT) was performed to optimize the geometry of complexes through IR and UV spectra of the complexes that ligand substitution did not affect the geometry and theoretical IR and UV spectra showed good resemblance to the experimental data. The docking studies calculated the lowest-energy between complexes and DNA with the minor grooves mode.

Therapeutic targeting of angiogenesis molecular pathways in angiogenesis-dependent diseases.

Angiogenesis is a critical step in the progression of almost all human malignancies and some other life-threatening diseases. Anti-angiogenic therapy is a novel and effective approach for treatment of angiogenesis-dependent diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. In this article, we will review the main strategies developed for anti-angiogenic therapies beside their clinical applications, the major challenges, and the latest advances in the development of anti-angiogenesis-based targeted therapies.

Long-term Evaluation of Corneal Biomechanical Properties After Corneal Cross-linking for Keratoconus: A 4-Year Longitudinal Study.

PURPOSE: To compare the long-term changes in corneal biomechanics, topography, and tomography before and 4 years after corneal cross-linking (CXL) with the Dresden protocol and correlate these changes with visual acuity. METHODS: In this longitudinal study, 18 eyes of 18 patients with progressive keratoconus who were treated with CXL were included. All patients received a standard ophthalmological examination and were examined by Placido disc-based topography, Scheimpflug tomography, and biomechanical assessments with the Corvis ST (OCULUS Optikgeräte GmbH, Wetzlar, Germany) and Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Buffalo, NY) before and 4 years after CXL. The main outcome measures were dynamic corneal response (DCR) parameters obtained from the Corvis ST, corneal hysteresis (CH), corneal resistance factor (CRF), visual acuity, refraction, corneal curvature, and corneal thickness. RESULTS: There were no significant differences in mean visual acuity, refraction, intraocular pressure, corneal topography, corneal astigmatism in both corneal surfaces, maximum keratometry, corneal thickness at apical and thinnest points, thickness profile indices, corneal volume, and specular microscopy before and 4 years after CXL (P > .05). Significant changes were observed in many DCR parameters, including radius at highest concavity and integrated inverse radius, both of which were consistent with stiffening. The CH and CRF values after CXL were not statistically significant. The new parameters using the Corvis ST include integrated inverse concave radius, which showed a significant decrease 1.07 ± 0.93 mm-1, consistent with stiffening. The corneal stiffness parameter at the first applanation, Ambrósio's Relational Thickness to the horizontal profile, deformation amplitude ratio, and Corvis Biomechanical Index as a combined biomechanical screening parameter did not show significant changes. CONCLUSIONS: CXL is a minimally invasive treatment option to prevent keratoconus progression over 4 years. Pressure-derived biomechanical parameters obtained from the ORA did not show any change following CXL at 4 years of follow-up, whereas the Corvis ST DCR parameters detected changes in corneal biomechanical properties. [J Refract Surg. 2018;34(12):849-856.].

DJ1 and microRNA-214 act synergistically to rescue myoblast cells after ischemia/reperfusion injury.

Ischemia/reperfusion injury is a tissue injury occurring post-reperfusion of tissues with pre-existing ischemia. A good blood supply to tissues aids in the survival of ischemic tissue, however, due to prolonged ischemia the levels of ATP decrease and pH declines leading to acidosis. Reduced ATP leads to an increase in the AMP/ATP ratio, causing cessation of intracellular calcium transport, hence calcium overload and cell death. In this study, we demonstrate the synergistic and antagonistic effect of DJ1 and microR-214 (miR-214) in rescuing myoblast C2C12 cells after ischemia/reperfusion in an in vitro model. Both DJ1 and miR-214 were cloned into a hypoxic inducible expression cassette and transfected into the C2C12 cells. We showed that DJ1 and miR-214 have synergistic effects in reducing intracellular lactate dehydrogenase and intracellular transient calcium levels after reoxygenation compared to control cells, in addition to reducing cell death via necrosis. Western blotting revealed a decrease in autophagosome formation in LC3II/I ratio and an increase in AKT expression in cells transfected with DJ1 and miR-214. Using quantitative real-time PCR, we demonstrated that DJ1 and miR-214 significantly reduced the expression of pro-apoptotic factors and autophagy compared to control. The results indicated DJ1 is an endogenous oxidative stress molecule and miR-214 is a potent inhibitor of the sodium calcium exchanger channel. DJ1 had the greatest effect to inhibiting mitochondrial cell death pathways by possibly acting as a modulator of autophagy. Additionally, we have concluded that miR-214 has an inhibitory effect on extrinsic cell death pathways such as necrosis and autophagy.

Construction and Development of a Cardiac Tissue-Specific and Hypoxia-Inducible Expression Vector.

Purpose: Cardiovascular gene therapy is a sophisticated approach, thanks to the safety of vectors, stable transgene expression, delivery method, and different layers of the heart. To date, numerous expression vectors have been introduced in biotechnology and biopharmacy industries in relation to genetic manipulation. Despite the rapid growth of these modalities, they must be intelligently designed, addressing the cardiac-specific transgene expression and less side effects. Herein, we conducted a pilot project aiming to design a cardiac-specific hypoxia-inducible expression cassette. Methods: We explored a new approach to design an expression cassette containing cardiac specific enhancer, hypoxia response elements (HRE), cardiac specific promoter, internal ribosome entry site (IRES), and beta globin poly A sequence to elicit specific and inducible expression of the gene of interest. Enhanced green fluorescent protein (eGFP) was sub-cloned by BglII and NotI into the cassette. The specificity and inducible expression of the cassette was determined in both mouse myoblast C2C12 and mammary glandular tumor 4T1 as 'twin' cells. eGFP expression was evaluated by immunofluorescence microscope and flow cytometry at 520 nm emission peak. Results: Our data revealed that the designed expression cassette provided tissue specific and hypoxia inducible (O2<1%) transgene expression. Conclusion: It is suggested that cardiac-specific enhancer combined with cardiac-specific promoter are efficient for myoblast specific gene expression. As well, this is for the first time that HRE are derived from three well known hypoxia-regulated promoters. Therefore, there is no longer need to overlap PCR process for one repeated sequence just in one promoter.

A rare case of complicated pericardial effusion with Elizabethkingia meningoseptica from Iran.

Infections due to Elizabethkingia meningoseptica, a Gram-negative oxidative bacterium are frequently founded in neonatal and immunocompromised individuals. The notable characteristic of this organism is its multi-drug resistance to common antibiotics used for infections caused by Gram-negative bacteria. We report a rare case of complicated pericardial effusion due to E. meningoseptica in a 2-year-old boy, who was admitted with chief complaints of fever and tachypnea (mentioned by his parents) and suffered from a rare lung malignancy (lymphangioleiomyomatosis). He was successfully treated with vancomycin.  E. meningoseptica infection is a rare situation in immunocompetent hosts, and we concluded that this infection was probably originated from device medicine or even hands of healthcare workers.

Synthesis and biological evaluation of some novel diastereoselective benzothiazole ß-lactam conjugates.

Highly diastereoselective synthesis of some novel benzothiazole-substituted ß-lactam hybrids was achieved starting from (benzo[d]thiazol-2-yl)phenol as an available precursor. This is the first time (benzo[d]thiazol-2-yl)phenoxyacetic acid has been used as ketene source in synthesizing monocyclic 2-azetidinones. These compounds were evaluated for their antimicrobial activities against a large panel of Gram-positive and Gram-negative bacterial strains and moderate activities were encountered. Antimalarial data revealed that adding methoxyphenyl or ethoxyphenyl group on the ß-lactam ring makes compounds that are more potent. Moreover, hemolytic activity and mammalian cell toxicity survey of the compounds showed their potential as a medicine.

The enzyme-sensitive release of prodigiosin grafted ß-cyclodextrin and chitosan magnetic nanoparticles as an anticancer drug delivery system: Synthesis, characterization and cytotoxicity studies.

In present investigation, two glucose based smart tumor-targeted drug delivery systems coupled with enzyme-sensitive release strategy are introduced. Magnetic nanoparticles (Fe3O4) were grafted with carboxymethyl chitosan (CS) and ß-cyclodextrin (ß-CD) as carriers. Prodigiosin (PG) was used as the model anti-tumor drug, targeting aggressive tumor cells. The morphology, properties and composition and grafting process were characterized by transmission electron microscope (TEM), Fourier transform infrared spectroscopy (FT-IR), vibration sample magnetometer (VSM), X-ray diffraction (XRD) analysis. The results revealed that the core crystal size of the nanoparticles synthesized were 14.2±2.1 and 9.8±1.4nm for ß-CD and CS-MNPs respectively when measured using TEM; while dynamic light scattering (DLS) gave diameters of 121.1 and 38.2nm. The saturation magnetization (Ms) of bare magnetic nanoparticles is 50.10emucm-3, while modification with ß-CD and CS gave values of 37.48 and 65.01emucm-3, respectively. The anticancer compound, prodigiosin (PG) was loaded into the NPs with an encapsulation efficiency of approximately 81% for the ß-CD-MNPs, and 92% for the CS-MNPs. This translates to a drug loading capacity of 56.17 and 59.17mg/100mg MNPs, respectively. Measurement of in vitro release of prodigiosin from the loaded nanocarriers in the presence of the hydrolytic enzymes, alpha-amylase and chitosanase showed that 58.1 and 44.6% of the drug was released after one-hour of incubation. Cytotoxicity studies of PG-loaded nanocarriers on two cancer cell lines, MCF-7 and HepG2, and on a non-cancerous control, NIH/3T3 cells, revealed that the drug loaded nanoparticles had greater efficacy on the cancer cell lines. The selective index (SI) for free PG on MCF-7 and HepG2 cells was 1.54 and 4.42 respectively. This parameter was reduced for PG-loaded ß-CD-MNPs to 1.27 and 1.85, while the SI for CS-MNPs improved considerably to 7.03 on MCF-7 cells. Complementary studies by fluorescence and confocal microscopy and flow cytometry confirm specific targeting of the nanocarriers to the cancer cells. The results suggest that CS-MNPs have higher potency and are better able to target the prodigiosin toxicity effect on cancerous cells than ß-CD-MNPs.