Asma Sultana Shaik

Magnetic single-walled carbon nanotubes as efficient drug delivery nanocarriers in breast cancer murine model: noninvasive monitoring using diffusion-weighted magnetic resonance imaging as sensitive imaging biomarker.

Purpose Targeting doxorubicin (DOX) by means of single-walled carbon nanotube (SWCNT) nanocarriers may help improve the clinical utility of this highly active therapeutic agent. Active targeting of SWCNTs using tumor-specific antibody and magnetic attraction by tagging the nanotubes with iron oxide nanoparticles can potentially reduce the unnecessary side effects and provide enhanced theranostics. In the current study, the in vitro and in vivo efficacy of DOX-loaded SWCNTs as theranostic nanoprobes was evaluated in a murine breast cancer model. Methods Iron-tagged SWCNTs conjugated with Endoglin/CD105 antibody with or without DOX were synthetized and extensively characterized. Their biocompatibility was assessed in vitro in luciferase (Luc2)-expressing 4T1 (4T1-Luc2) murine breast cancer cells using TiterTACS™ Colorimetric Apoptosis Detection Kit (apoptosis induction), poly (ADP-ribose) polymerase (marker for DNA damage), and thiobarbituric acid-reactive substances (oxidative stress generation) assays, and the efficacy of DOX-loaded SWCNTs was evaluated by measuring the radiance efficiency using bioluminescence imaging (BLI). Tumor progression and growth were monitored after 4T1-Luc2 cells inoculation using noninvasive BLI and magnetic resonance imaging (MRI) before and after subsequent injection of SWCNT complexes actively and magnetically targeted to tumor sites. Results Significant increases in apoptosis, DNA damage, and oxidative stress were induced by DOX-loaded SWCNTs. In addition, a tremendous decrease in bioluminescence was observed in a dose- and time-dependent manner. Noninvasive BLI and MRI revealed successful tumor growth and subsequent attenuation along with metastasis inhibition following DOX-loaded SWCNTs injection. Magnetic tagging of SWCNTs was found to produce significant discrepancies in apparent diffusion coefficient values providing a higher contrast to detect treatment-induced variations as noninvasive imaging biomarker. In addition, it allowed their sensitive noninvasive diagnosis using susceptibility-weighted MRI and their magnetic targeting using an externally applied magnet. Conclusion Enhanced therapeutic efficacy of DOX delivered through antibody-conjugated magnetic SWCNTs was achieved. Further, the superiority of apparent diffusion coefficient measurements using diffusion-weighted MRI was found to be a sensitive imaging biomarker for assessment of treatment-induced changes.

Combination of drug-conjugated SWCNT nanocarriers for efficient therapy of cancer stem cells in a breast cancer animal model

Targeting breast cancer and more specifically cancer stem cell (CSC) subpopulation, responsible for tumor growth, resistance and self-renewal, using combination of therapeutic drugs selectively delivered via biocompatible nanocarriers, provides a novel approach for effective therapy. Here, we propose to evaluate the potential therapeutic efficacy of combining Paclitaxel and Salinomycin drugs actively targeted to both breast cancer and CSCs in xenograft murine model after conjugation with biocompatible CD44 antibody conjugated SWCNTs via hydrazone linker allowing pH-responsive release mechanism near the acidic tumor microenvironment. Both in vitro investigations on MDA-MB-231, sorted CSC negative or CSC positive fractions and in vivo evaluations on tumor-bearing mice using noninvasive bioluminescence and magnetic resonance imaging confirmed the enhanced therapeutic effect of the combined therapy compared to treatment with individual drug-conjugated nanocarriers or free drug suspensions. Thus, confirmed the great promise of the developed SWCNTs drug delivery system for effective breast cancer treatment by targeting and eradicating both whole tumor cells and CSCs populations.

Preferential Macrophage Recruitment and Polarization in LPS-Induced Animal Model for COPD: Noninvasive Tracking Using MRI

Noninvasive imaging of macrophages activity has raised increasing interest for diagnosis of chronic obstructive respiratory diseases (COPD), which make them attractive vehicles to deliver contrast agents for diagnostic or drugs for therapeutic purposes. This study was designed to monitor and evaluate the migration of differently polarized M1 and M2 iron labeled macrophage subsets to the lung of a LPS-induced COPD animal model and to assess their polarization state once they have reached the inflammatory sites in the lung after intravenous injection. Ex vivo polarized bone marrow derived M1 or M2 macrophages were first efficiently and safely labeled with amine-modified PEGylated dextran-coated SPIO nanoparticles and without altering their polarization profile. Their biodistribution in abdominal organs and their homing to the site of inflammation in the lung was tracked for the first time using a free-breathing non-invasive MR imaging protocol on a 4.7T magnet after their intravenous administration. This imaging protocol was optimized to allow both detection of iron labeled macrophages and visualization of inflammation in the lung. M1 and M2 macrophages were successfully detected in the lung starting from 2 hours post injection with no variation in their migration profile. Quantification of cytokines release, analysis of surface membrane expression using flow cytometry and immunohistochemistry investigations confirmed the successful recruitment of injected iron labeled macrophages in the lung of COPD mice and revealed that even with a continuum switch in the polarization profile of M1 and M2 macrophages during the time course of inflammation a balanced number of macrophage subsets predominate.

Preferential magnetic targeting of carbon nanotubes to cancer sites: noninvasive tracking using MRI in a murine breast cancer model

AIM This study evaluated the improvement in magnetic targeting of single-walled carbon nanotubes (SWCNTs) in a 4T1-induced breast cancer murine model and compared their enhanced delivery with active targeted SWCNTs conjugated with a specific antibody for prospective applications as drug-delivery nanocarriers. MATERIALS & METHODS Polyvinylpyrrolidone SWCNTs, loaded with iron oxide nanoparticles to improve their magnetic resonance detection and magnet attraction using an optimized flexible magnet positioned over the tumor site were developed. They were equally conjugated with Endoglin/CD105 antibody for SWCNTs active targeting. A noninvasive MRI protocol was then optimized to allow in vivo imaging of tumor site, sensitive detection of SWCNTs and apparent diffusion coefficient measurements. Special focus was devoted to evaluate the biocompatibility of the used SWCNTs. RESULTS Iron-tagged SWCNTs exhibited very high magnetic resonance r2* relaxivities allowing their sensitive detection using noninvasive MRI and enhanced targeting using the magnet. Biocompatibility evaluations confirmed their safety for animal administration. Both T2* and apparent diffusion coefficient measurements confirmed their enhanced magnetic targeting starting from 2 h postinjection while a lower, but statistically significant enhanced targeting of antibody-conjugated active targeting was observed starting from 24 h postinjection of iron-tagged SWCNT + CD105 samples. CONCLUSION These results demonstrate the efficiency of magnetic targeting to specifically deliver higher load of iron-tagged SWCNTs as novel nanocarriers for cancer theranostics and allow their sensitive detection using noninvasive MRI.

Evaluation of cytotoxicity and genotoxicity of pesticide mixtures on lymphocytes

Abstract The cytotoxicity and genotoxicity of pesticide mixtures viz. endosulfan + chlorpyrifos, chlorpyrifos + profenofos, and endosulfan + profenofos were evaluated on cultured human peripheral blood lymphocytes using assays for cell viability, and genotoxicity using chromosomal aberrations test and comet assay. The LC50 values for cytotoxicity were 3.50 μM, 4.18 μM, and 10.5 μM for profenofos, endosulfan, and chlorpyrifos respectively. When combined in equimolar concentrations, the LC50 values for cytotoxicity were 1.4 μM, 1.8 μM, and 2.0 μM for endosulfan + chlorpyrifos, chlorpyrifos + profenofos, and endosulfan + profenofos, respectively. Higher concentrations of individual pesticides (0.5–4.0 μM) but very low concentrations of pesticide mixtures caused significant DNA damage. Additive index values indicated a synergistic effect of toxicity for endosulfan + chlorpyrifos combination (1.12 TTU). The binary mixture of chlorpyrifos + profenofos showed an additive toxicity (0.46 TTU) while an antagonistic effect was observed for endosulfan + profenofos combination. Synergism could be due to these complementary pesticides simultaneously acting in different ways, magnifying their efficacy, whereas an additive interaction would imply that the chemicals are acting by the same mechanism and at the same target. Analysis of toxicity of pesticide mixtures may serve as important biomarker for occupational and household exposure to pesticides, with different modes of action.

A novel anti-IL4Rα nanoparticle efficiently controls lung inflammation during asthma

Drug resistance and the harmful side effects accompanying the prolonged corticosteroid treatment of chronic pulmonary diseases prompted the development of more specific anti-inflammatory approaches. Several strategies aiming to block IL4Rα, the receptor for a key pro-inflammatory pathway, were investigated. However, their efficiency was limited, mostly due to the systemic or subcutaneous route of administrations. In this paper, we examined the ability of an intranasal treatment with biocompatible nanoparticles targeting IL4Rα to control lung inflammation in ovalbumin (OVA)-sensitized mice. OVA-sensitized mice were treated with anti-IL4Rα-conjugated nanoparticles. The levels of pro-inflammatory cytokines in the lungs and broncho-alveolar lavage fluid (BALF) were determined using a cytokine array assay. The effects of nanoparticle treatment on the activation of lung inflammatory cells and their ability to proliferate and produce cytokines were determined using fluorescence-activated cell sorting (FACS) analysis. Lung inflammation was also monitored using immunohistochemical staining. Treatment with the anti-IL4Rα nanoparticles significantly decreased pro-inflammatory cytokine expression and release in BALF and airway lung tissue in mice. The numbers of lung tissue lymphocytes, neutrophils and eosinophils were also decreased. Interestingly, anti-IL4Rα nanoparticles deactivated CD4 and CD8 T cells in lung tissue and inhibited their ability to produce pro-inflammatory cytokines to a significantly lower level than the treatment with free anti-IL4Rα. Moreover, they induced a sustained low level of lung inflammation for 1 week following the last instillation compared with the treatment with free anti-IL4Rα antibodies. Together, this data suggested that the enhanced tissue penetrability and sustainability of these nanoparticles improved the strength and durability of the immunosuppressive effects of anti-IL4Rα.

Magnetic Targeting and Delivery of Drug-Loaded SWCNTs Theranostic Nanoprobes to Lung Metastasis in Breast Cancer Animal Model: Noninvasive Monitoring Using Magnetic Resonance Imaging.

PurposeIn this study, we aimed to develop novel therapeutic and diagnostic approaches by improving the targeting of doxorubicin-loaded single-walled carbon nanotubes (SWCNTs) to metastatic regions, and monitor their preferential homing and enhanced therapeutic effect using noninvasive free-breathing magnetic resonance imaging (MRI) and bioluminescence imaging.ProceduresHigh-energy flexible magnets were specifically positioned over the metastatic tumor sites in the lungs. SWCNTs biodistribution, tumor progression, and subsequent treatment efficiency were assessed following administration of the magnetically attracted doxorubicin-loaded anti-CD105 conjugated nanocarriers.ResultsThe use of high-energy magnets offered improved theranostic effect of doxorubicin-loaded nanocarriers, by magnetically targeting them towards metastatic tumor sites in the lungs. MRI allowed sensitive monitoring of nanocarriers biodistribution in the abdominal organs, their preferential homing towards the metastatic sites, and their enhanced therapeutic effect.ConclusionsCombination of noninvasive MRI to localize sensitively the tumor sites, with specific positioning of magnets that can enhance the magnetic targeting of nanocarriers, allowed increasing the treatment efficiency.

Blocking Interleukin-4 Receptor α Using Polyethylene Glycol Functionalized Superparamagnetic Iron Oxide Nanocarriers to Inhibit Breast Cancer Cell Proliferation

Purpose The specific targeting of interleukin-4 receptor α (IL4Rα) receptor offers a promising therapeutic approach for inhibition of tumor cell progression in breast cancer patients. In the current study, the in vitro efficacy of superparamagnetic iron oxide nanoparticles conjugated with anti-IL4Rα blocking antibodies (SPION-IL4Rα) via polyethylene glycol polymers was evaluated in 4T1 breast cancer cells. Materials and Methods Cell viability, reactive oxygen species generation, and apoptosis frequency were assessed in vitro in 4T1 cancer cell lines following exposure to SPION-IL4Rα alone or combined with doxorubicin. In addition, immunofluorescence assessments and fluorimetrywere performed to confirm the specific targeting and interaction of the developed nanocarriers with IL4Rα receptors in breast cancer cells. Results Blocking of IL4Rα receptors caused a significant decrease in cell viability and induced apoptosis in 4T1 cells. In addition, combined treatment with SPION-IL4Rα+doxorubicin caused significant increases in cell death, apoptosis, and oxidative stress compared to either SPION-IL4Rα or doxorubicin alone, indicating the enhanced therapeutic efficacy of this combination. The decrease in fluorescence intensity upon immunofluorescence and fluorimetry assays combined with increased viability and decreased apoptosis following the blocking of IL4Rα receptors confirmed the successful binding of the synthesized nanocarriers to the target sites on murine 4T1 breast cancerous cells. Conclusion These results suggest that SPION-IL4Rα nanocarriers might be used for successfulreduction of tumor growth and inhibition of progression of metastasis in vivo.

Colorectal cancer: A review of the genome-wide association studies in the kingdom of Saudi Arabia

Genome-wise association studies (GWAS) identify risk variants and modifiers that can influence the pathophysiological processes involved in colorectal cancer (CRC) and thus are important to detect associations between disease phenotypes. Our literature review, performed as per PRISMA statement indicates a significant lack of GWAS functional studies in Saudi Arabia. Therefore, studies on sequencing and mapping are needed to identify gene variants that play a role in the pathophysiology of CRC in this specific population. Because it is not apt to generalize disease associations found in other racial and/or ethnic groups to the Arabic or Middle Eastern population, it is very important to conduct GWAS taking into account multiple ethnicities in this region. In addition, linkage studies and case–control studies that include the various confounding and epigenetic factors are needed for appropriate diagnosis of CRC. We recommend that studies in this region be conducted to understand the role of gene–environment interactions across the various ethnic groups, stages of cancer, tumor type, clinical variables, and the population risk to CRC.