Abhishek Gupta

Bio: Abhishek Gupta is an academic researcher from University of Sydney. The author has contributed to research in topics: Diffusion (business) & Photon upconversion. The author has an hindex of 8, co-authored 23 publications receiving 251 citations. Previous affiliations of Abhishek Gupta include Commonwealth Scientific and Industrial Research Organisation & University of Western Sydney.

Applications for Transition-Metal Chemistry in Contrast-Enhanced Magnetic Resonance Imaging

Abstract: Contrast-enhanced magnetic resonance imaging (MRI) is an indispensable tool for diagnostic medicine. However, safety concerns related to gadolinium in commercial MRI contrast agents have emerged in recent years. For patients suffering from severe renal impairment, there is an important unmet medical need to perform contrast-enhanced MRI without gadolinium. There are also concerns over the long-term effects of retained gadolinium within the general patient population. Demand for gadolinium-free MRI contrast agents is driving a new wave of inorganic chemistry innovation as researchers explore paramagnetic transition-metal complexes as potential alternatives. Furthermore, advances in personalized care making use of molecular-level information have motivated inorganic chemists to develop MRI contrast agents that can detect pathologic changes at the molecular level. Recent studies have highlighted how reaction-based modulation of transition-metal paramagnetism offers a highly effective mechanism to achieve MRI contrast enhancement that is specific to biochemical processes. This Viewpoint highlights how recent advances in transition-metal chemistry are leading the way for a new generation of MRI contrast agents.

Photochemical tissue bonding with chitosan adhesive films

Abstract: Background: Photochemical tissue bonding (PTB) is a promising sutureless technique for tissue repair. PTB is often achieved by applying a solution of rose bengal (RB) between two tissue edges, which are irradiated by a green laser to crosslink collagen fibers with minimal heat production. In this study, RB has been incorporated in chitosan films to create a novel tissue adhesive that is laser-activated. Methods: Adhesive films, based on chitosan and containing ~0.1 wt% RB were manufactured and bonded to calf intestine by a solid state laser (l = 532 nm, Fluence~110 J/cm 2 , spot size~0.5 cm). A single-column tensiometer, interfaced with a personal computer, tested the bonding strength. K-type thermocouples recorded the temperature (T) at the adhesive-tissue interface during laser irradiation. Human fibroblasts were also seeded on the adhesive and cultured for 48 hours to assess cell growth. Results: The RB-chitosan adhesive bonded firmly to the intestine with adhesion strength of 15 ± 2 kPa, (n = 31). The adhesion strength dropped to 0.5 ± 0.1 (n = 8) kPa when the laser was not applied to the adhesive. The average temperature of the adhesive increased from 26°C to 32°C during laser exposure. Fibroblasts grew confluent on the adhesive without morphological changes. Conclusion: A new biocompatible chitosan adhesive has been developed that bonds photochemically to tissue with minimal temperature increase.

Delivery of polymeric nanostars for molecular imaging and endoradiotherapy through the enhanced permeability and retention (EPR) effect.

Abstract: Expression levels of biomarkers are generally unknown at initial diagnosis. The development of theranostic probes that do not rely on biomarker availability would expand therapy options for cancer patients, improve patient selection for nanomedicine and facilitate treatment of inoperable patients or patients with acquired therapy resistance. Herein, we report the development of star polymers, also known as nanostars, that allow for molecular imaging and/or endoradiotherapy based on passive targeting via the enhanced permeability and retention (EPR) effect.Methods: We synthesised a star copolymer, consisting of 7-8 centre-cross-linked arms that were modified with Gd3+ for magnetic resonance imaging (MRI), and functionalised either with Zr-89 for in vivo quantification and positron emission tomography (PET) imaging, or with Lu-177 for endoradiotherapy. H-1 longitudinal relaxivities were determined over a continuum of magnetic field strengths ranging from 0.24 mT - 0.94 T at 37 degrees C (nuclear magnetic relaxation dispersion (NMRD) profile) and T-1-weighted MRI contrast enhancement was visualized at 3 T and 7 T. PET imaging and ex vivo biodistribution studies were performed in mice bearing tumours with high EPR (CT26) or low EPR (BxPC3) characteristics. Therapy studies were performed in mice with high EPR tumours and mean absorbed organ doses were estimated for a standard human model.Results: The star copolymer with Gd3+ displayed a significantly superior contrast enhancement ability (T-1 = 0.60 s) compared to the standard clinical contrast agent Gadovist (T-1 = 1.0 s). Quantification of tumour accumulation using the radiolabelled nanostars in tumour-bearing mice demonstrated an exceptionally high uptake in tumours with high EPR characteristics (14.8 - 21.7 %ID/g). Uptake of the star polymers in tumours with low EPR characteristics was significantly lower (P<0.001), suggesting passive tumour accumulation of the nanostars via the EPR effect. Survival of mice treated with high dose Lu-177-labelled star polymers was significantly higher than survival of mice treated with lower therapy doses or control mice (P=0.001), demonstrating the utility of the Lu-177-labelled star polymers as platforms for endoradiotherapy.Conclusion: Our work highlights the potential of star polymers as probes for the molecular imaging of cancer tissue or for the passive delivery of radionuclides for endoradiotherapy. Their high functionalisability and high tumour accumulation emphasises their versatility as powerful tools for nanomedicine.

Proton MR CSF analysis and a new software as predictors for the differentiation of meningitis in children

Abstract: This article describes proton MR spectroscopic analysis of cerebrospinal fluid of 167 children suffering from meningitis and 24 control cases. Quantification of 12 well-separated and commonly observed cerebrospinal fluid metabolites viz., beta-hydroxybutyrate, lactate, alanine, acetate, acetone, acetoacetate, pyruvate, glutamine, citrate, creatine/creatinine, glucose (total) and urea was carried out using Bruker's NMRQUANT software with respect to a known concentration of sodium-3-(trimethylsilyl)-2,2,3,3-d4-propionate (TSP), serving as an external reference. The assignment of urea in CSF is reported for the first time by NMR. The presence of cyclopropane, observed for the first time in tuberculous meningitis overall in 85.1% of cases, acts as a finger-print marker for the differential diagnosis. Multivariate discriminant function analysis was carried out for the proton MR-detected metabolite information and the clinical symptoms data of the meningitis and control cases to find the important descriptors for classification, followed by a re-validation of the entire database. It was found that the control could be differentiated from the disease group with a success rate of 96.4%, followed by the differential diagnosis of tuberculous meningitis with a corresponding value of 77.2%. Excluding the presence of cyclopropane, bacterial meningitis could be classified 84.4% correct and viral meningitis with a rate of 83.3%. It is proposed that the NMR spectroscopic information, along with other routine clinical features, may serve as an additional diagnostic tool for the differential diagnosis of meningitis in children.

Nanoassemblies of Gd-DTPA-monooleyl and glycerol monooleate amphiphiles as potential MRI contrast agents.

Abstract: Self-assembly of lipid-based amphiphiles into various supramolecular nanostructured particles has been used in creating novel nanomaterials with diverse applications in drug delivery and diagnostic imaging. Here we report on Gd(III) chelated DTPA amphiphiles with an oleyl chain (Gd–DTPA–MO) incorporated within the self-assembly matrix of glycerol monooleate (GMO), an inverse cubic phase forming system, at varying compositions. The dispersed colloidal nanoassemblies were explored for their potential as magnetic resonance imaging (MRI) contrast agents. We investigated the homogeneity of the mixed amphiphiles in bulk phases by differential scanning calorimetry (DSC) and their lyotropic phase behaviour by synchrotron small angle X-ray scattering (SAXS). The liquid crystalline nanostructures, morphology and the size distribution of the nanoassemblies were studied by synchrotron SAXS, cryogenic transmission electron microscopy (cryo-TEM) and dynamic light scattering (DLS). SAXS and cryo-TEM results revealed the formation of inverse cubosomes in dispersions with ≤1 mol% of Gd–DTPA–MO, and liposomal and rod-shaped micellar aggregates with >1 mol%. The stability of cubosomal nanoassemblies was assessed in the presence of fetal bovine serum, showing minimal effect on their nanostructures. In vitro relaxivity studies were performed at four different magnetic field strengths (0.54, 7.05, 9.40 and 11.74 T). All the colloidal dispersions displayed enhanced longitudinal relaxivities per Gd over Magnevist, a commercially available contrast agent, at both low and high magnetic field strengths. In addition, cubosomes with 3D-periodic interior nanostructures, extensive water channels and high interfacial surface area, showed promise as high field contrast agents. These stable colloidal particles also have potential to be used as combined delivery matrices for diagnostics and therapeutics (theranostics).

Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry

Abstract: Metabolism has an essential role in biological systems. Identification and quantitation of the compounds in the metabolome is defined as metabolic profiling, and it is applied to define metabolic changes related to genetic differences, environmental influences and disease or drug perturbations. Chromatography-mass spectrometry (MS) platforms are frequently used to provide the sensitive and reproducible detection of hundreds to thousands of metabolites in a single biofluid or tissue sample. Here we describe the experimental workflow for long-term and large-scale metabolomic studies involving thousands of human samples with data acquired for multiple analytical batches over many months and years. Protocols for serum- and plasma-based metabolic profiling applying gas chromatography-MS (GC-MS) and ultraperformance liquid chromatography-MS (UPLC-MS) are described. These include biofluid collection, sample preparation, data acquisition, data pre-processing and quality assurance. Methods for quality control-based robust LOESS signal correction to provide signal correction and integration of data from multiple analytical batches are also described.

Systems level studies of mammalian metabolomes: the roles of mass spectrometry and nuclear magnetic resonance spectroscopy

Abstract: The study of biological systems in a holistic manner (systems biology) is increasingly being viewed as a necessity to provide qualitative and quantitative descriptions of the emergent properties of the complete system. Systems biology performs studies focussed on the complex interactions of system components; emphasising the whole system rather than the individual parts. Many perturbations to mammalian systems (diet, disease, drugs) are multi-factorial and the study of small parts of the system is insufficient to understand the complete phenotypic changes induced. Metabolomics is one functional level tool being employed to investigate the complex interactions of metabolites with other metabolites (metabolism) but also the regulatory role metabolites provide through interaction with genes, transcripts and proteins (e.g. allosteric regulation). Technological developments are the driving force behind advances in scientific knowledge. Recent advances in the two analytical platforms of mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy have driven forward the discipline of metabolomics. In this critical review, an introduction to metabolites, metabolomes, metabolomics and the role of MS and NMR spectroscopy will be provided. The applications of metabolomics in mammalian systems biology for the study of the health–disease continuum, drug efficacy and toxicity and dietary effects on mammalian health will be reviewed. The current limitations and future goals of metabolomics in systems biology will also be discussed (374 references).

Magnetic Resonance Imaging Physical Principles And Sequence Design

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The EPR effect and beyond: Strategies to improve tumor targeting and cancer nanomedicine treatment efficacy.

Abstract: Following its discovery more than 30 years ago, the enhanced permeability and retention (EPR) effect has become the guiding principle for cancer nanomedicine development. Over the years, the tumor-targeted drug delivery field has made significant progress, as evidenced by the approval of several nanomedicinal anticancer drugs. Recently, however, the existence and the extent of the EPR effect - particularly in patients - have become the focus of intense debate. This is partially due to the disbalance between the huge number of preclinical cancer nanomedicine papers and relatively small number of cancer nanomedicine drug products reaching the market. To move the field forward, we have to improve our understanding of the EPR effect, of its cancer type-specific pathophysiology, of nanomedicine interactions with the heterogeneous tumor microenvironment, of nanomedicine behavior in the body, and of translational aspects that specifically complicate nanomedicinal drug development. In this virtual special issue, 24 research articles and reviews discussing different aspects of the EPR effect and cancer nanomedicine are collected, together providing a comprehensive and complete overview of the current state-of-the-art and future directions in tumor-targeted drug delivery.