60 research outputs found
Exploring the fundamentals of nanomaterials design for biomolecular sensing and cancer imaging
No full textSubmission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-12-01The student, Subhendu Pandit, accepted the attached license on 2022-08-15 at 22:15.The student, Subhendu Pandit, submitted this Dissertation for approval on 2022-08-15 at 22:47.This Dissertation was approved for publication on 2022-08-23 at 16:05.DSpace SAF Submission Ingestion Package generated from Vireo submission #17887 on 2023-04-12 at 11:33:57Over the last few decades despite significant improvements in chemotherapy, radiation therapy, and other traditional drug-based therapies for cancer treatment, surgical resection is still one of the best ways of removing solid cancer tumors. If a cancer tumor can be precisely resected, without leaving any positive cancer margin behind and without unnecessary removal of healthy tissues, it can lead to remission and good quality of life for the patient. Currently, in operating rooms, surgeons primarily rely on their visual and tactile senses to resect a cancer tumor. This often leads to imprecise resection, especially in irregular tumors and non-palpable tumors, leading to multiple follow-up surgeries and often relapse of cancer. Pre-operative imaging modalities like CT/MRI/PET images provide rough guidance for the surgeons to locate cancer tumors but due to deformation of tissues, real-time intra-operative image-guidance guidance is required to perform precision surgeries. Optical fluorescence imaging in the near-infrared window with appropriate contrast agents and imaging devices could be used for real-time image guidance for cancer surgery. Optical fluorescence-based molecular imaging holds the promise to bridge pre-operative imaging with intra-operative reality.
Currently, there are only three FDA-approved near-infrared (NIR) fluorescent agents, indocyanine green, methylene blue, and OTL38. Indocyanine green and methylene blue are blood pool agents, which have been repurposed to be used in image-guided surgery because of their FDA approval. OTL38, on the other hand, is a folate-receptor-targeted NIR dye developed specifically for image-guided surgery applications. To push the forefront of optical fluorescence image-guided surgery, new biocompatible NIR-fluorescent contrast agents with desired pharmacokinetic properties need to be developed specifically for image-guided surgery. Here we have explored three nanomaterials, carbon dots, semiconductor polymeric nanoparticles, and albumin-based probes, for their potential application in image-guided surgery.
Carbon dots (CDs) are a class of fluorescent nanomaterials that are biocompatible, biodegradable, easy to synthesize, and have bright and stable fluorescence. Most importantly, carbon dots contain no heavy metal, which is a long-term toxicity concern for most inorganic fluorescent nanoparticles. If CDs could be tuned to have NIR emission and can be effectively targeted to be delivered to cancer tumors, CDs could be an excellent contrast agent for image-guided surgery. However, the emission mechanism and electronic structure of CDs are poorly understood. In this thesis, we have explored various surface modifications of CDs to tune their optical properties and understand how those alter their emission behavior. We have shown that crosslinking the surface carboxylic acids of CDs with bisamines leads to a blue shift of fluorescence emission and changes their cellular uptake properties. We have also studied how surface modification of CDs with electron-donating or electron-accepting groups changes their photophysical properties in bulk and at the single-particle level. We also observed a probable near-infrared emitting aggregated state in CDs at very high concentrations and tried to capture the aggregated state with polymeric encapsulation and with lipid nanoparticles but both the approaches did not work. Finally, we have conducted scanning tunneling microscopy (STM) studies on phenylenediamine-derived multi-color CDs to understand the origin of their multi-color emission. We have imaged the ground state electronic band structure of these materials at a sub-single-particle resolution to understand their possible fluorescence mechanism. All these studies provide us with insight into the fluorescence mechanism of CDs to tune them for various biomedical and energy applications. The fluorescence emission of CDs is heavily influenced by the chemical environment around it. The surface defects in CDs are believed to be the main emission center of CDs, and the electronic structure of those groups is influenced by the pH, solvent, and other external factors. CDs change their emission behavior with non-covalent interactions (electrostatic, π-π, H-bonding, hydrophobic interaction, etc.) with the surrounding environment. We used this property of CDs to make multiple array-based sensors for detecting proteins and metal ions. We developed a surface-functionalized CD-array for sensing proteins in the buffer and human serum. We also developed another array-based sensor with the crosslinked CDs to detect proteins. We showed metal ion sensing with the crosslinked CD array and with an associated CD structure array.
Next, we have explored a nanoformulation of semiconductor polymeric nanoparticles (SPNs) for their potential use in image-guided surgery. SPNs have emerged as a promising class of nanoparticles that are comprised of optically active semiconducting polymers (SPs). As SPs are organic and biologically inert, SPNs essentially circumvent the issue of heavy metal ion-induced toxicity to living organisms and thereby possess good biocompatibility. We developed a nanoformulation of fluorescent SPNs by coating them with targeting ligand-modified red blood cell membranes (RBCm). With different ligand modifications on RBCm coating (folate and cRGD insertions) we could target different receptors, folate receptors and αVβ3 integrins, on cancer cells. With our biomimetic coating, we could achieve enhanced blood circulation, precise tumor targeting, and reduced macrophage uptake. We also chose two SPNs for our nanoformulations in such a way that both of them can be excited with a single laser excitation but the fluorescence emission signal could be separated. Being able to target two biomarkers together, with multiplexed imaging agents, helps us better image heterogeneous tumors and leads to better resection. The single laser excitation helps further reduce the instrumentation clutter in operating rooms. These nanoformulations provide us with a platform to develop biomimetic nanoparticles, particularly for image-guided surgery applications.
Optical fluorescence guidance has been the primary modality for intra-operative imaging, but it suffers from the problem of poor penetration depth. Radio guidance, together with optical fluorescence guidance can address the penetration depth problem of unimodal optical probes. Here we have developed an albumin-based probe for bimodal fluorescence and PET imaging. We have done the synthesis and characterization of the albumin-based probes to understand how albumin can be modified to incorporate two imaging modalities together. We have looked at the cellular uptake of the probes and their in vivo biodistribution to determine the feasibility of clinical translation. The PET images reveal that, unlike the unimodal probes, our bimodal probe gets heavily stuck in the liver like most other nanoparticles and raises the long-term toxicity problem. Our bimodal albumin-based probes could still be useful for IGS because of their ability to target gp60 proteins to actively transcytose into cancer tumors but that needs further careful evaluation for conclusive evidence.
In summary, we have studied CDs, biomimetic SPNs, and albumin-based fluorescence-PET probes to determine their potential in clinical translation as an IGS probe. For CDs, we have done mainly fundamental studies to understand their emission properties to be able to eventually tune CDs to have NIR emission for IGS applications. We have shown that we could build array-based sensors with surface-functionalized CDs for biomolecular detection. For biomimetic SPNs, we have done in vitro and in vivo studies to show their enhanced blood circulation, precise tumor targeting, reduced macrophage uptake, and multiplexing ability for targeting multiple biomarkers at the same time for potential application in IGS. We have also developed an albumin-based bi-modal probe for a fluorescence-PET signal for radio guidance along with fluorescence guidance for IGS
Atlanto-occipital fusion: A case report
No full textThe atlas is the first cervical vertebra. In the history of anatomy, due to its primary function of supporting the skull, it has been innumerably compared with Atlas the Greek God, who holds the globe of the earth on his shoulders. This vertebra is devoid of a body and has two prominent lateral masses bearing a pair of superior concave facets and inferior smooth facets each. Atlanto-occipital fusion may be unilateral or bilateral, complete or incomplete and symptomatic or asymptomatic. In our, case atlanto-occipital fusion was observed in the skull of a male cadaver. Our study will be of significance to clinicians in the specialties of radiodiagnosis, orthopedics, neurosurgery and anesthesiology. Because of a lack of knowledge of developmental malformation in the craniocervical region, sudden death can occur during clinical manipulation. Head and neck surgeons must keep in mind that such anomaly can exist without any prior symptoms. The specimen seen represents a case of congenital fusion. The articular processes of the specimen are fused between the occipital and the atlas bones. Atlanto-occipital fusion decreases the diameter of the foramen magnum and produce neurovascular symptoms
Environmental regulation and development : a cross-country empirical analysis
No full textThe authors develop comparative indices of environmental policy and performance for 31 countries using a quantified analysis of reports prepared for the United Nations Conference on Environmental and Development. In cross-country regressions, they find a very strong, continuous association between their indicators and national income per capita, particularly when adjusted for purchasing power parity. Their results suggest a characteristic progression in development. Poor agrarian economies focus first on natural resource protection. With increased urbanization and industrialization, countries move from initial regulation of water pollution to air pollution control. The authors highlight the importance of institutional development. Environmental regulation is more advanced in developing countries with relatively secure property rights, effective legal and judicial systems, and efficient public administration.Public Health Promotion,Environmental Economics&Policies,Health Economics&Finance,Agricultural Research,Economic Theory&Research,Environmental Economics&Policies,Health Economics&Finance,Agricultural Research,Economic Theory&Research,Environmental Governance
Balloon pulmonary valvotomy – Not just a simple balloon dilatation
No full textAbstractBalloon pulmonary valvotomy is the preferred mode of treatment in patients with isolated pulmonary valvar stenosis and has shown good long term results. It is generally considered a safe procedure with few complications. There have been however, case reports of potentially fatal acute severe pulmonary edema occurring after the procedure in some patients. The cause of this complication and its pathophysiology is still not clear. Its occurrence is also infrequent with less than 5 cases reported till now. We report a case of pulmonary valvar stenosis which developed acute severe refractory pulmonary edema immediately after balloon pulmonary valvotomy
Functionalized Two-Dimensional MoS<sub>2</sub> with Tunable Charges for Selective Enzyme Inhibition
No full textRecent advances in
the synthesis and functionalization of two-dimensional
(2D) nanomaterials have allowed us to explore their interaction with
biological systems. 2D nanomaterials, owing to their unique layered
structure and a high surface-to-volume ratio, are very promising systems
for various biological applications. Transition metal dichalcogenides
(TMDs) are a unique class of 2D nanomaterials known for their easy
surface functionalization using thiol ligands. Interactions of functionalized
MoS2, a TMD, with different proteins are worth exploring
as that might give us an overall insight about the interaction of
these materials with bio-macromolecules. Here, we have chemically
exfoliated MoS2 and functionalized it with surface groups
having different charges (negative, neutral, positive, and zwitterionic).
Interaction of these functionalized MoS2 with two model
proteins, chymotrypsin (ChT) and β-galactosidase (β-gal),
were explored. Positively charged MoS2 inhibited the enzymatic
activity of β-gal, whereas the activity of ChT was inhibited
by negatively charged MoS2. Polyethylene glycol-functionalized
neutral MoS2 did not affect any of the proteins, but the
zwitterionic ligand-functionalized MoS2 inhibits ChT and
causes hyperactivity in β-gal. The nature of the inhibition
was found to be noncompetitive. We also studied the changes in the
secondary structure of proteins upon inhibition to assess their biocompatibility.
In brief, we have explored interactions between differently functionalized
MoS2 nanomaterials and two model proteins, ChT and β-gal,
as a proof of concept study toward the future development of 2D material-based
enzyme inhibitors and for their other biological applications
Graphene Oxide as a Carbocatalyst for a Diels-Alder Reaction in an Aqueous Medium
No full textThe Diels-Alder (DA) reaction, a 4+2] cycloaddition reaction, is highly important in synthetic organic chemistry and is frequently used in the synthesis of natural products containing six-membered rings. Herein, we report an efficient protocol for the DA reaction between 9-hydroxymethylanthracene and N-substituted maleimides using two-dimensional graphene oxide (GO) as a heterogeneous carbocatalyst in an aqueous medium at room temperature. High yields, a wide substrate scope, low temperature, excellent functional group tolerance, atom economy, and water as a green solvent are noteworthy features of this protocol. The heterogeneous GO catalyst can be easily recovered and used multiple times without any significant loss in catalytic activity
Abstract LB-317: Identification of a novel preclinical candidate for CDK7 inhibition
No full textAbstract
Cyclin-dependent kinase 7 (CDK7) is an important constituent of the cellular transcriptional machinery, where it phosphorylates the C-terminal domain (CTD) of RNAP polymerase II (RNAPII). Because many tumor types are critically dependent on transcription for maintenance of their oncogenic state, pharmacological modulation of CDK7 kinase activity is considered as an approach to treat cancer. Multiple series of covalent CDK7 inhibitors were identified by iterative medicinal chemistry efforts and SAR based approach. These compounds were optimized towards attaining good physicochemical properties, high potency, good selectivity and desirable pharmacokinetic profile to achieve anti-tumor activity. We have now identified a pre-clinical candidate AU-BGB-002 which is highly potent in inhibiting CDK7 in biochemical as well as cellular assays while fully efficiently engaging the target. In a panel of kinases, AU-BGB-002 shows selectivity for CDK7. A panel of cell lines derived from a diverse set of indications are sensitive to AU-BGB-002. AU-BGB-002 exhibits excellent drug-like characteristics including solubility, permeability, metabolic stability and good oral bioavailability. When tested in a xenograft model, AU-BGB-002 treatment resulted in dose dependent tumor growth inhibition in AML xenograft model with tumor stasis at a dose of 10 mg/kg. Potent inhibiton of tumor growth was accompanied by complete target engagement and suppression of pS5RNAPII RNAPolII Ser5 phosphorylation in a parallel PK-PD study. Efficacy studies in additional xenograft models, advanced DMPK and toxicity studies are ongoing for this compound. In summary, we have identified a novel and selective CDK7 covalent inhibitor candidate with desirable drug-like properties that shows excellent efficacy in an AML xenograft model. Findings presented here support further development of AU-BGB-002 for the treatment of cancer.
Citation Format: Leena K. Satyam, Ramulu Poddutoori, Subhendu Mukherjee, Sivapriya Marappan, Sreevalsam Gopinath, Aravind Basavaraju, Lakshmi Narayana Kaza, Manoj Kumar Pothuganti, Shilpa Nayak, Nandish C, Amith A, Ravindra MV, Dabbeeru Madhu Babu, Nagaraju A, Suraj Tgore, Thomas Antony, Chetan Pandit, Murali Ramachandra, Shekar Chelur, Girish Daginakatte, Susanta Samajdar. Identification of a novel preclinical candidate for CDK7 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-317. doi:10.1158/1538-7445.AM2017-LB-317</jats:p
2D-MoS<sub>2</sub>‑Based β‑Lactamase Inhibitor for Combination Therapy against Drug-Resistant Bacteria
No full textDespite the remarkable
improvement in modern medicine, the ever-increasing
abundance of antibiotic-resistant microorganisms remains a catastrophic
threat to global health care. β-Lactamase is playing one of
the major roles in antibiotic resistance by making the conventional
antibacterial agents abortive by destroying their lactam ring. The
combination therapy of traditional antibiotics along with β-lactamase
inhibitors is a potential solution to this problem. In this work,
we have screened various functionalized two-dimensional molybdenum
disulfide (2D-MoS2) nanomaterials as enzyme inhibitors
that effectively bind with β-lactamase enzyme and reveal competitive
inhibition. Among these, carboxylate-functionalized negatively charged
2D-MoS2 is the most potent inhibitor, and in vitro combinatorial application of this with conventional antibiotics
has been able to remarkably suppress relevant drug-resistant bacterial
growth rate. This study will help to further explore different surface-functionalized
2D nanomaterials with improved β-lactamase inhibition to fight
against multidrug-resistant bacterial infections
Paravalvular leak closure with two large size devices
No full textAbstractParavalvular leaks (PVL) after valve replacement surgeries are not uncommon. A significant number of these patients need some form of intervention as they commonly present with heart failure or severe hemolysis. Surgical correction is associated with high mortality and morbidity. Device closure of PVLs has been found to have good results. Since there are no devices designed specifically for PVL closure, large PVL closure is difficult. Occasional larger PVLs have been closed with a combination of a device and smaller coils. We present here a case of very large sized mitral PVL, in a patient with high risk for surgery, which was closed with two large size devices
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