Publications by authors named "Sanjay K Jain"

173 Publications

I-Iodo-DPA-713 Positron Emission Tomography in a Hamster Model of SARS-CoV-2 Infection.

Mol Imaging Biol 2021 Aug 23. Epub 2021 Aug 23.

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Purpose: Molecular imaging has provided unparalleled opportunities to monitor disease processes, although tools for evaluating infection remain limited. Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by lung injury that we sought to model. Activated macrophages/phagocytes have an important role in lung injury, which is responsible for subsequent respiratory failure and death. We performed pulmonary PET/CT with I-iodo-DPA-713, a low-molecular-weight pyrazolopyrimidine ligand selectively trapped by activated macrophages cells, to evaluate the local immune response in a hamster model of SARS-CoV-2 infection.

Procedures: Pulmonary I-iodo-DPA-713 PET/CT was performed in SARS-CoV-2-infected golden Syrian hamsters. CT images were quantified using a custom-built lung segmentation tool. Studies with DPA-713-IRDye680LT and a fluorescent analog of DPA-713 as well as histopathology and flow cytometry were performed on post-mortem tissues.

Results: Infected hamsters were imaged at the peak of inflammatory lung disease (7 days post-infection). Quantitative CT analysis was successful for all scans and demonstrated worse pulmonary disease in male versus female animals (P < 0.01). Increased I-iodo-DPA-713 PET activity co-localized with the pneumonic lesions. Additionally, higher pulmonary I-iodo-DPA-713 PET activity was noted in male versus female hamsters (P = 0.02). DPA-713-IRDye680LT also localized to the pneumonic lesions. Flow cytometry demonstrated a higher percentage of myeloid and CD11b + cells (macrophages, phagocytes) in male versus female lung tissues (P = 0.02).

Conclusion: I-Iodo-DPA-713 accumulates within pneumonic lesions in a hamster model of SARS-CoV-2 infection. As a novel molecular imaging tool, I-Iodo-DPA-713 PET could serve as a noninvasive, clinically translatable approach to monitor SARS-CoV-2-associated pulmonary inflammation and expedite the development of novel therapeutics for COVID-19.
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http://dx.doi.org/10.1007/s11307-021-01638-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381721PMC
August 2021

Hydrological modelling of a snow/glacier-fed western Himalayan basin to simulate the current and future streamflows under changing climate scenarios.

Sci Total Environ 2021 Nov 5;795:148871. Epub 2021 Jul 5.

Department of Water Resources Development and Management, Indian Institute of Technology, Roorkee-247667, India. Electronic address:

Himalayan rivers are the paramount source of water supply to millions of people in northern India for drinking, irrigation and hydropower generation. Several researches reported that the hydrological regime of these Himalayan rivers is vulnerable to climate change. In order to understand the hydrologic response of their headwaters and examine the climate change impacts on streamflow, a hydrological modelling study is carried out in the upper part of the Satluj river basin in western Himalaya by using a temperature index based SWAT (Soil Water Assessment Tool) model. The model performed well for both calibration (years 1986-2000) and validation (2001-2005) periods against the observed daily streamflow at Rampur (R ≈ 0.9 and NSE ≥ 0.85). The study reveals that having a larger snow covered area, the snowmelt runoff is the major contributor to the Satluj river discharge at Rampur that comes out to be about 68-71% of the average annual water yield of about 600 mm. The actual evapotranspiration comes out to be about 14% of precipitation. The water yield of the basin is about 50% of the precipitation, for which the major part is generated in early summer. Further, to study the climate change impact on future streamflow, the downscaled data of CORDEX CCSM4 under two Representative Concentration Pathways (RCP4.5 and RCP8.5) scenarios are used. The bias correction is applied at point level to remove biases from future time series of downscaled data and subsequently loaded into the SWAT model to simulate the future streamflows at the end of the century. The future climate variability in terms of precipitation and temperature exhibited that the climate in the region would become wetter and warmer. A 14% to 21% of increase in annual precipitation is predicted towards the end of the century from the current average annual precipitation of about 420 mm under RCP4.5 and RCP8.5, respectively. Similar to precipitation, the temperature will also be increased by 2.18 °C to 5.71 °C (in both the RCPs) than the current temperature values. The changed climate conditions in future are transformed into the possible range of stream flows using the SWAT model and found that the future climate would increase the streamflow by over 11%-19% at the end of the century under RCP4.5 and RCP8.5 scenarios, respectively. The outcome of this study can be used to develop the suitable strategies for sustainable water management in the region.
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http://dx.doi.org/10.1016/j.scitotenv.2021.148871DOI Listing
November 2021

Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model.

mBio 2021 08 13;12(4):e0097421. Epub 2021 Jul 13.

W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

In the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more severe outcomes are reported in males than in females, including hospitalizations and deaths. Animal models can provide an opportunity to mechanistically interrogate causes of sex differences in the pathogenesis of SARS-CoV-2. Adult male and female golden Syrian hamsters (8 to 10 weeks of age) were inoculated intranasally with 10 50% tissue culture infective dose (TCID) of SARS-CoV-2/USA-WA1/2020 and euthanized at several time points during the acute (i.e., virus actively replicating) and recovery (i.e., after the infectious virus has been cleared) phases of infection. There was no mortality, but infected male hamsters experienced greater morbidity, losing a greater percentage of body mass, developed more extensive pneumonia as noted on chest computed tomography, and recovered more slowly than females. Treatment of male hamsters with estradiol did not alter pulmonary damage. Virus titers in respiratory tissues, including nasal turbinates, trachea, and lungs, and pulmonary cytokine concentrations, including interferon-β (IFN-β) and tumor necrosis factor-α (TNF-α), were comparable between the sexes. However, during the recovery phase of infection, females mounted 2-fold greater IgM, IgG, and IgA responses against the receptor-binding domain of the spike protein (S-RBD) in both plasma and respiratory tissues. Female hamsters also had significantly greater IgG antibodies against whole-inactivated SARS-CoV-2 and mutant S-RBDs as well as virus-neutralizing antibodies in plasma. The development of an animal model to study COVID-19 sex differences will allow for a greater mechanistic understanding of the SARS-CoV-2-associated sex differences seen in the human population. Men experience more severe outcomes from coronavirus disease 2019 (COVID-19) than women. Golden Syrian hamsters were used to explore sex differences in the pathogenesis of a human isolate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After inoculation, male hamsters experienced greater sickness, developed more severe lung pathology, and recovered more slowly than females. Sex differences in disease could not be reversed by estradiol treatment in males and were not explained by either virus replication kinetics or the concentrations of inflammatory cytokines in the lungs. During the recovery period, antiviral antibody responses in the respiratory tract and plasma, including to newly emerging SARS-CoV-2 variants, were greater in female than in male hamsters. Greater lung pathology during the acute phase combined with lower antiviral antibody responses during the recovery phase of infection in males than in females illustrate the utility of golden Syrian hamsters as a model to explore sex differences in the pathogenesis of SARS-CoV-2 and vaccine-induced immunity and protection.
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http://dx.doi.org/10.1128/mBio.00974-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406232PMC
August 2021

Chemiluminescent Protease Probe for Rapid, Sensitive, and Inexpensive Detection of Live .

ACS Cent Sci 2021 May 14;7(5):803-814. Epub 2021 Apr 14.

Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, United States.

Tuberculosis (TB) is a top-ten cause of death worldwide. Successful treatment is often limited by insufficient diagnostic capabilities, especially at the point of care in low-resource settings. The ideal diagnostic must be fast, be cheap, and require minimal clinical resources while providing high sensitivity, selectivity, and the ability to differentiate live from dead bacteria. We describe here the development of a fast, luminescent, and affordable sensor of Hip1 (FLASH) for detecting and monitoring drug susceptibility of (). FLASH is a selective chemiluminescent substrate for the protease Hip1 that, when processed, produces visible light that can be measured with a high signal-to-noise ratio using inexpensive sensors. FLASH is sensitive to fmol of recombinant Hip1 enzyme and can detect as few as thousands of cells in culture or in human sputum samples within minutes. The probe is highly selective for compared to other nontuberculous mycobacteria and can distinguish live from dead cells. Importantly, FLASH can be used to measure antibiotic killing of in culture with greatly accelerated timelines compared to traditional protocols. Overall, FLASH has the potential to enhance both TB diagnostics and drug resistance monitoring in resource-limited settings.
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http://dx.doi.org/10.1021/acscentsci.0c01345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161474PMC
May 2021

Rapid detection of SARS-CoV-2 using a radiolabeled antibody.

Nucl Med Biol 2021 Jul-Aug;98-99:69-75. Epub 2021 May 25.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Radiology, Weill Cornell Medical College, New York, NY, USA. Electronic address:

Purpose: Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus 2019 disease (COVID-19), poses a serious risk to humanity and represents a huge challenge for healthcare systems worldwide. Since the early days of the COVID-19 pandemic, it has been evident that adequate testing is an essential step in limiting and controlling the spread of SARS-CoV-2. Here, we present an accurate, inexpensive, scalable, portable, and rapid detection kit to directly detect SARS-CoV-2 in biological samples that could even be translated for population testing. We have demonstrated that our method can reliably identify viral load and could be used to reach those fractions of the population with limited access to more sophisticated and expensive tests.

Procedures: The proposed SARS-CoV-2 detection kit is based on the combination of a SARS-CoV-2-targeted antibody (CR3022) that targets spike protein S1 domain on the viral surface. This antibody was radiolabeled with a long-lived isotope (Iodine-125) to allow us to detect bound antibody in samples with SARS-CoV-2. We used a series of in vitro assays to determine sensitivity and specificity and facilitate automation of the testing kit. Bound antibody was extracted from saliva samples via a centrifugation step and a semi-permeable membrane. Our kit was further validated using SARS-CoV-2 virions.

Results: We were able to accomplish radiosynthesis of [I]I-CR3022 reliably without loss of binding. The SARS-CoV-2-sensing antibody was shown to maintain its spike S1 affinity and to bind to as low as 2.5-5 ng of spike protein. We then used beads-bound spike S1 to develop a separation kit which proved to be both easy to use and inexpensive. The kit made it possible to extract bound antibody from the saliva-like sample. We were able to validate the separation kit using intact SARS-CoV-2 virions and showed that our kit can detect a viral concentration as low as 19,700 PFU/mL (~ 9.22%TBF) and as high as 1,970,000 PFU/mL (45.04%TBF).

Conclusion: Here we report the development and validation of a SARS-CoV-2 detection system based on the combination of a specific radiolabeled antibody and a separation membrane. We demonstrate our system to be comparable to other SARS-CoV-2 detection kits already approved by the FDA and believe this technology could be easily deployed to countries with limited resources for the diagnosis of COVID-19. Furthermore, workflows could be easily adapted to target other antigens and therefore other types of diseases.
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http://dx.doi.org/10.1016/j.nucmedbio.2021.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144098PMC
June 2021

Current and future perspectives on functional molecular imaging in nephro-urology: theranostics on the horizon.

Theranostics 2021 7;11(12):6105-6119. Epub 2021 Apr 7.

Department of Nuclear Medicine, University Hospital Wuerzburg, Wuerzburg, Germany.

In recent years, a paradigm shift from single-photon-emitting radionuclide radiotracers toward positron-emission tomography (PET) radiotracers has occurred in nuclear oncology. Although PET-based molecular imaging of the kidneys is still in its infancy, such a trend has emerged in the field of functional renal radionuclide imaging. Potentially allowing for precise and thorough evaluation of renal radiotracer urodynamics, PET radionuclide imaging has numerous advantages including precise anatomical co-registration with CT images and dynamic three-dimensional imaging capability. In addition, relative to scintigraphic approaches, PET can allow for significantly reduced scan time enabling high-throughput in a busy PET practice and further reduces radiation exposure, which may have a clinical impact in pediatric populations. In recent years, multiple renal PET radiotracers labeled with C, Ga, and F have been utilized in clinical studies. Beyond providing a precise non-invasive read-out of renal function, such radiotracers may also be used to assess renal inflammation. This manuscript will provide an overview of renal molecular PET imaging and will highlight the transformation of conventional scintigraphy of the kidneys toward novel, high-resolution PET imaging for assessing renal function. In addition, future applications will be introduced, e.g. by transferring the concept of molecular image-guided diagnostics and therapy (theranostics) to the field of nephrology.
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http://dx.doi.org/10.7150/thno.58682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058716PMC
July 2021

Imaging infections in patients using pathogen-specific positron emission tomography.

Sci Transl Med 2021 04;13(589)

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

represent the largest group of bacterial pathogens in humans and are responsible for severe, deep-seated infections, often resulting in sepsis or death. They are also a prominent cause of multidrug-resistant (MDR) infections, and some species are recognized as biothreat pathogens. Tools for noninvasive, whole-body analysis that can localize a pathogen with specificity are needed, but no such technology currently exists. We previously demonstrated that positron emission tomography (PET) with 2-deoxy-2-[F]fluoro-d-sorbitol (F-FDS) can selectively detect infections in murine models. Here, we demonstrate that uptake of F-FDS by bacteria occurs via a metabolically conserved sorbitol-specific pathway with rapid in vitro F-FDS uptake noted in clinical strains, including MDR isolates. Whole-body F-FDS PET/computerized tomography (CT) in 26 prospectively enrolled patients with either microbiologically confirmed infection or other pathologies demonstrated that F-FDS PET/CT was safe, could rapidly detect and localize infections due to drug-susceptible or MDR strains, and differentiated them from sterile inflammation or cancerous lesions. Repeat imaging in the same patients monitored antibiotic efficacy with decreases in PET signal correlating with clinical improvement. To facilitate the use of F-FDS, we developed a self-contained, solid-phase cartridge to rapidly (<10 min) formulate ready-to-use F-FDS from commercially available 2-deoxy-2-[F]fluoro-d-glucose (F-FDG) at room temperature. In a hamster model, F-FDS PET/CT also differentiated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia from secondary pneumonia-a leading cause of complications in hospitalized patients with COVID-19. These data support F-FDS as an innovative and readily available, pathogen-specific PET technology with clinical applications.
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http://dx.doi.org/10.1126/scitranslmed.abe9805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120649PMC
April 2021

Sex differences in lung imaging and SARS-CoV-2 antibody responses in a COVID-19 golden Syrian hamster model.

bioRxiv 2021 Apr 4. Epub 2021 Apr 4.

In the ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more severe outcomes are reported in males compared with females, including hospitalizations and deaths. Animal models can provide an opportunity to mechanistically interrogate causes of sex differences in the pathogenesis of SARS-CoV-2. Adult male and female golden Syrian hamsters (8-10 weeks of age) were inoculated intranasally with 10 TCID of SARS-CoV-2/USA-WA1/2020 and euthanized at several time points during the acute (i.e., virus actively replicating) and recovery (i.e., after the infectious virus has been cleared) phases of infection. There was no mortality, but infected male hamsters experienced greater morbidity, losing a greater percentage of body mass, developing more extensive pneumonia as noted on chest computed tomography, and recovering more slowly than females. Treatment of male hamsters with estradiol did not alter pulmonary damage. Virus titers in respiratory tissues, including nasal turbinates, trachea, and lungs, and pulmonary cytokine concentrations, including IFNb and TNFa, were comparable between the sexes. However, during the recovery phase of infection, females mounted two-fold greater IgM, IgG, and IgA responses against the receptor-binding domain of the spike protein (S-RBD) in both plasma and respiratory tissues. Female hamsters also had significantly greater IgG antibodies against whole inactivated SARS-CoV-2 and mutant S-RBDs, as well as virus neutralizing antibodies in plasma. The development of an animal model to study COVID-19 sex differences will allow for a greater mechanistic understanding of the SARS-CoV-2 associated sex differences seen in the human population.
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http://dx.doi.org/10.1101/2021.04.02.438292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020969PMC
April 2021

Sulforaphane exhibits in vitro and in vivo antiviral activity against pandemic SARS-CoV-2 and seasonal HCoV-OC43 coronaviruses.

bioRxiv 2021 Mar 25. Epub 2021 Mar 25.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has incited a global health crisis. Currently, there are no orally available medications for prophylaxis for those exposed to SARS-CoV-2 and limited therapeutic options for those who develop COVID-19. We evaluated the antiviral activity of sulforaphane (SFN), a naturally occurring, orally available, well-tolerated, nutritional supplement present in high concentrations in cruciferous vegetables with limited side effects. SFN inhibited in vitro replication of four strains of SARS-CoV-2 as well as that of the seasonal coronavirus HCoV-OC43. Further, SFN and remdesivir interacted synergistically to inhibit coronavirus infection in vitro. Prophylactic administration of SFN to K18-hACE2 mice prior to intranasal SARS-CoV-2 infection significantly decreased the viral load in the lungs and upper respiratory tract and reduced lung injury and pulmonary pathology compared to untreated infected mice. SFN treatment diminished immune cell activation in the lungs, including significantly lower recruitment of myeloid cells and a reduction in T cell activation and cytokine production. Our results suggest that SFN is a promising treatment for prevention of coronavirus infection or treatment of early disease.
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http://dx.doi.org/10.1101/2021.03.25.437060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010735PMC
March 2021

Visualizing the dynamics of tuberculosis pathology using molecular imaging.

J Clin Invest 2021 03;131(5)

Center for Infection and Inflammation Imaging Research.

Nearly 140 years after Robert Koch discovered Mycobacterium tuberculosis, tuberculosis (TB) remains a global threat and a deadly human pathogen. M. tuberculosis is notable for complex host-pathogen interactions that lead to poorly understood disease states ranging from latent infection to active disease. Additionally, multiple pathologies with a distinct local milieu (bacterial burden, antibiotic exposure, and host response) can coexist simultaneously within the same subject and change independently over time. Current tools cannot optimally measure these distinct pathologies or the spatiotemporal changes. Next-generation molecular imaging affords unparalleled opportunities to visualize infection by providing holistic, 3D spatial characterization and noninvasive, temporal monitoring within the same subject. This rapidly evolving technology could powerfully augment TB research by advancing fundamental knowledge and accelerating the development of novel diagnostics, biomarkers, and therapeutics.
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http://dx.doi.org/10.1172/JCI145107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919721PMC
March 2021

Promising Antifungal Potential of Engineered Non-ionic Surfactant-Based Vesicles: In Vitro and In Vivo Studies.

AAPS PharmSciTech 2021 Jan 3;22(1):19. Epub 2021 Jan 3.

Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar, Madhya Pradesh, 470003, India.

Fungal keratitis (FK) is a corneal infection caused by different fungal species. It is treated by the topical application of natamycin (NAT). Nevertheless, this approach faces many limitations like toxic effects, frequent dosing, resistance, and patient discomfort. The present research reports the development of trimethyl chitosan (TMC) coated mucoadhesive cationic niosomes by a modified thin-film hydration method. TMC was synthesized using a one-step carbodiimide method and characterized by H-NMR and degree of quaternization (53.74 ± 1.06%). NAT, cholesterol (CHOL), span 60 (Sp60), and dicetyl phosphate (DCP) were used to prepare niosomes which were incubated with TMC to obtain mucoadhesive cationic NAT loaded niosomes (MCNNs). MCNNs showed a spherical shape with 1031.12 ± 14.18 nm size (PDI below 0.3) and 80.23 ± 5.28% entrapment efficiency. In vitro drug release studies showed gradual drug release from TMC coated niosomes as compared to the uncoated niosomes. MIC assay and disk diffusion assay revealed promising in vitro antifungal potential of MCNNs similar to the marketed formulation. For investigating in vivo performance, ocular retention and pharmacokinetics, ocular irritation, and ulcer healing studies were performed using the rabbit model. Mucoadhesive property and prolonged local drug release improved the safety and efficacy of NAT, suggesting that the developed niosomes could be an emerging system for effective treatment of fungal keratitis.
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http://dx.doi.org/10.1208/s12249-020-01900-zDOI Listing
January 2021

New Generation of Biocompatible Nanocarriers with Targeting Potential.

Curr Pharm Des 2020 ;26(42):5364

Department of Pharm. Sciences, Dr. Harisingh Gour University, SAGAR (MP), India.

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http://dx.doi.org/10.2174/138161282642201208101540DOI Listing
April 2021

Emerging potential of niosomes in ocular delivery.

Expert Opin Drug Deliv 2021 01 23;18(1):55-71. Epub 2020 Sep 23.

Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya , Sagar, India.

Introduction: Niosomes have recently grabbed attention as one of the best tools for various site-specific drug delivery systems, including ophthalmic drug delivery. Surfactants (nonionic; tweens and spans) of different HLB values and cholesterol are the fundamental components for these formulations. It is an alternative controlled ocular drug delivery system to liposomes to overcome the problems associated with sterilization, large-scale production, and stability. It also enhances the adhesion or retention ability of drug at the ocular site. Hydrophilic or lipophilic or amphoteric drugs can be easily encapsulated in niosomes. Besides, niosomes are a leading vesicular system compatible with most of the drugs for site-specific delivery.

Areas Covered: This article reveals challenges and barriers for ocular drug delivery, various transporters and receptors present in the ocular region for the transportation of therapeutics as well as nutrients, and various method of preparations, loading methods and application potential of niosomes in ocular drug delivery.

Expert Opinion: Niosomes, a vesicular system offers numerous advantages and applicability because of its good stability, non-immunogenicity, permeation potential, and controlled release ability etc. This drug delivery system has been efficiently used in the treatment of many ocular diseases.
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http://dx.doi.org/10.1080/17425247.2020.1822322DOI Listing
January 2021

Imaging Bacteria with Radiolabelled Probes: Is It Feasible?

J Clin Med 2020 Jul 25;9(8). Epub 2020 Jul 25.

Nuclear Medicine Department, University of Pretoria, Pretoria 0001, South Africa.

Bacterial infections are the main cause of patient morbidity and mortality worldwide. Diagnosis can be difficult and delayed as well as the identification of the etiological pathogen, necessary for a tailored antibiotic therapy. Several non-invasive diagnostic procedures are available, all with pros and cons. Molecular nuclear medicine has highly contributed in this field by proposing several different radiopharmaceuticals (antimicrobial peptides, leukocytes, cytokines, antibiotics, sugars, etc.) but none proved to be highly specific for bacteria, although many agents in development look promising. Indeed, factors including the number and strain of bacteria, the infection site, and the host condition, may affect the specificity of the tested radiopharmaceuticals. At the Third European Congress on Infection/Inflammation Imaging, a round table discussion was dedicated to debate the pros and cons of different radiopharmaceuticals for imaging bacteria with the final goal to find a consensus on the most relevant research steps that should be fulfilled when testing a new probe, based on experience and cumulative published evidence.
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http://dx.doi.org/10.3390/jcm9082372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464306PMC
July 2020

Engineered liposomes bearing camptothecin analogue for tumour targeting: and studies.

J Liposome Res 2020 Aug 11:1-16. Epub 2020 Aug 11.

Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, India.

Topotecan (TPT) is a semi-synthetic, water-soluble derivative of camptothecin, which inhibits the action of topoisomerase I in the S-phase of the cell cycle leading to cell death. For the effective delivery of TPT to cancer cells, pH-sensitive sialic acid modified liposomes were developed. These liposomes were prepared by the thin-film hydration method using the active loading technique. Vesicle size, polydispersity index (PDI), zeta potential, and percentage entrapment efficiency were determined to be 167±3.78nm, 0.243, -8.39mV, and 79.88±1.67%, respectively. The pH-sensitive sialic acid (SA) conjugated liposomes enhanced the drug release at acidic pH 4 (92.33±4.21%) as compared to physiological pH 7.4 (63.11±4.51%). A Sulforhodamine B (SRB) cytotoxicity assay was performed in Murine sarcoma S180 cell lines and the GI value of free TPT, Lipo, P-Lipo, SA-P-Lipo, and Adriamycin (ADR) were determined to be 10.07±0.15, 27.33±1.01, 28.76±0.87, 15.7±0.45, and 11.5±0.21µg/mL, respectively. Results obtained from the apoptosis study revealed that cell death by a combination of early apoptosis and apoptosis caused by SA-P-Lipo was ∼24 fold higher than the control. These results demonstrated that pH-sensitive sialic acid conjugated liposomes will be a potential formulation for improving the antitumor efficacy of TPT. However, further research is necessitated to expedite its applicability in clinical regimen in order to ascertain its safety and efficacy.
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http://dx.doi.org/10.1080/08982104.2020.1801725DOI Listing
August 2020

Evaluation of Musculoskeletal and Pulmonary Bacterial Infections With [I]FIAU PET/CT.

Mol Imaging 2020 Jan-Dec;19:1536012120936876

The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Purpose: Imaging is limited in the evaluation of bacterial infection. Direct imaging of in situ bacteria holds promise for noninvasive diagnosis. We investigated the ability of a bacterial thymidine kinase inhibitor ([I]FIAU) to image pulmonary and musculoskeletal infections.

Methods: Thirty-three patients were prospectively accrued: 16 with suspected musculoskeletal infection, 14 with suspected pulmonary infection, and 3 with known rheumatoid arthritis without infection. Thirty-one patients were imaged with [I]FIAU PET/CT and 28 with [F]FDG PET/CT. Patient histories were reviewed by an experienced clinician with subspecialty training in infectious diseases and were determined to be positive, equivocal, or negative for infection.

Results: Sensitivity, specificity, positive-predictive value, negative-predictive value, and accuracy of [I]FIAU PET/CT for diagnosing infection were estimated as 7.7% to 25.0%, 0.0%, 50%, 0.0%, and 20.0% to 71.4% for musculoskeletal infections and incalculable-100.0%, 51.7% to 72.7%, 0.0% to 50.0%, 100.0%, and 57.1% to 78.6% for pulmonary infections, respectively. The parameters for [F]FDG PET/CT were 75.0% to 92.3%, 0.0%, 23.1% to 92.3%, 0.0%, and 21.4% to 85.7%, respectively, for musculoskeletal infections and incalculable to 100.0%, 0.0%, 0.0% to 18.2%, incalculable, and 0.0% to 18.2% for pulmonary infections, respectively.

Conclusions: The high number of patients with equivocal clinical findings prevented definitive conclusions from being made regarding the diagnostic efficacy of [I]FIAU. Future studies using microbiology to rigorously define infection in patients and PET radiotracers optimized for image quality are needed.
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http://dx.doi.org/10.1177/1536012120936876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325456PMC
July 2021

Advanced imaging tools for childhood tuberculosis: potential applications and research needs.

Lancet Infect Dis 2020 11 23;20(11):e289-e297. Epub 2020 Jun 23.

Tuberculosis Clinic, Pima County Health Department, Tucson, AZ, USA; Division of Infectious Diseases, University of Arizona College of Medicine, Tucson, AZ, USA.

Tuberculosis is the leading cause of death globally that is due to a single pathogen, and up to a fifth of patients with tuberculosis in high-incidence countries are children younger than 16 years. Unfortunately, the diagnosis of childhood tuberculosis is challenging because the disease is often paucibacillary and it is difficult to obtain suitable specimens, causing poor sensitivity of currently available pathogen-based tests. Chest radiography is important for diagnostic evaluations because it detects abnormalities consistent with childhood tuberculosis, but several limitations exist in the interpretation of such results. Therefore, other imaging methods need to be systematically evaluated in children with tuberculosis, although current data suggest that when available, cross-sectional imaging, such as CT, should be considered in the diagnostic evaluation for tuberculosis in a symptomatic child. Additionally, much of the understanding of childhood tuberculosis stems from clinical specimens that might not accurately represent the lesional biology at infection sites. By providing non-invasive measures of lesional biology, advanced imaging tools could enhance the understanding of basic biology and improve on the poor sensitivity of current pathogen detection systems. Finally, there are key knowledge gaps regarding the use of imaging tools for childhood tuberculosis that we outlined in this Personal View, in conjunction with a proposed roadmap for future research.
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http://dx.doi.org/10.1016/S1473-3099(20)30177-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606757PMC
November 2020

Rabbit model of implant-associated spinal infection.

Dis Model Mech 2020 07 28;13(7). Epub 2020 Jul 28.

Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

Post-surgical implant-associated spinal infection is a devastating complication commonly caused by Biofilm formation is thought to reduce penetration of antibiotics and immune cells, contributing to chronic and difficult-to-treat infections. A rabbit model of a posterior-approach spinal surgery was created, in which bilateral titanium pedicle screws were interconnected by a plate at the level of lumbar vertebra L6 and inoculated with a methicillin-resistant (MRSA) bioluminescent strain. whole-animal bioluminescence imaging (BLI) and bacterial cultures demonstrated a peak in bacterial burden by day 14, when wound dehiscence occurred. Structures suggestive of biofilm, visualized by scanning electron microscopy, were evident up to 56 days following infection. Infection-induced inflammation and bone remodeling were also monitored using F-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) and computed tomography (CT). PET imaging signals were noted in the soft tissue and bone surrounding the implanted materials. CT imaging demonstrated marked bone remodeling and a decrease in dense bone at the infection sites. This rabbit model of implant-associated spinal infection provides a valuable preclinical approach to investigate the pathogenesis of implant-associated spinal infections and to evaluate novel therapeutics.
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http://dx.doi.org/10.1242/dmm.045385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406311PMC
July 2020

Cavitary tuberculosis: the gateway of disease transmission.

Lancet Infect Dis 2020 06 5;20(6):e117-e128. Epub 2020 May 5.

Center for Tuberculosis Research, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Center for Infection and Inflammation Imaging Research, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Tuberculosis continues to be a major threat to global health. Cavitation is a dangerous consequence of pulmonary tuberculosis associated with poor outcomes, treatment relapse, higher transmission rates, and development of drug resistance. However, in the antibiotic era, cavities are often identified as the most extreme outcome of treatment failure and are one of the least-studied aspects of tuberculosis. We review the epidemiology, clinical features, and concurrent standards of care for individuals with cavitary tuberculosis. We also discuss developments in the understanding of tuberculosis cavities as dynamic physical and biochemical structures that interface the host response with a unique mycobacterial niche to drive tuberculosis-associated morbidity and transmission. Advances in preclinical models and non-invasive imaging can provide valuable insights into the drivers of cavitation. These insights will guide the development of specific pharmacological interventions to prevent cavitation and improve lung function for individuals with tuberculosis.
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http://dx.doi.org/10.1016/S1473-3099(20)30148-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357333PMC
June 2020

Curcumin Based Drug Delivery Systems for Cancer Therapy.

Curr Pharm Des 2020 ;26(42):5430-5440

Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar (M.P.), 470 003, India.

Cancer accounts for the second major cause of death globally. Conventional cancer therapies lead to systemic toxicity that forbids their long term application. Besides, tumor resistance and recurrence have been observed in the majority of cases. Thus, the development of such therapy, which will pose minimum side effects, is the need of the hour. Curcumin or diferuloylmethane (CUR) is a natural polyphenol bioactive (obtained from Curcuma longa) which possesses anti-cancer and chemo-preventive activity. It acts by modulating various components of signaling cascades that are involved in cancer cell proliferation, invasion, and apoptosis process. It interacts with the adaptive and innate immune systems of our body and causes tumor regression. This may be the reason behind the attainment of in vivo anti-tumor activity at a very low concentration. Its ease of availability, safety profile, low cost, and multifaceted role in cancer prevention and treatment has made it a promising agent for chemoprevention of many cancers. Regardless of the phenomenal properties, its clinical utility is haltered due to its low aqueous solubility, poor bioavailability, rapid metabolism, and low cellular uptake. In the last few years, a variety of novel drug carriers have been fabricated to enhance the bioavailability and pharmacokinetic profile of CUR to attain better targeting of cancer. In this review, the recent developments in the arena of nanoformulations, like liposomes, polymeric NPs, solid lipid NPs (SNPs), polymeric micelles, nanoemulsions, microspheres, nanogels, etc. in anticancer therapy have been discussed along with a brief overview of the molecular targets for CUR in cancer therapy and role of CUR in cancer immunotherapy.
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http://dx.doi.org/10.2174/1381612826666200429095503DOI Listing
April 2021

Stability and Viability of SARS-CoV-2.

N Engl J Med 2020 05 13;382(20):1962-1963. Epub 2020 Apr 13.

Johns Hopkins Hospital, Baltimore, MD

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http://dx.doi.org/10.1056/NEJMc2007942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225025PMC
May 2020

Radiosynthesis and Biodistribution of F-Linezolid in -Infected Mice Using Positron Emission Tomography.

ACS Infect Dis 2020 05 9;6(5):916-921. Epub 2020 Apr 9.

Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School, Newark, New Jersey 07103, United States.

Oxazolidinones are a novel class of antibacterials with excellent activity against resistant Gram-positive bacteria including strains causing multidrug-resistant tuberculosis (TB). Despite their excellent efficacy, optimal dosing strategies to limit their toxicities are still under development. Here, we developed a novel synthetic strategy for fluorine-18-radiolabeled oxazolidinones. As proof-of-concept, we performed whole-body F-linezolid positron emission tomography (PET) in a mouse model of pulmonary TB for noninvasive measurements of time-activity curves in multiple compartments with subsequent confirmation by tissue gamma counting. After intravenous injection, F-linezolid rapidly distributed to all organs with excellent penetration into -infected lungs. Drug biodistribution studies with PET can provide unbiased, drug measurements, which could boost efforts to optimize antibiotic dosing strategies.
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http://dx.doi.org/10.1021/acsinfecdis.9b00473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212803PMC
May 2020

Caspase-Based PET for Evaluating Pro-Apoptotic Treatments in a Tuberculosis Mouse Model.

Mol Imaging Biol 2020 12;22(6):1489-1494

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Purpose: Despite recent advances in antimicrobial treatments, tuberculosis (TB) remains a major global health threat. Mycobacterium tuberculosis proliferates in macrophages, preventing apoptosis by inducing anti-apoptotic proteins leading to necrosis of the infected cells. Necrosis then leads to increased tissue destruction, reducing the penetration of antimicrobials and immune cells to the areas where they are needed most. Pro-apoptotic drugs could be used as host-directed therapies in TB to improve antimicrobial treatments and patient outcomes.

Procedure: We evaluated [F]-ICMT-11, a caspase-3/7-specific positron emission tomography (PET) radiotracer, in macrophage cell cultures and in an animal model of pulmonary TB that closely resembles human disease.

Results: Cells infected with M. tuberculosis and treated with cisplatin accumulated [F]-ICMT-11 at significantly higher levels compared with that of controls, which correlated with levels of caspase-3/7 activity. Infected mice treated with cisplatin with increased caspase-3/7 activity also had a higher [F]-ICMT-11 PET signal compared with that of untreated infected animals.

Conclusions: [F]-ICMT-11 PET could be used as a noninvasive approach to measure intralesional pro-apoptotic responses in situ in pulmonary TB models and support the development of pro-apoptotic host-directed therapies for TB.
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http://dx.doi.org/10.1007/s11307-020-01494-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529691PMC
December 2020

C-PABA as a PET Radiotracer for Functional Renal Imaging: Preclinical and First-in-Human Study.

J Nucl Med 2020 11 20;61(11):1665-1671. Epub 2020 Mar 20.

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland

Aminobenzoic acid (PABA) has been previously used as an exogenous marker to verify completion of 24-h urine sampling. Therefore, we hypothesized that PABA radiolabeled with C might allow high-quality dynamic PET of the kidneys with less radiation exposure than other agents because of its shorter biologic and physical half-life. We evaluated if C-PABA can visualize renal anatomy and quantify function in healthy rats and rabbits and in a first-in-humans study on healthy volunteers. Healthy rats and rabbits were injected with C-PABA intravenously. Subsequently, dynamic PET was performed, followed by postmortem tissue-biodistribution studies. C-PABA PET was directly compared with the current standard, Tc-mercaptoacetyltriglycin, in rats. Three healthy human subjects also underwent dynamic PET after intravenous injection of C-PABA. In healthy rats and rabbits, dynamic PET demonstrated a rapid accumulation of C-PABA in the renal cortex, followed by rapid excretion through the pelvicalyceal system. In humans, C-PABA PET was safe and well tolerated. There were no adverse or clinically detectable pharmacologic effects in any subject. The cortex was delineated on PET, and the activity gradually transited to the medulla and then pelvis with high spatiotemporal resolution. C-PABA demonstrated fast renal excretion with a very low background signal in animals and humans. These results suggest that C-PABA might be used as a novel radiotracer for functional renal imaging, providing high-quality spatiotemporal images with low radiation exposure.
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http://dx.doi.org/10.2967/jnumed.119.239806DOI Listing
November 2020

Flagging Bacteria with Radiolabeled d-Amino Acids.

ACS Cent Sci 2020 Feb 19;6(2):97-99. Epub 2020 Feb 19.

Center for Infection and Inflammation Imaging Research, and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.

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http://dx.doi.org/10.1021/acscentsci.0c00096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047284PMC
February 2020

Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions.

Nat Med 2020 04 17;26(4):529-534. Epub 2020 Feb 17.

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure. However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments. In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration-time profiles in humans. Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study using dynamic [C]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [C]rifampin PET-CT was safe and demonstrated spatially compartmentalized rifampin exposures in pathologically distinct TB lesions within the same patients, with low cavity wall rifampin exposures. Repeat PET-CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patients. Similar findings were recapitulated by PET-CT in experimentally infected rabbits with cavitary TB and confirmed using postmortem mass spectrometry. Integrated modeling of the PET-captured concentration-time profiles in hollow-fiber bacterial kill curve experiments provided estimates on the rifampin dosing required to achieve cure in 4 months. These data, capturing the spatial and temporal heterogeneity of intralesional drug PK, have major implications for antimicrobial drug development.
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http://dx.doi.org/10.1038/s41591-020-0770-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160048PMC
April 2020

Radiotracer Development for Bacterial Imaging.

J Med Chem 2020 03 21;63(5):1964-1977. Epub 2020 Feb 21.

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States.

Bacterial infections remain a major threat to humanity and are a leading cause of death and disability. Antimicrobial resistance has been declared as one of the top ten threats to human health by the World Health Organization, and new technologies are urgently needed for the early diagnosis and monitoring of deep-seated and complicated infections in hospitalized patients. This review summarizes the radiotracers as applied to imaging of bacterial infections. We summarize the recent progress in the development of pathogen-specific imaging and the application of radiotracers in understanding drug pharmacokinetics as well as the local biology at the infection sites. We also highlight the opportunities for medicinal chemists in radiotracer development for bacterial infections, with an emphasis on target selection and radiosynthetic approaches. Imaging of infections is an emerging field. Beyond clinical applications, these technologies could provide unique insights into disease pathogenesis and expedite bench-to-bedside translation of new therapeutics.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069783PMC
March 2020

Molecular Imaging of Diabetic Foot Infections: New Tools for Old Questions.

Int J Mol Sci 2019 Nov 28;20(23). Epub 2019 Nov 28.

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Diabetic foot infections (DFIs) are a common, complex, and costly medical problem with increasing prevalence. Diagnosing DFIs is a clinical challenge due to the poor specificity of the available methods to accurately determine the presence of infection in these patients. However, failure to perform an opportune diagnosis and provide optimal antibiotic therapy can lead to higher morbidity for the patient, unnecessary amputations, and increased healthcare costs. Novel developments in bacteria-specific molecular imaging can provide a non-invasive assessment of the infection site to support diagnosis, determine the extension and location of the infection, guide the selection of antibiotics, and monitor the response to treatment. This is a review of recent research in molecular imaging of infections in the context of DFI. We summarize different clinical and preclinical methods and the translational implications aimed to improve the care of patients with DFI.
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http://dx.doi.org/10.3390/ijms20235984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928969PMC
November 2019

Basics to advances in nanotherapy of colorectal cancer.

Drug Deliv Transl Res 2020 04;10(2):319-338

Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Central University, Sagar, 470 003 (M.P.), India.

Colorectal cancer (CRC) is the third most common cancer existing across the globe. It begins with the formation of polyps leading to the development of metastasis, especially in advanced stage patients, who necessitate intensive chemotherapy that usually results in a poor response and high morbidity owing to multidrug resistance and severe untoward effects to the non-cancerous cells. Advancements in the targeted drug delivery permit the targeting of tumor cells without affecting the non-tumor cells. Various nanocarriers such as liposomes, polymeric nanoparticles, carbon nanotubes, micelles, and nanogels, etc. are being developed and explored for effective delivery of cytotoxic drugs to the target site thereby enhancing the drug distribution and bioavailability, simultaneously subduing the side effects. Moreover, immunotherapy for CRC is being explored for last few decades. Few clinical trials have even potentially benefited patients suffering from CRC, still immunotherapy persists merely an experimental alternative. Assessment of the ongoing and completed trials is to be warranted for effective treatment of CRC. Scientists are paying efforts to develop novel carrier systems that may enhance the targeting potential of low therapeutic index chemo- and immune-therapeutics. Several preclinical studies have revealed the superior efficacy of nanotherapy in CRC as compared to conventional approaches. Clinical trials are being recruited to ascertain the safety and efficacy of CRC therapies. The present review discourses in a nutshell the molecular interventions including the genetics, signaling pathways involved in CRC, and advances in various strategies explored for the treatment of CRC with a special emphasis on nanocarriers based drug targeting.
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http://dx.doi.org/10.1007/s13346-019-00680-9DOI Listing
April 2020

Molecular Imaging: a Novel Tool To Visualize Pathogenesis of Infections .

mBio 2019 10 29;10(5). Epub 2019 Oct 29.

Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Molecular imaging is an emerging technology that enables the noninvasive visualization, characterization, and quantification of molecular events within living subjects. Positron emission tomography (PET) is a clinically available molecular imaging tool with significant potential to study pathogenesis of infections in humans. PET enables dynamic assessment of infectious processes within the same subject with high temporal and spatial resolution and obviates the need for invasive tissue sampling, which is difficult in patients and generally limited to a single time point, even in animal models. This review presents current state-of-the-art concepts on the application of molecular imaging for infectious diseases and details how PET imaging can facilitate novel insights into infectious processes, ongoing development of pathogen-specific imaging, and simultaneous measurements of intralesional antimicrobial pharmacokinetics in multiple compartments, including privileged sites. Finally, the potential clinical applications of this promising technology are also discussed.
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http://dx.doi.org/10.1128/mBio.00317-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819656PMC
October 2019
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