Piyush Kumar

Optimized Carbohydrate-Based Nanogel Formulation to Sensitize Hypoxic Tumors

Molecular Pharmaceutics, 2023

Solid tumors are often poorly vascularized, which impairs oxygen supply and drug delivery to the ... more Solid tumors are often poorly vascularized, which impairs oxygen supply and drug delivery to the cells. This often leads to genetic and translational adaptations that promote tumor progression, invasion, metastasis, and resistance to conventional chemo-/radiotherapy and immunotherapy. A hypoxia-directed nanosensitizer formulation of a hypoxia-activated prodrug (HAP) was developed by encapsulating iodoazomycin arabinofuranoside (IAZA), a 2-nitroimidazole nucleoside-based HAP, in a functionally modified carbohydrate-based nanogel, facilitating delivery and accrual selectively in the hypoxic head and neck and prostate cancer cells. Although IAZA has been reported as a clinically validated hypoxia diagnostic agent, recent studies have pointed to its promising hypoxia-selective anti-tumor properties, which make IAZA an excellent candidate for further exploration as a multimodal theranostic of hypoxic tumors. The nanogels are composed of a galactose-based shell with an inner core of thermoresponsive (di(ethylene glycol) methyl ethyl methacrylate). Optimization of the nanogels led to high IAZA-loading capacity (≅80−88%) and a slow time-controlled release over 50 h. Furthermore, nanoIAZA (encapsulated IAZA) displayed superior in vitro hypoxia-selective cytotoxicity and radiosensitization in comparison to free IAZA in the head and neck (FaDu) and prostate (PC3) cancer cell lines. The acute systemic toxicity profile of the nanogel (NG1) was studied in immunocompromised mice, indicating no signs of toxicity. Additionally, growth inhibition of subcutaneous FaDu xenograft tumors was observed with nanoIAZA, demonstrating that this nanoformulation offers a significant improvement in tumor regression and overall survival compared to the control.

format_quoteNanoIAZA significantly improved tumor regression with enhanced overall survival in mice, indicating promising therapeutic potential over controls.format_quote

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Identification of proteins and cellular pathways targeted by 2-nitroimidazole hypoxic cytotoxins

Redox Biology, 2021

Tumour hypoxia negatively impacts therapy outcomes and continues to be a major unsolved clinical ... more Tumour hypoxia negatively impacts therapy outcomes and continues to be a major unsolved clinical problem. Nitroimidazoles are hypoxia selective compounds that become entrapped in hypoxic cells by forming drugprotein adducts. They are widely used as hypoxia diagnostics and have also shown promise as hypoxiadirected therapeutics. However, little is known about the protein targets of nitroimidazoles and the resulting effects of their modification on cancer cells. Here, we report the synthesis and applications of azidoazomycin arabinofuranoside (N 3-AZA), a novel click-chemistry compatible 2-nitroimidazole, designed to facilitate (a) the LC-MS/MS-based proteomic analysis of 2-nitroimidazole targeted proteins in FaDu head and neck cancer cells, and (b) rapid and efficient labelling of hypoxic cells and tissues. Bioinformatic analysis revealed that many of the 62 target proteins we identified participate in key canonical pathways including glycolysis and HIF1A signaling that play critical roles in the cellular response to hypoxia. Critical cellular proteins such as the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the detoxification enzyme glutathione S-transferase P (GSTP1) appeared as top hits, and N 3-AZA adduct formation significantly reduced their enzymatic activities only under hypoxia. Therefore, GAPDH, GSTP1 and other proteins reported here may represent candidate targets to further enhance the potential for nitroimidazole-based cancer therapeutics.

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The Synthesis of Novel 5-Trifluoroethyl Ethers of Thymidine

Nucleosides and Nucleotides

ABSTRACT

The Synthesis of Novel 5-Trifluoroethoxy Pyrimidine Nucleosides

Nucleosides and Nucleotides

ABSTRACT

Clinical production, stability studies and PET imaging with 16-alpha-[18F]fluoroestradiol ([18F]FES) in ER positive breast cancer patients

Journal of Pharmacy Pharmaceutical Sciences a Publication of the Canadian Society For Pharmaceutical Sciences Societe Canadienne Des Sciences Pharmaceutiques, 2007

Purpose: 18F-Fluoroestradiol [18F]FES has emerged as a valuable PET tracer to predict the respons... more Purpose: 18F-Fluoroestradiol [18F]FES has emerged as a valuable PET tracer to predict the response to hormone therapy in recurrent or metastatic breast cancer patients. A clinically acceptable product requires a rapid reliable synthesis and must be demonstrated to maintain chemical stability and receptor specific uptake during patient studies. [18F]FES then becomes a dependable tracer for the evaluation and management of breast cancer patients. Methods: An improved automated radiosynthesis of [18F]FES was developed. Stability studies of the injectible form of [18F]FES were performed up to 24 h after dose formulation under normal storage conditions. A comparative FES/FDG PET imaging in ER+ breast cancer patients is reported. Results: The improved synthesis procedure utilizes fewer hydrolysis steps and a single high performance liquid column chromatography (HPLC) purification of the labeled mixture affording [18F]FES in good yield with high radiochemical purity (>99%). Stability studies with purified [18F]FES in saline/ethanol (85:15 v/v) indicated no radiolytic or chemical degradation of this radiopharmaceutical when stored for 24 h at 20-24 degrees C. Positron Emission Tomography (PET) studies with [18F]FES and [18F]FDG in estrogen receptor positive (ER+) breast cancer patients indicated that while FDG accumulation was seen in all metabolically hyperactive sites, the uptake of FES clearly delineated the ER+ tissues regions. Conclusions: An improved automated synthesis of [18F]FES has been developed and the integrity of this product has been validated by long term stability studies and clinical PET imaging studies in ER+ breast cancer patients. A lack of concordance between FES and FDG uptake in a patient with metastatic breast cancer suggests specificity of the FES for tumors expressing estrogen receptors.

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Synthesis and antiinflammatory activity of N-substituted-dihydropyridylacetic acids, esters, and amides

Drug Design and Delivery, 1988

A group of N-substituted-1,4-dihydropyridylacetic acids (13-16), esters (4-12), and amides (17-23... more A group of N-substituted-1,4-dihydropyridylacetic acids (13-16), esters (4-12), and amides (17-23) were synthesized in order to investigate the effect of 4-substituents (R2 = Ph, n-Bu or Me) and alpha-substituents (R3 = H, Me) on antiinflammatory activity. In the acetic ester class of compounds, the relative activities (R2-substituents) were Ph greater than n-Bu greater than Me. The presence of an R3 methyl substituent enhanced activity. Increasing the length of the alkyl ester substituent enhanced activity, since the tri-ester (7) was more active than the bis-ester (6), and the bis-ester (11) was more active than the mono-ester (10). The relative order of antiinflammatory potency was generally ester greater than amide greater than acid. Methyl 2-methyl-2-(-1-[4-phenyl-3-(4,4-dimethyloxazolin-2-yl)-1,4-dihy dropyridyl]) acetate (9) was the most active antiinflammatory agent in the series, reducing inflammation 73.9% at 3 hr after a 100 mg/kg po dose.

Synthesis, radiofluorination, and hypoxia-selective studies of FRAZ: A configurational and positional analogue of the clinical hypoxia marker, [ 18F]-FAZA

Bioorgan Med Chem, 2010

The current work evaluates 1-alpha-d-(2-deoxy-2-fluororibofuranosyl)-2-nitroimidazole (FRAZ), a n... more The current work evaluates 1-alpha-d-(2-deoxy-2-fluororibofuranosyl)-2-nitroimidazole (FRAZ), a novel azomycin nucleoside that is a potential radiosensitizer of tumor hypoxia. FRAZ is a ribose analogue of 1-alpha-d-(2-deoxy-2-fluoroarabinofuranosyl)-2-nitroimidazole ([(18)F]-FAZA), a clinically used hypoxia marker. Preliminary assessment of the cytotoxicity and hypoxia-specific in vitro binding in HCT-110 colorectal cancer cells indicate that the radiosensitization properties of FRAZ are similar to that of FAZA, with a sensitizer enhancement ratio (SER) of approximately 1.8. An automated radiosynthesis of [(18)F]-FRAZ using a commercial automated synthesis unit (ASU) was established (synthesis time approximately 32 min; radiochemical yield (decay uncorrecetd) approximately 22%) to facilitate its application in PET-based diagnosis of hypoxic tumors.

α-Trifluoromethyl-β-alanyl glycine (F3MBAG) : a novel mammalian metabolite of trifluridine (F3TdR)

Biochemical Pharmacology, 1994

ABSTRACT

A One-Pot Synthesis of 1-α- And 1-β-D-Arabinofuranosyl-2-Nitroimidazoles: Synthons to the Markers of Tumor Hypoxia

Nucleosides Nucleotides and Nucleic Acids, Jun 24, 2011

ABSTRACT

Characterization of the murine EMT-6 tumor model with [18F]FDG, [18F]FLT and [18F]FAZA using dynamic small animal PET imaging

Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2010

Synthesis of Bromophenyl β-D-Glucuronides: Hydrophilic Precursors of Lipophilic Standards in the Analysis of Environmental Polychlorinated Biphenyls

Collection of Czechoslovak Chemical Communications, 2006

... Manju TANDON a1, Piyush KUMAR b1,*, Haiyan XIA a2,+, Lili WANG a3,+ and ... Lowe and Brydone ... more

Compounds Useful in Imaging and Therapy

Novel compounds for hypoxic cell therapy and imaging

Comparison of F-18-FAZA and F-18-FMISO as hypoxia tracers in cell culture studies and experimental tumors

α-trifluoromethyl-β-alanyl glycine (F3MBAG): A novel mammalian metabolite of trifluridine (F3TdR)

Biochemical Pharmacology, 1994

ABSTRACT

ChemInform Abstract: Stereospecific Deuteration of α-Furanosyl Azomycin Nucleosides: A Model Reaction for Tritium Radiolabeling

ChemInform, 2008

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Some new 2-substituted thio 5-(4'-pyridyl)-1,3,4-oxadiazoles as possible antitubercular compounds

Polish journal of pharmacology and pharmacy, 1981

Monoamine oxidase inhibitory activity of 2-aryl-3-(5'-chlorobenzophenon-2'-yl)-quinazolin-4-(3H)-ones

Indian journal of physiology and pharmacology

Index Medicus for South-East Asia Region (IMSEAR) is a compiled and maintained by Information Man... more

Some novel organosilanes as potent anti-tubercular agents

Die Pharmazie, 1981

Synthesis and antiinflammatory activity of N-substituted-dihydropyridylacetic acids, esters, and amides

Drug design and delivery, 1987

A group of N-substituted-1,4-dihydropyridylacetic acids (13-16), esters (4-12), and amides (17-23... more A group of N-substituted-1,4-dihydropyridylacetic acids (13-16), esters (4-12), and amides (17-23) were synthesized in order to investigate the effect of 4-substituents (R2 = Ph, n-Bu or Me) and alpha-substituents (R3 = H, Me) on antiinflammatory activity. In the acetic ester class of compounds, the relative activities (R2-substituents) were Ph greater than n-Bu greater than Me. The presence of an R3 methyl substituent enhanced activity. Increasing the length of the alkyl ester substituent enhanced activity, since the tri-ester (7) was more active than the bis-ester (6), and the bis-ester (11) was more active than the mono-ester (10). The relative order of antiinflammatory potency was generally ester greater than amide greater than acid. Methyl 2-methyl-2-(-1-[4-phenyl-3-(4,4-dimethyloxazolin-2-yl)-1,4-dihy dropyridyl]) acetate (9) was the most active antiinflammatory agent in the series, reducing inflammation 73.9% at 3 hr after a 100 mg/kg po dose.

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