Khaled Nasr - Academia.edu (original) (raw)

Papers by Khaled Nasr

HortScience

Black cohosh [Actaea racemosa L.; syn. Cimicifuga racemosa (L.) Nutt.] is a medicinal plant nativ... more Black cohosh [Actaea racemosa L.; syn. Cimicifuga racemosa (L.) Nutt.] is a medicinal plant native to America and the woodlands of eastern North America. The roots and rhizomes of black cohosh, used by Native Americans to ease childbirth and treat menstrual cramps, rheumatism, headaches, coughs, asthma, and snakebites, are currently popular as an herbal remedy in the United States and Europe for the relief of discomfort associated with menopause. To determine chemical variation among populations of this perennial plant, root samples from 33 locations within the natural range of the species, ranging from Massachusetts to South Carolina and west to Missouri and Tennessee, were collected and chemically analyzed by HPLC-PDA using a C-18 reversed phase column (Phenomenex) for separation of the chemical constituents. The constituents were identified by comparison with commercial standards, including actein, methyl-beta-arabinopyranoside, caffeic acid, cimicifugoside, cimicifugoside H1, ci...

European Journal of Radiology

Contrast Media & Molecular Imaging

Widespread use of screening mammography has recently increased the detection of breast microcalci... more Widespread use of screening mammography has recently increased the detection of breast microcalcifications. These nonpalpable microcalcifications with specific features in breast tissues are clinically considered an early indicator of breast carcinoma. Our goal in this study was to develop a murine breast microcalcification model for optimizing in vivo imaging. Recombinant human BMP-2 was expressed in E. coli, and the purified bioactive protein was used as inducing factor for the production of breast microcalcifications in a murine animal model. Syngeneic breast tumors were obtained by injection of MDA-MB-231 human breast cancer cells with Matrigel into the mammary fat pad of female nude mice. Different doses of bioactive rhBMP-2 were administered either as single or multiple intraperitoneal injections or directly into tumor on a weekly basis. Three weeks after the first injection of rhBMP-2, the microcalcification of breast tumor was detected by microcomputed tomography followed by...

... Jeong Heon Lee, Hak Soo Choi, Khaled A. Nasr, Miyoung Ha§, Yangsun Kim§, and John V. Fr... more ... Jeong Heon Lee, Hak Soo Choi, Khaled A. Nasr, Miyoung Ha§, Yangsun Kim§, and John V. Frangioni*. Robotic Chemistry Group, Center for Molecular Imaging, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, United States. ...

Journal of the American Chemical Society, 2015

Given the known water exchange rate limitations of a previously reported Zn(II)-sensitive MRI con... more Given the known water exchange rate limitations of a previously reported Zn(II)-sensitive MRI contrast agent, GdDOTA-diBPEN, new structural targets were rationally designed to increase the rate of water exchange to improve MRI detection sensitivity. These new sensors exhibit fine-tuned water exchange properties and, depending on the individual structure, demonstrate significantly improved longitudinal relaxivities (r1). Two sensors in particular demonstrate optimized parameters and therefore show exceptionally high longitudinal relaxivities of about 50 mM-1s-1 upon binding to Zn(II) and human serum albumin (HSA). This value demonstrates a 3-fold increase in r1 compared to that displayed by the original sensor, GdDOTA-diBPEN. In addition, this study provides important insights into the interplay be-tween structural modifications, water exchange rate, and kinetic stability properties of the sensors. The new high relaxivity agents were used to successfully image Zn(II) release from in the mouse pancreas in vivo during glucose stimulated insulin secretion.

Journal of Magnetic Resonance, 2015

Here we report the polarization of the solvent OH protons by SABRE using standard iridium-based c... more Here we report the polarization of the solvent OH protons by SABRE using standard iridium-based catalysts under slightly acidic conditions. Solvent polarization was observed in the presence of a variety of structurally similar N-donor substrates while no solvent enhancement was observed in the absence of substrate or para-hydrogen (p-H2). Solvent polarization was sensitive to the polarizing field and catalyst:substrate ratio in a manner similar to that of substrate protons. SABRE experiments with pyridine-d5 suggest a mechanism where hyperpolarization is transferred from the free substrate to the solvent by chemical exchange while measured hyperpolarization decay times suggest a complimentary mechanism which occurs by direct coordination of the solvent to the catalytic complex. We found the solvent hyperpolarization to decay nearly 3 times more slowly than its characteristic spin-lattice relaxation time suggesting that the hyperpolarized state of the solvent may be sufficiently long lived (∼20s) to hyperpolarize biomolecules having exchangeable protons. This route may offer future opportunities for SABRE to impact metabolic imaging.

Theranostics, 2015

Recent advances in near-infrared (NIR) fluorescence imaging enabled real-time intraoperative dete... more Recent advances in near-infrared (NIR) fluorescence imaging enabled real-time intraoperative detection of bone metastases, bone growth, and tissue microcalcification. Pamidronate (PAM) has been widely used for this purpose because of its high binding affinity toward bone and remarkable therapeutic effects. Herein we describe the development of a series of PAM-conjugated NIR fluorophores that varied in net charges and hydrophobicity, and compared their bone targeting efficiency, biodistribution, and blood clearance. Since the targeting moiety, PAM, is highly negatively charged but small, the overall in vivo bone targeting and biodistribution were mediated by the physicochemical properties of conjugated fluorophores.

Molecular imaging, 2010

Low back pain is a prevalent medical condition that is difficult to diagnose and treat. Current i... more Low back pain is a prevalent medical condition that is difficult to diagnose and treat. Current imaging methods are unable to correlate pain reliably with spinal structures, and surgical removal of painful damaged or degenerating disks is technically challenging. A contrast agent specific for the intervertebral disk could assist in the detection, diagnosis, and surgical treatment of low back pain. The styryl pyridinium (FM) fluorophores were characterized and structure-activity relationships between chemical structure and in vivo uptake were established. Two novel FM fluorophores with improved optical properties for imaging the intervertebral disks were synthesized and evaluated in mice, rats, and pigs. After a single systemic injection, eight of eight FM fluorophores provided high-contrast imaging of the trigeminal ganglia, whereas six of eight provided high-contrast imaging of the dorsal root ganglia. Unexpectedly, three of eight FM fluorophores provided high-contrast imaging of a...

Molecular imaging, 2011

Nerve damage is the major morbidity of many surgeries, resulting in chronic pain, loss of functio... more Nerve damage is the major morbidity of many surgeries, resulting in chronic pain, loss of function, or both. The sparing of nerves during surgical procedures is a vexing problem because surrounding tissue often obscures them. To date, systemically administered nerve-highlighting contrast agents that can be used for nerve-sparing image-guided surgery have not been reported. In the current study, physicochemical and optical properties of 4,4'-[(2-methoxy-1,4-phenylene)di-(1E)-2,1-ethenediyl]bis-benzenamine (BMB) and a newly synthesized, red-shifted derivative 4-[(1E)-2-[4-[(1E)-2-[4-aminophenyl]ethenyl]-3-methoxyphenyl]ethenyl]-benzonitrile (GE3082) were characterized in vitro and in vivo. Both agents crossed the blood-nerve barrier and blood-brain barrier and rendered myelinated nerves fluorescent after a single systemic injection. Although both BMB and GE3082 also exhibited significant uptake in white adipose tissue, GE3082 underwent a hypsochromic shift in adipose tissue that p...

PLoS ONE, 2013

Nerve damage is a major morbidity associated with numerous surgical interventions. Yet, nerve vis... more Nerve damage is a major morbidity associated with numerous surgical interventions. Yet, nerve visualization continues to challenge even the most experienced surgeons. A nerve-specific fluorescent contrast agent, especially one with near-infrared (NIR) absorption and emission, would be of immediate benefit to patients and surgeons. Currently, there are only three classes of small molecule organic fluorophores that penetrate the blood nerve barrier and bind to nerve tissue when administered systemically. Of these three classes, the distyrylbenzenes (DSBs) are particularly attractive for further study. Although not presently in the NIR range, DSB fluorophores highlight all nerve tissue in mice, rats, and pigs after intravenous administration. The purpose of the current study was to define the pharmacophore responsible for nerve-specific uptake and retention, which would enable future molecules to be optimized for NIR optical properties. Structural analogs of the DSB class of small molecules were synthesized using combinatorial solid phase synthesis and commercially available building blocks, which yielded more than 200 unique DSB fluorophores. The nerve-specific properties of all DSB analogs were quantified using an ex vivo nerve-specific fluorescence assay on pig and human sciatic nerve. Results were used to perform quantitative structure-activity relationship (QSAR) modeling and to define the nerve-specific pharmacophore. All DSB analogs with positive ex vivo fluorescence were tested for in vivo nerve specificity in mice to assess the effect of biodistribution and clearance on nerve fluorescence signal. Two new DSB fluorophores with the highest nerve to muscle ratio were tested in pigs to confirm scalability.

Organic Letters, 2009

The N-dicyclopropylmethyl (Dcpm) residue, introduced into amino acids via reaction of dicycloprop... more The N-dicyclopropylmethyl (Dcpm) residue, introduced into amino acids via reaction of dicyclopropylmethanimine hydrochloride with an amino acid ester followed by sodium cyanoborohydride or triacetoxyborohydride reduction, can be used as an amide bond protectant for peptide synthesis. Examples which demonstrate the amelioration of aggregation effects include syntheses of the alanine decapeptide and the prion peptide (106-126). Avoidance of cyclization to † Abbreviations used: ACN = acetonitrile; BSA = bistrimethylsilylacetamide; Bsmoc = benzothiophenesulfonyl-2-methyloxycarbonyl; Dcpm = dicyclopropylmethyl; DIC = diisopropylcarbodiimide; Dmcp = dimethylcyclopropyl-methyl; DODT = 3,6-dioxa-1,8octanedithiol; Fmoc = 9-fluorenemethyloxycarbonyl; N-HATU = 1-[bis(dimethylamino)methylene]-1-H-1,2,3-triazolo[4,5-b] pyridinium hexafluorophosphate 3-oxide; N-HBTU = 1-[bis(dimethylamino)methylene]-1-H-benzotriazolium hexafluorophosphate 3oxide; Hmb = 2-hydroxy-4-methoxybenzyl; HOAt = 1-hydroxy-7-azabenzotriazole; Phth = o-phthaloyl; TFA = trifluoroacetic acid; TFFH = tetramethyl fluoroformamidinium hexafluorophosphate. carpino@chem.umass.edu. § On leave of absence from the Protein

Nature Nanotechnology, 2010

Inorganic/organic hybrid nanoparticles are potentially useful in biomedicine, but to avoid non-sp... more Inorganic/organic hybrid nanoparticles are potentially useful in biomedicine, but to avoid non-specific background fluorescence and long-term toxicity, they need to be cleared from the body within a reasonable timescale 1 . Previously, we have shown that rigid spherical nanoparticles such as quantum dots can be cleared by the kidneys if they have a hydrodynamic diameter of approximately 5.5 nm and a zwitterionic surface charge 2 . Here, we show that quantum dots functionalized with highaffinity small-molecule ligands that target tumours can also be cleared by the kidneys if their hydrodynamic diameter is less than this value, which sets an upper limit of 5-10 ligands per quantum dot for renal clearance. Animal models of prostate cancer and melanoma show receptor-specific imaging and renal clearance within 4 h post-injection. This study suggests a set of design rules for the clinical translation of targeted nanoparticles that can be eliminated through the kidneys.

Molecular Imaging and Biology, 2011

Purpose: The favorable pharmacokinetics and clinical safety profile of metal-chelated 1,4,7,10tet... more Purpose: The favorable pharmacokinetics and clinical safety profile of metal-chelated 1,4,7,10tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) suggests that it might be an ideal hapten for pretargeted radioimmunotherapy. In an effort to minimize hapten retention in normal tissues and determine the effect of various chemical adducts on in vivo properties, a series of DOTA-based derivatives were evaluated. Procedures: Biodistribution and whole-body clearance were evaluated for 177 Lu-labeled DOTA, DOTA-biotin, a di-DOTA peptide, and DOTA-aminobenzene in normal CD1 mice. Kidney, liver, and bone marrow doses were estimated using standard Medical Internal Radiation Dose methodology. Results: All haptens demonstrated similar low tissue and whole-body retention, with 2-4% of the injected dose remaining in mice 4 h postinjection. The kidney is predicted to be dose limiting for all 177 Lu-labeled haptens tested with an estimated kidney dose of approximately 0.1 mGy/MBq. Conclusions: We present here a group of DOTA-based haptens that exhibit rapid clearance and exceptionally low whole-body retention 4 h postinjection. Aminobenzene, tyrosine-lysine, and biotin groups have minimal effects on the blood clearance and biodistribution of 177 Lu-DOTA.

Journal of the American Chemical Society, 2009

Assigned from data sets measured in water at 2, 25, and 60 °C containing 13 C=O NMR chemical shif... more Assigned from data sets measured in water at 2, 25, and 60 °C containing 13 C=O NMR chemical shifts and [θ] 222 ellipticities, helical propensities are reported for the twenty genetically coded amino acids, as well as for norvaline and norleucine. These have been introduced by chemical synthesis at central sites within length-optimized, spaced, solubilized Ala 19 hosts. The resulting polyalaninederived, quantitative propensity sets express for each residue its temperature-dependent but contextindependent tendency to forgo a coil state and join a preexisting helical conformation. imply that at 2 °C all are strong breakers: ΔΔ G mean = +0.63 ± 0.11, but at 60 °C their breaking tendencies are dramatically attenuated and converge toward the mean: ΔΔ G mean = +0.25 ± 0.07. Accurate modeling of helix-rich proteins found in thermophiles, mesophiles, and organisms that flourish near 0 °C thus requires appropriately matched propensity sets. Comparisons are offered between the temperaturedependent propensity assignments of this study and those previously assigned by the Scheraga group; the special problems that attend propensity assignments for charged residues are illustrated by lysine guest data; and comparisons of errors in helicity assignments from shifts and ellipticity data show that the former provide superior precision and accuracy.

The Journal of Organic Chemistry, 2008

We present two new synthetic strategies to rigid multivalent scaffolds of the general structure 1... more We present two new synthetic strategies to rigid multivalent scaffolds of the general structure 1 based on adamantane. Both routes start from arylated adamantane derivatives and give the target compounds 12 and 18 in 5 and 7 steps, respectively. These scaffolds have been designed for the assembly of multivalent binders for cell surface epitopes. The adamantane nucleus exposes three carboxylic acid groups in a well defined tripodal geometry for conjugation of targeting ligands. In addition, an amino group at the fourth bridgehead position provides a flexible linker for attachment of effector molecules such as contrast agents, radiotracers, or cytotoxins without interfering with the cell binding process.