Mikhail I. Papisov

Harvard University, Cambridge, Massachusetts, United States

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Publications (36)164.42 Total impact

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    ABSTRACT: In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4-(benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine -3-carboxylic acid) was reacted with [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF in an HPLC injector loop to produce the radiotracer in a good yield (6 ± 3% uncorrected radiochemical yield) and high specific activity (143 ± 90 GBq·µmol-1 at end-of-synthesis). PET imaging of normal rats revealed rapid brain uptake at baseline (0.37 ± 0.08% ID/cc (percent of injected dose per cubic centimeter) at peak, 15-60 s), which was followed by fast washout. After pretreatment with isradipine (2 mg·kg-1, i.p.), whole brain radioactivity uptake was diminished by 25%-40%. This preliminary study confirms that [11C]isradipine can be synthesized routinely for research studies and is brain penetrating. Further work on Ca2+-channel radiotracer development is planned.
    Molecules 06/2015; 20(6):9550-9. DOI:10.3390/molecules20069550 · 2.42 Impact Factor
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    Scientific Reports 05/2015; 5:10187. DOI:10.1038/srep10187 · 5.58 Impact Factor
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    Mikhail I Papisov · Vasily V. Belov · Kimberley S. Gannon
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    ABSTRACT: Presently, there are no effective treatments for several diseases involving the CNS, which is protected by the blood-brain, blood-CSF and blood-arachnoid barriers. Traversing any of these barriers is difficult, especially for macromolecular drugs and particulates. However, there is significant experimental evidence that large molecules can be delivered to the CNS through the cerebro-spinal fluid (CSF). The flux of the interstitial fluid in the CNS parenchyma, as well as the macro flux of CSF in the leptomeningeal space, are believed to be generally opposite to the desirable direction of CNS-targeted drug delivery. On the other hand, the available data suggest that the layer of pia mater lining the CNS surface is not continuous, and the continuity of the leptomeningeal space (LMS) with the perivascular spaces penetrating into the parenchyma provides an unexplored avenue for drug transport deep into the brain via CSF. The published data generally do not support the view that macromolecule transport from the LMS to CNS is hindered by the interstitial and CSF fluxes. The data strongly suggest that leptomeningeal transport depends on the location and volume of the administered bolus and consists of four processes: (i) pulsation-assisted convectional transport of the solutes with CSF, (ii) active "pumping" of CSF into the periarterial spaces, (iii) solute transport from the latter to and within the parenchyma, and (iv) neuronal uptake and axonal transport. The final outcome will depend on the drug molecule behavior in each of these processes, which have not been studied systematically. The data available to date suggest that many macromolecules and nanoparticles can be delivered to CNS in biologically significant amounts (>1% of the administered dose); mechanistic investigation of macromolecule and particle behavior in CSF may result in a significantly more efficient leptomeningeal drug delivery than previously thought.
    Molecular Pharmaceutics 01/2013; 10(5). DOI:10.1021/mp300474m · 4.79 Impact Factor
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    Chandra Mushti · Mikhail I Papisov I Papisov
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    ABSTRACT: Among the currently available positron emitters suitable for Positron Emission Tomography (PET), 124I has the longest physical half-life (4.2 days). The long half-life and well-investigated behavior of iodine in vivo makes 124I very attractive for pharmacological studies. In this communication, we describe a simple yet effective method for the synthesis of novel 124I labeled compounds intended for PET imaging of arylsulfatase activity in vivo. Arylsulfatases have important biological functions, and genetic deficiencies of such functions require pharmacological replacement, the efficacy of which must be properly and non-invasively evaluated. These enzymes, even though their natural substrates are mostly of aliphatic nature, hydrolyze phenolic sulfates to phenol and sulfuric acid. The availability of [124I]iodinated substrates is expected to provide a PET-based method for measuring their activity in vivo. The currently available methods of synthesis of iodinated arylsulfates usually require either introducing of a protected sulfate ester early in the synthesis or introduction of sulfate group at the end of synthesis in a separate step. The described method gives the desired product in one step from an aryl-alkyl cyclic sulfate. When treated with iodide, the source cyclic sulfate opens with substitution of iodide at the alkyl center and gives the desired arylsulfate monoester.
    Molecules 12/2012; 17(11):13266-74. DOI:10.3390/molecules171113266 · 2.42 Impact Factor
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    Mikhail I. Papisov · V. Belov · A. J. Fischman · E. Belova · J. Titus · M. Gagne · C. Gillooly
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    ABSTRACT: Presently, there are no effective treatments for several diseases involving the central nervous system (CNS). While several novel molecular approaches are being developed, many of them require delivery of macromolecular or supramolecular agents to the CNS tissues protected by the blood–brain and blood–arachnoid barriers. A variety of approaches that are being developed for overcoming or bypassing the barriers are based on complex transfer processes. The delivery of biopharmaceuticals and other macromolecules and particulates to the CNS, especially through the leptomeningeal (intrathecal) route, includes a variety of stages, such as leptomeningeal propagation, drainage to the systemic circulation, and penetration into the CNS. The investigation of complex pharmacokinetics that includes convective, as well as diffusional and active transfer processes, greatly benefit from real-time non-invasive in vivo monitoring of the drug transport. Pharmacological positron emission tomography (PET) imaging, which enables such monitoring, plays an increasingly significant role in drug delivery and biopharmacology. PET is a powerful tool for quantitative in vivo tracking of molecules labeled with positron-emitting radionuclides. The high sensitivity, format, and accuracy of the data (similar to those of conventional tissue sampling biodistribution studies) make PET a readily adoptable pharmacological technique. In contrast to the conventional studies, PET also allows for longitudinal nonterminal same-animal studies. The latter may not only improve the data statistics, but also enable preclinical studies (especially in large and/or rare animals) not feasible under the conventional approach. This paper is intended to demonstrate the character of data that can be obtained by PET and to demonstrate how the main patterns of the leptomeningeal route pharmacokinetics can be investigated using this method. Examples of data processing are taken from our recent studies of five model proteins in rats and nonhuman primates.
    06/2012; 2(3). DOI:10.1007/s13346-012-0073-3
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    ABSTRACT: Presently, there are no effective treatments for conditions characterized by protein misfolding, such as Alzheimer’s, Parkinson’s, and other diseases involving CNS. Since misfolding occurs at the earliest stage of the disease, it is likely to be involved in subsequent pathological developments. It has been found that NPT002 (bacteriophage M13) directly dissociates aggregates of misfolded proteins that form amyloid, including amyloid-β, tau and α-synuclein. For CNS applications, NPT002 requires delivery to the brain parenchyma, the target tissue. NPT002 is an elongated ~950 nm particle that cannot penetrate into the brain from the blood. Furthermore, phage particles, due to their size, cannot be effectively transported in vivo by diffusion. Considering the physiology of the leptomeningeal space, intrathecal administration appears to be a promising convection-driven avenue for NPT002 delivery. In this paper, we use positron emission tomography to investigate the transport of NPT002 in Macaca fascicularis. The data suggest that approximately 50 % of the administered dose can reach the cerebral leptomeningeal space after a single lumbar intrathecal injection. A biologically significant fraction of the phage then enters the brain, resulting in potentially therapeutic cortical and subcortical exposure.
    06/2012; 2(3). DOI:10.1007/s13346-012-0074-2
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    ABSTRACT: A major challenge for the treatment of many central nervous system (CNS) disorders is the lack of convenient and effective methods for delivering biological agents to the brain. Mucopolysaccharidosis II (Hunter syndrome) is a rare inherited lysosomal storage disorder resulting from a deficiency of iduronate-2-sulfatase (I2S). I2S is a large, highly glycosylated enzyme. Intravenous administration is not likely to be an effective therapy for disease-related neurological outcomes that require enzyme access to the brain cells, in particular neurons and oligodendrocytes. We demonstrate that intracerebroventricular and lumbar intrathecal administration of recombinant I2S in dogs and nonhuman primates resulted in widespread enzyme distribution in the brain parenchyma, including remarkable deposition in the lysosomes of both neurons and oligodendrocytes. Lumbar intrathecal administration also resulted in enzyme delivery to the spinal cord, whereas little enzyme was detected there after intraventricular administration. Mucopolysaccharidosis II model is available in mice. Lumbar administration of recombinant I2S to enzyme deficient animals reduced the storage of glycosaminoglycans in both superficial and deep brain tissues, with concurrent morphological improvements. The observed patterns of enzyme transport from cerebrospinal fluid to the CNS tissues and the resultant biological activity (a) warrant further investigation of intrathecal delivery of I2S via lumbar catheter as an experimental treatment for the neurological symptoms of Hunter syndrome and (b) may have broader implications for CNS treatment with biopharmaceuticals.
    PLoS ONE 01/2012; 7(1):e30341. DOI:10.1371/journal.pone.0030341 · 3.23 Impact Factor
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    ABSTRACT: With the growing no. of biotechnol. products and drug delivery systems entering preclin. and clin. studies, pharmacol. imaging studies with PET play an increasingly significant role. Such studies often require investigation of slow and complex pharmacokinetics (PK). This suggests labeling of the drug candidate with radionuclides that have long phys. half-lives. Among the currently available PET positron emitters, 124I has the longest phys. half-life (4.2 days). This, combined with the well-investigated behavior of iodine in vivo, makes 124I very attractive for pharmacol. studies. However, the high energy of the positrons emitted by 124I and the presence of single photons in the 124I emission can potentially introduce limitations in the quant. anal. of the images. The objective of this research was to det. whether the use of 124I as a PET label provides data quality suitable for PK studies. The study was carried out using MicroPET P4 scanner (Siemens/Concorde Microsystems). Spatial resoln., count-rate performance, sensitivity and scatter fraction were measured using a line source and a cylindrical phantom. Model animal studies in rats and cynomolgus monkeys were carried out using human recombinant proteins. The proteins were labeled with 124I, up to 185 MBq/mg. The transaxial and axial spatial resolns. in the center of the camera were satisfactory and higher for OSEM3D/MAP than FORE-2DFBP (FWHM 2.52 vs 3.31 mm, and 3.10 vs 3.69 mm). Linearity of the true coincidence count-rate was obsd. up to 44 MBq. Animal studies demonstrated excellent delineation and resoln. of even very small organs. At optimal doses, 2-10 MBq per animal for rodents and 4-10 MBq per kg of body wt. for larger animals, the quality of numerical data was appropriate for PK anal. in all exptl. timeframes from minutes (dynamic studies) to 10 days. Overall, the data suggest that 124I is an excellent label for quant. pharmacol. PET imaging studies. [on SciFinder(R)]
    Molecular Pharmaceutics 03/2011; 8(3-3):736-747. DOI:10.1021/mp100358f · 4.79 Impact Factor
  • V. P. Torchilinl · M. I. Papisov
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    ABSTRACT: Abstract The hypothesis is suggested describing the molecular mechanism of protective action of poly(ethylene glycol) on liposomes in vivo on the basis of polymer properties in solvent. The protective layer of polymer on the liposome surface is considered as a “cloud” of possible conformations of macromolecules. If polymer is water-soluble and has flexible main chain, the density of this cloud is high enough to prevent the interaction of opsonins with liposome. At the same time, certain optimal concentration of the protective polymer can be found, when more loose areas in polymeric “clouds” can be used for the immobilization of antibodies on liposomes. As a result, long-circulating targeted liposomes can be obtained.
    Journal of Liposome Research 09/2008; 4(1):725-739. DOI:10.3109/08982109409037068 · 1.53 Impact Factor
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    ABSTRACT: Non-bioadhesive, fully biodegradable soluble polymers would be very instrumental in advanced biomedical applications, such as gene and drug delivery and tissue engineering. However, rational development of such materials is hindered by the complexity of macromolecule interactions with biological milieu. The prevalence of carbohydrates in naturally occurring interface structures suggests an alternative, biomimetic approach. Interface carbohydrates, regardless of their biological function, have common non-signaling substructures (e.g., acetal and ketal groups, secondary and primary alcohols). We hypothesized that hydrophilic polymers (polyals) consisting of acyclic units built of non-signaling carbohydrate substructures would be highly biocompatible and non-bioadhesive, while intrachain acetal or ketal groups would enable nonenzymatic biodegradation upon uptake by cells. Acyclic hydrophilic polyals can be prepared via either polymerization of suitable monomers or lateral cleavage of cyclic polyals (e.g., polysaccharides). In this study, model polyals were produced via lateral cleavage of polyaldoses and polyketoses. Best results were achieved using dextran B-512 as a precursor. The resultant poly[hydroxymethylethylene hydroxymethylformal], in agreement with the hypothesis, demonstrated excellent biological properties and technological flexibility. Materials of this type can potentially have several applications in pharmacology and bioengineering.
    Biomacromolecules 09/2005; 6(5):2659-70. DOI:10.1021/bm0502157 · 5.75 Impact Factor
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    ABSTRACT: Modification of proteins with hydrophilic polymers is an effective strategy for regulation of protein pharmacokinetics. However, conjugates of slowly or non-biodegradable materials, such as poly(ethylene glycol), are known to cause long-lasting cell vacuolization, in particular in renal epithelium. Conjugates of more degradable polymers, e.g., polysaccharides, have a significant risk of immunotoxicity. Polymers that combine complete degradability, long circulation in vivo, and low immuno and chemical toxicity would be most beneficial as protein conjugate components. This study explores new fully biodegradable hydrophilic polymers, hydrophilic polyals. They are nontoxic, stable at physiological conditions, and undergo proton-catalyzed hydrolysis at lysosomal pH. The model enzyme-polyal conjugates were prepared with 61-98% yield using conventional and novel conjugation techniques and retained 90-95% of specific activity. The model conjugates showed a significant prolongation of protein circulation in rodents, with a 5-fold reduction in the renal accumulation. The data suggests that hydrophilic polyals may be useful in designing protein conjugates with improved properties.
    Biomacromolecules 09/2005; 6(5):2648-58. DOI:10.1021/bm049210k · 5.75 Impact Factor
  • M I Papisov · A Yurkovetskiy · S Syed · N Koshkina · M Yin · A Hiller · A J Fischman
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    ABSTRACT: Lymph nodes are primary germination and proliferation sites for many types of pathogens. Maintaining therapeutic levels of appropriate chemotherapeutic agents in the lymph node tissue is critical for the treatment of both infection and cancer. This study was intended to develop a systemic route for loading lymph node phagocytes with drugs, using a lymph node specific nanocarrier. The latter is assembled as a 10-15 nm particle with a drug-carrying core and a phagocyte-homing poly(1-->6)-alpha-d-glucose based interface. Biokinetics and microdistribution of the model carrier were investigated in vivo. Nanocarrier accumulation in lymph nodes reached 30-35% dose/g in central lymph nodes, with deposition in various phagocytic cell populations. The latter included cells harboring inhaled microparticles translocated to lymph nodes from the lungs. In view of the nanocarrier ability to transport and release significant amounts of various drug substances, the data suggests feasibility of systemic drug loading to lymphatic phagocytes and, through drug release, to the neighboring cells.
    Molecular Pharmaceutics 02/2005; 2(1):47-56. DOI:10.1021/mp0499149 · 4.79 Impact Factor
  • A V Yurkovetskiy · A Hiller · S Syed · M Yin · X M Lu · A J Fischman · M I Papisov
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    ABSTRACT: A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t(1/2) = 2.2 +/- 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t(1/2) = 2.1 +/- 0.2 h, while the conjugate half-life was 14.2 +/- 1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics.
    Molecular Pharmaceutics 09/2004; 1(5):375-82. DOI:10.1021/mp0499306 · 4.79 Impact Factor
  • Mikhail I Papisov
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    ABSTRACT: The development of long-circulating, RES-avoiding liposomes has become a remarkable milestone in the progress of contemporary pharmacology. Drugs incorporated in such liposomes are protected from fast metabolization and clearance, and can be further targeted to a desired tissue site. Ideally, future developments should result in drug carriers which can identify and act upon their targets with even higher efficiency and selectivity, preferably close to or exceeding that of the natural immune cells.Further increasing carrier `inertness' with regard to the normal biological milieu is the major requirement for future success. The ability of natural blood components to circulate with blood for several days and weeks presents both the motivation and the challenge for further research. Today, even the best available preparations are inferior to natural proteins and cells with regard to their ability to remain in circulation by approximately two orders of magnitude.In view of the above, it seems vitally important to determine the mechanisms responsible for glycolipid- or polymer-modified liposome protection against RES, and whether any potentially useful mechanisms have been underutilized. Furthermore, identification of quantitative dependencies between liposome structure and pharmacokinetics (and mechanisms underlying such dependencies) would benefit future research and reduce the cost of development.This paper discusses the relationships between liposome structure and circulation with respect to the theoretical mechanistic models of mass transfer, liposome interactions with cells and blood proteins, and boundary effects resulting from surface modification. Special attention is paid to the practical application and limitations of the models.
    Advanced drug delivery reviews 07/1998; 32(1-32):119-138. DOI:10.1016/S0169-409X(97)00135-X · 12.71 Impact Factor
  • M Papisov · R Weissleder
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    ABSTRACT: Efficient diagnosis and therapy of diseases affecting lymph nodes rely on the availability of drugs that are retained by lymph nodes. Intralymphatically or interstitially administered macromolecular carriers accumulate efficiently in draining lymph nodes. However, because of the high variability of lymphatic networks and drainage routes, systemic administration of lymphotropic carriers would be preferable and currently represents a major focus in lymphotropic drug design. This review focuses on advances in the development of intravenous drug carriers and briefly discusses agents used for local delivery.
    Critical Reviews in Therapeutic Drug Carrier Systems 02/1996; 13(1-2):57-84. · 3.17 Impact Factor
  • L Harika · R Weissleder · K Poss · M I Papisov
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    ABSTRACT: To determine the pharmacokinetic and magnetic resonance (MR) imaging properties of diethylenetriaminepentaacetic acid (DTPA) conjugated with a polyglucose-associated macrocomplex (PGM), which accumulates in lymph nodes. In 124 normal and 20 tumor-bearing rats, Gd-DTPA PGM was administered intravenously in doses of 2, 10, 20 mumol gadolinium per kilogram of tissue. Mean blood half-life was 2 hours. Maximum accumulation in peripheral (33.0% injected dose [ID]/g +/- 16.2 [standard deviation]) and central lymph nodes (63.2% ID/g +/- 16.5) was observed within 24 hours after administration. The optimum dose range was 10-20 mumol Gd/kg in rats. At 24 hours after administration of 20 mumol Gd/kg, the signal-to-noise ratio increased from 30.9 +/- 0.4 to 83.2 +/- 5.2 in normal lymph nodes (P < .001). Differentiation between normal and metastatic lymph nodes was improved. When labeled with Gd-DTPA, the PGM-based graft copolymer significantly increases signal intensity at MR imaging of normal but not metastatic lymph nodes without causing distortion artifacts.
    Radiology 02/1996; 198(2):365-70. DOI:10.1148/radiology.198.2.8596833 · 6.21 Impact Factor
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    ABSTRACT: A variety of iron oxide preparations with long blood half-lives have been synthesized for MR imaging. Potential applications of these agents include MR angiography, RES imaging, target specific imaging and neuronal transport imaging. This chapter reviews types of iron oxide and mechanisms that are responsible for a prolonged plasma half-life.
    Advanced Drug Delivery Reviews 09/1995; 16(2-16):321-334. DOI:10.1016/0169-409X(95)00033-4 · 12.71 Impact Factor
  • Mikhail I. Papisov
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    ABSTRACT: The relationships between polymer structure and circulation in vivo are discussed on the basis of a mathematical model of polymer transfer. Significant differences in polymer distribution in liquid compartments allow to divide long-circulating polymers and particulates into two groups, large (non-extravasating) and small (extravasating) polymers. Transfer processes that members of these two groups undergo are distinctively different and can be described by different idealized models. Although polymers of both classes may consist of the same constituents, their in vivo localization in liquid compartments and capability of cooperative interactions with components of biological systems may be essentially different. Therefore, relative impact of polymer structure on biokinetics of large and small polymers may differ. Minimization of polymer clearance due to interactions with biological systems and renal filtration is important in the development of long-circulating polymers. Hydrophilic interface brushes assembled of non-reactive polymer chains proved to be effective in prolongation of circulation of both extravasating and non-extravasating polymers, although prolongation mechanisms may differ.
    Advanced Drug Delivery Reviews 09/1995; 16(2-3-16):127-139. DOI:10.1016/0169-409X(95)00021-X · 12.71 Impact Factor
  • H Frank · R Weissleder · M Papisov
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    ABSTRACT: A magnetically labeled antimyosin (MION-AM) has previously been developed for immunospecific MR imaging in vivo. The current study was designed to extend previous feasibility studies and to correlate MR infarct size to that determined by histopathology. The left anterior coronary artery (LAD) was temporarily occluded in rabbits (n = 10) and subsequently reperfused for 1 h prior to the administration of 100 mumol Fe/kg of MION-AM (corresponding to 0.5 mg AM). One hour after i.v. administration, the infarcted myocardium appeared hypointense by MRI as a result of target-specific attachment of the magnetic T2 label to damaged but not normal myocardium. There was a close correlation between infarct size determined by MR and pathology (SE 2500/30: r = 0.92, p < or = 0.0001; SE 2500/60: r = 0.85, p < or = 0.0001). Our results are evidence that a) immunospecific magnetic probes can be utilized for cardiac MR imaging, and b) that these or similar agents may aid in the quantitation of myocardial infarct size.
    Zeitschrift für Kardiologie 05/1995; 84(4):311-5. · 0.97 Impact Factor
  • L Harika · R Weissleder · K Poss · C Zimmer · M I Papisov · T J Brady
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    ABSTRACT: A model system of a paramagnetic lymphotropic MR contrast agent (Gd-DTPA labeled polyglucose associated macrocomplex, PGM) for T1-weighted MR imaging of lymph nodes in rats and rabbits was evaluated. Pharmacokinetic (tissue accumulation) and MR imaging data (optimal dose and timing parameters) were obtained in normal rats (n = 88) after subcutaneous (SC) injection of paramagnetic, radiolabeled [111In]Gd-DTPA-PGM. A rabbit model of lymph node metastases (n = 8) was ultimately used to demonstrate the potential of MR imaging with Gd-DTPA-PGM for nodal tumor detection. Maximum concentrations of Gd-DTPA-PGM were found in popliteal and paraaortic lymph nodes within 24 h after SC administration, and highest lymph node SNR values were obtained by MR imaging at this time point. The optimum imaging dose was 6-12 mumol Gd/kg. Tumor-lymph node contrast increased from 0.0 +/- 1.2 precontrast to 19.2 +/- 6.5 (spoiled gradient echo sequence, TR 50/TE 7/flip angle 60 degrees) postcontrast and conspicuity of nodal metastases was improved. Gd-DTPA-PGM accumulates in lymph nodes after SC administration and significantly enhances lymph node signal intensity of normal animals but not metastatic lymph nodes.
    Magnetic Resonance in Medicine 02/1995; 33(1):88-92. · 3.40 Impact Factor

Publication Stats

2k Citations
164.42 Total Impact Points

Institutions

  • 2004–2013
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1992–2012
    • Massachusetts General Hospital
      • Department of Radiology
      Boston, Massachusetts, United States
  • 1993–2005
    • Harvard Medical School
      • Department of Radiology
      Boston, Massachusetts, United States
  • 1995
    • University of Vienna
      Wien, Vienna, Austria