Mikhail I. Papisov

Massachusetts General Hospital, Boston, Massachusetts, United States

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Publications (30)125.03 Total impact

  • Mikhail I Papisov, Vasily Belov, Kimberley 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; · 4.57 Impact Factor
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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. · 3.53 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):736-747. · 4.57 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 01/2005; 6(5):2648-58. · 5.37 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 01/2005; 6(5):2659-70. · 5.37 Impact Factor
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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 01/2004; 1(5):375-82. · 4.57 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; · 11.96 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. · 6.34 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. · 2.68 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; · 12.89 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; · 12.89 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
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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. · 3.27 Impact Factor
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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 μmol 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°) 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 01/1995; 33(1):88-92. · 3.27 Impact Factor
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    ABSTRACT: To investigate specific surface characteristics of magnetic contrast agents based on a monocrystalline iron oxide nanoparticle (MION) that may determine their uptake and/or transport by axons. MION were modified to have a range of surface charges or were covalently linked to wheat germ agglutinin (WGA), a neurotropic protein. Each agent was injected directly into the sciatic nerves or femoral arteries of rats (n = 22), and magnetic resonance (MR) images were obtained several days later. The imaging results then were correlated with results at postmortem histologic examination. Substantial uptake and/or transport by axons occurred only after intraneural injection and only if the agent had a strong surface charge or was covalently linked to WGA. The sciatic nerves appeared as uniformly hypointense structures having lengths proportional to the time from injection to imaging, and the calculated transport rates (4-7 mm/d) were consistent with slow axonal transport. Numerous Schwann cells and macrophages acquired large fractions of the injected agents and contributed substantially to the imaging results. Those characteristics of MION-based contrast agents that promote efficacy after intraneural injection may impede delivery to the nerve after intraarterial injection.
    Radiology 12/1994; 193(2):485-91. · 6.34 Impact Factor
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    ABSTRACT: The hypothetical model is built explaining the molecular mechanism of protective action of poly(ethylene glycol) on liposomes in vivo. The protective layer of the polymer on the liposome surface is considered as a statistical 'cloud' of polymer possible conformations in solution. Computer simulation was used to demonstrate that relatively a small number of liposome-grafted molecules of hydrophilic and flexible polymer can create a dense protective conformational cloud over the liposome surface preventing opsonizing protein molecules from contacting liposome. A more rigid polymer fails to form this dense protective cloud, even when hydrophilic. Computer simulation was also used to reveal possible heterogeneity of reactive sites on a polymer-coated liposome surface, and to estimate the optimal polymer-to-lipid ratio for efficient liposome protection. Experiments have been performed with the quenching of liposome-associated fluorescent label (nitrobenzoxadiazole or fluorescein) with protein (rhodamine-ovalbumin or anti-fluorescein antibody) from solution. It was shown that poly(ethylene glycol) grafting to liposomes hinders protein interaction with the liposome surface, whereas liposome-grafted dextran (more rigid polymer) in similar quantities does not affect protein-liposome interaction. Highly-reactive and low-reactive populations of chemically identical reactive sites have been found on polymer-coated liposomes. Experimental data satisfactory confirm the suggested mechanism for the longevity of polymer-modified liposome.
    Biochimica et Biophysica Acta 11/1994; 1195(1):11-20. · 4.66 Impact Factor
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    ABSTRACT: To investigate the utility of a monocrystalline iron oxide nanoparticle (MION) as a contrast agent in magnetic resonance (MR) imaging of lymph nodes. Pharmacokinetic data were obtained in rats after intravenous, subcutaneous, and intraarterial injection of indium-111-MION-46. MR imaging was performed to determine optimal dosages and pulse sequences in rats. Models of lymph node metastasis in rabbits and lymph node hyperplasia in rats were used to demonstrate the efficacy of MION in differentiation of malignant and benign adenopathies. Biokinetic data indicate that nodal accumulation occurs primarily after extravasation of agent into the interstitial space (slow component) and subsequent trapping by lymph node macrophages (fast component). Relatively low concentrations (15-25 mumol Fe per kilogram for peripheral nodes after intraarterial injection) decrease signal intensity of nodes at MR imaging. Lymph node accumulation of MION-46 is high. Modification of injection techniques that alter capillary permeability allows use of systemically administered agent at doses as low as 15-25 mumol Fe per kilogram.
    Radiology 05/1994; 191(1):225-30. · 6.34 Impact Factor
  • Journal of Controlled Release - J CONTROL RELEASE. 01/1994; 28:325-326.
  • Journal of Controlled Release - J CONTROL RELEASE. 01/1994; 28:293-294.
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    ABSTRACT: Surface-modified LS have been used for the specific delivery of heavy metal-based imaging agents. The liposome surface was modified with PEG, AMmAb, Dext-SA, chelating agent DTPA-PE, and with NGPE-modified chelating polymer: DTPA-NPLL-NGPE. The hypothesis is suggested attempting to explain the phenomenon of long circulation of PEG-coated LS from the point of view of statistical properties of flexible polymer molecule in solution. Direct experiments using fluorescent labels were performed to prove the hypothesis. The calculations performed on the basis of the hypothesis were designed to find the optimal concentration of PEG on the LS surface, and suggested that it not only provides a protective effect but also does not create steric hindrances for the surface-immobilized mAb. As a result, long circulating targeted ILS have been prepared. Intravenously administered 111In-labelled PEG-AMmAb-LS were targeted to the area of experimental myocardial infarction in rabbits under γ-scintigraphic control. Infarct-to-normal ratios of 111In radioactivity of about 20 were achieved. PEG-and Dext-modified liposomes with surface-incorporated Gd-labelled DTPA-PE or DTPA-NPLL-NGPE were used for the subcutaneous administration and subsequent NMR-imaging of lymph nodes in rabbits. Two mechanisms of MR-signal enhancement were found for the surface-modified Gd-containing LS: the increase in signal intensity due to the increase in water quantity in the vicinity of Gd atoms because of PEG-associated water; and better lymph node accumulation of Dext-LS via receptor-mediated endocytosis. Surface modification of LS opens the possibilitiy for targeted delivery of heavy metal-based imaging agents.
    Journal of Controlled Release. 01/1994;