Gunilla Jacobson

All Publications

• Proceedings: Pathways for Successful Translation of New Imaging Agents and Modalities-Phase III Studies JOURNAL OF NUCLEAR MEDICINE Gambhir, S. S., Shankar, L. K., Rosenthal, E., Warram, J. M., Ghesani, M., Hope, T. A., Jacobs, P. M., Jacobson, G. B., Wilson, T., Siegel, B. A. 2019; 60 (6): 736?44

  View details for DOI 10.2967/jnumed.118.219824

  View details for Web of Science ID 000470084400016

• Proceedings - Pathways for Successful Translation of New Imaging Agents and Modalities: Phase III Studies. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Gambhir, S. S., Shankar, L. K., Rosenthal, E., Warram, J. M., Ghesani, M. V., Hope, T. A., Jacobs, P. M., Jacobson, G. B., Wilson, T., Siegel, B. A. 2019

  Abstract

  Significant advances continue in the development of cancer-specific molecular imaging agents and modalities for diagnosing, staging, and treating various cancer types. For these advances to successfully translate to widespread clinical use, both regulatory approval by the U.S. Food and Drug Administration (FDA), and completion of the reimbursement approval process with the Centers for Medicare & Medicaid Services (CMS), must be achieved. To this end, methods for expediting these processes are being addressed by both agencies. This report summarizes a one-day meeting held May 15, 2017 with officials from the National Cancer Institute (NCI), FDA, and CMS; members of the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the World Molecular Imaging Society (WMIS), the American College of Radiology (ACR), the Radiological Society of North America (RSNA), the International Society for Strategic Studies in Radiology (IS3R), the Medical Imaging and Technology Alliance (MITA), molecular imaging scientists from some major hospitals/institutions and industry representatives, who joined together to learn about the pathways of approval, coverage, and payment decisions. The meeting's focus was three-part: i) to broaden the conversation to other agents/modalities and address both the reimbursement and regulatory components; ii) to present a current view of FDA regulatory innovations in cancer imaging development, a past and present view of PET/MI agent approval processes, and a current view of CMS reimbursement protocols; and iii) to discuss scientific issues involved in orchestrating agency-required Phase III clinical trials as presented through three case examples: a PET probe targeting the prostate specific membrane antigen (PSMA) for imaging prostate cancer, an optical antibody probe for image-guided head and neck cancer surgery targeting epidermal growth factor receptor (EGFR), and ultrasonography with targeted microbubbles against a neovasculature target, kinase insert domain receptor (KDR), for ovarian cancer. Additionally, the meeting served to provide more clarity to researchers on trial design, to delineate more uniformly required steps investigators should take to successfully translate their innovations. Reported here are the meeting's discussion items and recommendations for continued honing of the approval and reimbursement processes investigators must navigate.

  View details for PubMedID 30850482

• Electrochemically triggered release of acetylcholine from scCO2 impregnated conductive polymer films evokes intracellular Ca(2+) signaling in neurotypic SH-SY5Y cells. Journal of controlled release Löffler, S., Seyock, S., Nybom, R., Jacobson, G. B., Richter-Dahlfors, A. 2016; 243: 283-290

  Abstract

  Implantable devices for electronically triggered drug release are attractive to achieve spatial and temporal control over drug concentrations in patients. Realization of such devices is, however, associated with technical and biological challenges. Among these are containment of drug reservoirs, lack of precise control cues, as well as the charge and size of the drug. Here, we present a method for electronically triggered release of the quaternary ammonium cation acetylcholine (ACh) from an impregnated conductive polymer film. Using supercritical carbon dioxide (scCO2), a film of PEDOT/PSS (poly(3,4)-ethylenedioxythiophene doped with poly(styrenesulfonate)) is impregnated with the neurotransmitter acetylcholine. The gentle scCO2 process generated a dry, drug-impregnated surface, well suited for interaction with biological material, while maintaining normal electrochemical properties of the polymer. Electrochemical switching of impregnated PEDOT/PSS films stimulated release of ACh from the polymer matrix, likely due to swelling mediated by the influx and efflux of charged and solvated ions. Triggered release of ACh did not affect the biological activity of the drug. This was shown by real-time monitoring of intracellular Ca(2+) signaling in neurotypic cells growing on the impregnated polymer surface. Collectively, scCO2 impregnation of conducting polymers offers the first one-step, dopant-independent drug impregnation process, potentially facilitating loading of both anionic and cationic drugs that can be dissolved in scCO2 on its own or by using a co-solvent. We foresee that scCO2-loaded devices for electronically triggered drug release will create novel opportunities when generating active bio-coatings, tunable for specific needs, in a variety of medical settings.

  View details for DOI 10.1016/j.jconrel.2016.10.020

  View details for PubMedID 27793684

• Scaffold-mediated BMP-2 minicircle DNA delivery accelerated bone repair in a mouse critical-size calvarial defect model JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Keeney, M., Chung, M. T., Zielins, E. R., Paik, K. J., McArdle, A., Morrison, S. D., Ransom, R. C., Barbhaiya, N., Atashroo, D., Jacobson, G., Zare, R. N., Longaker, M. T., Wan, D. C., Yang, F. 2016; 104 (8): 2099-2107

  Abstract

  Scaffold-mediated gene delivery holds great promise for tissue regeneration. However, previous attempts to induce bone regeneration using scaffold-mediated non-viral gene delivery rarely resulted in satisfactory healing. We report a novel platform with sustained release of minicircle DNA (MC) from PLGA scaffolds to accelerate bone repair. MC was encapsulated inside PLGA scaffolds using supercritical CO2 , which showed prolonged release of MC. Skull-derived osteoblasts transfected with BMP-2 MC in vitro result in higher osteocalcin gene expression and mineralized bone formation. When implanted in a critical-size mouse calvarial defect, scaffolds containing luciferase MC lead to robust in situ protein production up to at least 60 days. Scaffold-mediated BMP-2 MC delivery leads to substantially accelerated bone repair as early as two weeks, which continues to progress over 12 weeks. This platform represents an efficient, long-term nonviral gene delivery system, and may be applicable for enhancing repair of a broad range of tissues types. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2099-2107, 2016.

  View details for DOI 10.1002/jbm.a.35735

  View details for Web of Science ID 000379736500025

  View details for PubMedID 27059085

• Swedish Medical Nanoscience Center at Karolinska Institutet NANOTECHNOLOGY REVIEWS Jacobson, G. B., Richter-Dahlfors, A. 2012; 1 (3): 273-279

  View details for DOI 10.1515/ntrev-2012-0006

  View details for Web of Science ID 000208982500005

• In Vivo Sustained Release of siRNA from Solid Lipid Nanoparticles ACS NANO Lobovkina, T., Jacobson, G. B., Gonzalez-Gonzalez, E., Hickerson, R. P., Leake, D., Kaspar, R. L., Contag, C. H., Zare, R. N. 2011; 5 (12): 9977-9983

  Abstract

  Small interfering RNA (siRNA) is a highly potent drug in gene-based therapy with a challenge of being delivered in a sustained manner. Nanoparticle drug delivery systems allow for incorporating and controlled release of therapeutic payloads. We demonstrate that solid lipid nanoparticles can incorporate and provide sustained release of siRNA. Tristearin solid lipid nanoparticles, made by nanoprecipitation, were loaded with siRNA (4.4-5.5 wt % loading ratio) using a hydrophobic ion pairing approach that employs the cationic lipid DOTAP. Intradermal injection of these nanocarriers in mouse footpads resulted in prolonged siRNA release over a period of 10-13 days. In vitro cell studies showed that the released siRNA retained its activity. Nanoparticles developed in this study offer an alternative approach to polymeric nanoparticles for encapsulation and sustained delivery of siRNA with the advantage of being prepared from physiologically well-tolerated materials.

  View details for DOI 10.1021/nn203745n

  View details for Web of Science ID 000298316700073

  View details for PubMedID 22077198

  View details for PubMedCentralID PMC3246574

• Biodegradable Nanoparticles With Sustained Release of Functional siRNA in Skin JOURNAL OF PHARMACEUTICAL SCIENCES Jacobson, G. B., Gonzalez-Gonzalez, E., Spitler, R., Shinde, R., Leake, D., Kaspar, R. L., Contag, C. H., Zare, R. N. 2010; 99 (10): 4261-4266

  Abstract

  A key challenge in developing RNAi-based therapeutics is efficient delivery of functional short interfering RNA (siRNA) to target cells. To address this need, we have used a supercritical CO(2) process to incorporate siRNA in biodegradable polymer nanoparticles (NPs) for in vivo sustained release. By this means we have obtained complete encapsulation of the siRNA with minimal initial burst effect from the surface of the NPs. The slow release of a fluorescently labeled siRNA mimic (siGLO Red) was observed for up to 80 days in vivo after intradermal injection into mouse footpads. In vivo gene silencing experiments were also performed, showing reduction of GFP signal in the epidermis of a reporter transgenic mouse model, which demonstrates that the siRNA retained activity following release from the polymer NPs.

  View details for DOI 10.1002/jps.22147

  View details for Web of Science ID 000282473400012

  View details for PubMedID 20737633

• Nanoparticle Formation of Organic Compounds With Retained Biological Activity JOURNAL OF PHARMACEUTICAL SCIENCES Jacobson, G. B., Shinde, R., McCullough, R. L., Cheng, N. J., Creasman, A., Beyene, A., Hickerson, R. P., Quan, C., Turner, C., Kaspar, R. L., Contag, C. H., Zare, R. N. 2010; 99 (6): 2750-2755

  Abstract

  Many pharmaceuticals are formulated as powders to aid drug delivery. A major problem is how to produce powders having high purity, controlled morphology, and retained bioactivity. We demonstrate the use of supercritical carbon dioxide as an antisolvent for meeting this need for two model drug systems, quercetin, a sparingly soluble antioxidant, and short interfering RNA (siRNA), which can silence genes. In both cases we achieve retention of bioactivity as well as a narrow particle size distribution in which the particles are free of impurities.

  View details for DOI 10.1002/jps.22035

  View details for Web of Science ID 000278241800022

  View details for PubMedID 20039390

• Sustained release of nucleic acids from polymeric nanoparticles using microemulsion precipitation in supercritical carbon dioxide CHEMICAL COMMUNICATIONS Ge, J., Jacobson, G. B., Lobovkina, T., Holmberg, K., Zare, R. N. 2010; 46 (47): 9034-9036

  Abstract

  A general approach for producing biodegradable nanoparticles for sustained nucleic acid release is presented. The nanoparticles are produced by precipitating a water-in-oil microemulsion in supercritical CO(2). The microemulsion consists of a transfer RNA aqueous solution (water phase), dichloromethane containing poly(l-lactic acid)-poly(ethylene glycol) (oil phase), the surfactant n-octyl ?-D-glucopyranoside, and the cosurfactant n-butanol.

  View details for DOI 10.1039/c0cc04258g

  View details for Web of Science ID 000284482100040

  View details for PubMedID 21052588

• Sustained release of drugs dispersed in polymer nanoparticles ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Jacobson, G. B., Shinde, R., Contag, C. H., Zare, R. N. 2008; 47 (41): 7880-7882

  View details for DOI 10.1002/anie.200802260

  View details for Web of Science ID 000260062500019

  View details for PubMedID 18773393

  View details for PubMedCentralID PMC2586612

• Subcritical water extraction and beta-glucosidase-catalyzed hydrolysis of quercetin glycosides in onion waste GREEN CHEMISTRY Turner, C., Turner, P., Jacobson, G., Almgren, K., Waldeback, M., Sjoberg, P., Karlsson, E. N., Markides, K. E. 2006; 8 (11): 949-959

  View details for DOI 10.1039/b608011a

  View details for Web of Science ID 000241588000008

• Organic synthesis in water carbon dioxide microemulsions JOURNAL OF ORGANIC CHEMISTRY Jacobson, G. B., Lee, C. T., Johnston, K. P. 1999; 64 (4): 1201-1206

  View details for Web of Science ID 000078826200023

• Organic synthesis in water carbon dioxide emulsions JOURNAL OF ORGANIC CHEMISTRY Jacobson, G. B., Lee, C. T., daRocha, R. P., Johnston, K. P. 1999; 64 (4): 1207-1210

  View details for Web of Science ID 000078826200024

• Biphasic Catalysis in Water/Carbon Dioxide Emulsions, Journal of the American Chemical Society Jacobson, G. B., Lee, C. T., Johnston, K. P., Tumas, W. B. 1999; 121 (50)
• Synthesis of O-[C-11]acetyl CoA, O-[C-11]acetyl-L-carnitine, L-[C-11]carnitine labelled in specific positions, applied in PET studies on rhesus monkey NUCLEAR MEDICINE AND BIOLOGY Jacobson, G. B., Watanabe, Y., Valind, S., Kuratsune, H., Langstrom, B. 1997; 24 (5): 471-478

  Abstract

  The syntheses of L-carnitine, O-acetyl CoA, and O-acetyl-L-carnitine labelled with 11C at the 1- or 2-position of the acetyl group or the N-methyl position of carnitine, using the enzymes acetyl CoA synthetase and carnitine acetyltransferase, are described. With a total synthesis time of 45 min, O-[1-11C]acetyl CoA and O-[2[11C]acetyl CoA was obtained in 60-70% decay-corrected radiochemical yield, and O-[1-11C]acetyl-L-carnitine and O-[2-11C] acetyl-L-carnitine in 70-80% yield, based on [1-11C]acetate or [2-11C]acetate, respectively. By an N-methylation reaction with [11C]methyl iodide, L-[methyl-11C]carnitine was obtained within 30 min, and O-acetyl-L-[methyl-11C]carnitine within 40 min, giving a decay-corrected radiochemical yield of 60% and 40-50%, respectively, based on [11C]methyl iodide. Initial data of the kinetics of the different 11C-labelled L-carnitine and acetyl-L-carnitines in renal cortex of anaesthetized monkey (Macaca mulatta) are presented.

  View details for Web of Science ID A1997XP97800017

  View details for PubMedID 9290085

• Supercritical Fluid Extraction of 11C-Labelled Metabolites from Tissue using Supercritical Ammonia. ANAL. CHEM. Jacobson, R. B., Moulder, R., Lu, L., Bergström, M., Markides, K. E., Långström, B. 1997
• High Uptake of [2-11C]Acetyl-l-Carnitine into the Brain: A Pet Study Biochemical and Biophysical Research Communications Kuratsune, H., Watanabe, Y., Yamaguti, K., Jacobson, G., Takahashi, M., Machii, T., Onoe, H., Onoe, K., Kiyoshi, Valind, S., Kitani, T., Bengt 1997: 488
• Supercritical Fluid Synthesis and On-line Preparative Supercritical Fluid Chromatography of 11C-Labelled Compounds in Supercritical Ammonia. ACTA CHEM. SCAND. Jacobson, G. B., Markides, K. E., Långström, B. 1997; 51
• Acylcarnitine and Chronic Fatigue Syndrome. CARNITINE TODAY Kuratsune, H., Yamaguti, K., Watanabe, Y., Takahashi, M., Nakamoto, I., Machii, T., Jacobson, G. B., Onoe, H., Matsumura, K., Valind, S., Långström, B., Kitani, T. 1997
• Synthesis of 11 C-Labeled Guanidines in Supercritical Ammonia JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Jacobson, G. B., Westerberg, G., Markides, K. E., Långtsröm, B. 1997; 118 (29): 6868
• Methodological aspects for in vitro characterization of receptor binding using 11C-Labelled receptor ligands: a detailed study with the benzodiazepine receptor antagonist [11C]Ro 15-1788 NUCL. MED. BIOL. Sihver, W., Sihver, S., Bergström, M., Murata, T., Matsumura, K., Onoe, H., Andersson, Y., Bjurling, P., Fasth, K., Westerberg, G., Ögren, M., Jacobson, G., Lundqvist, H., Oreland, L., Watanabe, Y., Långström, B. 1997; 24 (8): 723
• PET and parathyroid L-[carbon-11]methionine accumulation in hyperparathyroidism JOURNAL OF NUCLEAR MEDICINE Sundin, A., Johansson, C., Hellman, P., Bergstrom, M., Ahlstrom, H., Jacobson, G. B., Langstrom, B., Rastad, J. 1996; 37 (11): 1766-1770

  Abstract

  The study was designed to characterize L-[methyl-11 C]methionine accumulation in abnormal parathyroid tissues of hyperparathyroidism (HPT).Thirty-four patients with primary (n = 32) or secondary HPT were investigated with PET before primary or reoperative (n = 25) parathyroid surgery. Parathyroid 11C-methionine accumulation was analyzed for integrated uptake values in defined tissue volumes standardized for the injected dose and body weight (SUV), four contiguous pixels of maximal accumulation (SUVhs), SUV multiplied by area of region of interest (SUVr) and by the excised tissue weight (SUVw). Transport rate constants (slope, slopehs) were calculated according to Patlak's formula using plasma 11C activity corrected for 11C-methionine metabolites.True-positive localization was achieved in 85% of patients in whom 81% of the excised parathyroid lesions were visualized; no false-positive results were obtained. Corresponding proportions were 59% and 57% for CT and 55% and 52% for ultrasound, respectively. In the true-positive cases, parathyroid SUV, SUVhs and transport rate constants were consistently higher (p < 0.01) than in the thyroid, pharynx-esophagus, neck muscle and apical lung. Parathyroid SUV, SUVhs and SUVr increased with intact serum parathyroid hormone and calcium values (p = 0.0001-0.031), and weight of the excised tissue correlated with SUV and SUVhs (p = 0.024, 0.044). Parathyroid SUVhs varied strongly with the transport rate constants (p = 0.0008), and SUVr as well as s-calcium values differed significantly between parathyroid adenomas (n = 11), chief cell hyperplasias (n = 13), inadvertent implants (n = 3) and parathyroid cancers (n = 3).Carbon-11-methionine PET has potential application in preoperative localization and metabolic characterization of abnormal parathyroid tissues in human HPT.

  View details for Web of Science ID A1996VR84600013

  View details for PubMedID 8917171

• Levodopa-induced changes in synaptic dopamine in patients with Parkinson's disease as measured by [C-11]raclopride displacement and PET NEUROLOGY Tedroff, J., PEDERSEN, M., Aquilonius, S. M., Hartvig, P., Jacobsson, G., Langstrom, B. 1996; 46 (5): 1430-1436

  Abstract

  Changes in striatal binding of [11C]raclopride, a dopamine D2 receptor antagonist, induced by acute levodopa administration, were evaluated with PET in 10 patients with idiopathic Parkinson's disease (PD). The patients were scanned on two occasions: drug-free and 15 minutes after a 5-minute intravenous infusion of 3 mg/kg levodopa. Levodopa administration produced reductions in striatal [11C]raclopride uptake index with a rostrocaudal gradient. The most pronounced reduction was found in the posterior putamen (to 82% of baseline), followed by the anterior putamen (to 88% of baseline) and the caudate nucleus (to 94% of baseline). The magnitude of [11C]raclopride uptake index reduction correlated with drug-free disability. Moreover, in four hemiparkinsonian patients, a reduction in [11C]raclopride uptake index was measured in the putamen contralateral to the parkinsonian symptoms. The present results demonstrate a positive correlation between striatal dopaminergic nerve-terminal deficiency and the capacity for levodopa to increase synaptic dopamine and displace [11C]raclopride binding, which corresponds to an accelerated amine turnover in dopamine-depleted striatal tissue. We therefore suggest that dopaminergic degeneration in PD is paralleled by a progressive acceleration of amine turnover. This mechanistic consequence of nigrostriatal degeneration, the selective restoration of synaptic dopaminergic neurotransmission in denervated striatal subregions, may explain the effectiveness of levodopa in producing symptomatic benefits in early PD. However, we also suggest that in the vastly denervated striatum, as in advanced PD, an excessive acceleration of amine turnover results in swings in levodopa-induced synaptic dopamine levels that are far beyond normal. This phenomenon most likely plays a key role in the pathogenesis underlying the development of motor-response complications in PD.

  View details for Web of Science ID A1996UK62800043

  View details for PubMedID 8628494

• IN-VITRO POSITRON EMISSION TOMOGRAPHY (PET) - USE OF POSITRON EMISSION TRACERS IN FUNCTIONAL IMAGING IN LIVING BRAIN-SLICES NEUROSCIENCE RESEARCH Matsumura, K., Bergstrom, M., Onoe, H., Takechi, H., Westerberg, G., Antoni, G., Bjurling, P., Jacobson, G. B., Langstrom, B., Watanabe, Y. 1995; 22 (2): 219-229

  Abstract

  Positron-emitting radionuclides have short half-lives and high radiation energies compared with radioisotopes generally used in biomedical research. We examined the possibility of applying positron emitter-labeled compounds to functional imaging in brain slices kept viable in an oxygenated buffer solution. Brain slices (300 microns thick) containing the striatum were incubated with positron emitter-labeled tracers for 30-45 min. The slices were then rinsed and placed on the bottom of a Plexiglas chamber filled with oxygenated Krebs-Ringer solution. The bottom of the chamber consisted of a thin polypropylene film to allow good penetration of beta+ particles from the brain slices. The chamber was placed on a storage phosphor screen, which has a higher sensitivity and a wider dynamic range than X-ray films. After an exposure period of 15-60 min, the screen was scanned by the analyzer and radioactivity images of brain slices were obtained within 20 min. We succeeded in obtaining quantitative images of (1) [18F]fluorodeoxyglucose uptake, (2) dopamine D2 receptor binding, (3) dopa-decarboxylase activity, and (4) release of [11C]dopamine preloaded as L-[11C]DOPA in the brain slice preparation. These results demonstrate that positron emitter-labeled tracers in combination with storage phosphor screens are useful for functional imaging of living brain slices as a novel neuroscience technique.

  View details for Web of Science ID A1995RB42100008

  View details for PubMedID 7566703

• Synthesis of [11C]Acetyl-CoA and [11C]Acetyl-L-Carnitine. Synth. Appl. Isot. Labelled Compounds Jacobson, G. B., Watanabe, Y., Kuratsune, H., Yamaguchi, K., Onoe , , Kittani , Valind , 1995; 118 (29): 375
• Synthesis of C-11-labelled compounds in supercritical ammonia 5th International Symposium on Synthesis and Applications of Isotopically Labelled Compounds 1994 Jacobson, G. B., Markides, K. E., Langstrom, B. JOHN WILEY & SONS LTD. 1995: 343?346

  View details for Web of Science ID A1995BD92K00059

• Synthesis of [C-11]acetyl-CoA and [C-11]acetyl-L-carnitine 5th International Symposium on Synthesis and Applications of Isotopically Labelled Compounds 1994 Jacobson, G. B., Watanabe, Y., Kuratsune, H., Yamaguchi, K., Onoe, H., Takahashi, M., Kitani, T., Valind, S., Langstrom, B. JOHN WILEY & SONS LTD. 1995: 375?377

  View details for Web of Science ID A1995BD92K00067

• SUPERCRITICAL-FLUID SYNTHESIS IN THE PREPARATION OF BETA(+)-EMITTING LABELED COMPOUNDS ACTA CHEMICA SCANDINAVICA Jacobson, G. B., Markides, K. E., Langstrom, B. 1994; 48 (5): 428-433

  View details for Web of Science ID A1994NL02900011