Sebastian P Pernal1,2, Alexander J Willis1, Michael E Sabo3, Laura M Moore4, Steven T Olson5, Sean C Morris4, Francis M Creighton3, Herbert H Engelhard1,2,6. 1. The Cancer Center, The University of Illinois at Chicago, Chicago, IL, USA. 2. Department of Neurosurgery, The University of Illinois at Chicago, Chicago, IL, USA. 3. UNandUP, LLC, St. Louis, MO, USA. 4. Pulse Therapeutics, Inc, St. Louis, MO, USA. 5. Department of Periodontics, The University of Illinois at Chicago, Chicago, IL, USA. 6. Department of Bioengineering, The University of Illinois at Chicago, Chicago, IL, USA.
Abstract
BACKGROUND: Thrombotic events continue to be a major cause of morbidity and mortality worldwide. Tissue plasminogen activator (tPA) is used for the treatment of acute ischemic stroke and other thrombotic disorders. Use of tPA is limited by its narrow therapeutic time window, hemorrhagic complications, and insufficient delivery to the location of the thrombus. Magnetic nanoparticles (MNPs) have been proposed for targeting tPA delivery. It would be advantageous to develop an improved in vitro model of clot formation, to screen thrombolytic therapies that could be enhanced by addition of MNPs, and to test magnetic drug targeting at human-sized distances. METHODS: We utilized commercially available blood and endothelial cells to construct 1/8th inch (and larger) biomimetic vascular channels in acrylic trays. MNP clusters were moved at a distance by a rotating permanent magnet and moved along the channels by surface walking. The effect of different transport media on MNP velocity was studied using video photography. MNPs with and without tPA were analyzed to determine their velocities in the channels, and their fibrinolytic effect in wells and the trays. RESULTS: MNP clusters could be moved through fluids including blood, at human-sized distances, down straight or branched channels, using the rotating permanent magnet. The greatest MNP velocity was closest to the magnet: 0.76 ± 0.03 cm/sec. In serum, the average MNP velocity was 0.10 ± 0.02 cm/sec. MNPs were found to enhance tPA delivery, and cause fibrinolysis in both static and dynamic studies. Fibrinolysis was observed to occur in 85% of the dynamic MNP + tPA experiments. CONCLUSION: MNPs hold great promise for use in augmenting delivery of tPA for the treatment of stroke and other thrombotic conditions. This model system facilitates side by side comparisons of MNP-facilitated drug delivery, at a human scale.
BACKGROUND: Thrombotic events continue to be a major cause of morbidity and mortality worldwide. Tissue plasminogen activator (tPA) is used for the treatment of acute ischemic stroke and other thrombotic disorders. Use of tPA is limited by its narrow therapeutic time window, hemorrhagic complications, and insufficient delivery to the location of the thrombus. Magnetic nanoparticles (MNPs) have been proposed for targeting tPA delivery. It would be advantageous to develop an improved in vitro model of clot formation, to screen thrombolytic therapies that could be enhanced by addition of MNPs, and to test magnetic drug targeting at human-sized distances. METHODS: We utilized commercially available blood and endothelial cells to construct 1/8th inch (and larger) biomimetic vascular channels in acrylic trays. MNP clusters were moved at a distance by a rotating permanent magnet and moved along the channels by surface walking. The effect of different transport media on MNP velocity was studied using video photography. MNPs with and without tPA were analyzed to determine their velocities in the channels, and their fibrinolytic effect in wells and the trays. RESULTS: MNP clusters could be moved through fluids including blood, at human-sized distances, down straight or branched channels, using the rotating permanent magnet. The greatest MNP velocity was closest to the magnet: 0.76 ± 0.03 cm/sec. In serum, the average MNP velocity was 0.10 ± 0.02 cm/sec. MNPs were found to enhance tPA delivery, and cause fibrinolysis in both static and dynamic studies. Fibrinolysis was observed to occur in 85% of the dynamic MNP + tPA experiments. CONCLUSION: MNPs hold great promise for use in augmenting delivery of tPA for the treatment of stroke and other thrombotic conditions. This model system facilitates side by side comparisons of MNP-facilitated drug delivery, at a human scale.
Authors: Martin Lundqvist; Johannes Stigler; Giuliano Elia; Iseult Lynch; Tommy Cedervall; Kenneth A Dawson Journal: Proc Natl Acad Sci U S A Date: 2008-09-22 Impact factor: 11.205
Authors: Antony Thomas; H Daniel Ou-Yang; Linda Lowe-Krentz; Vladimir R Muzykantov; Yaling Liu Journal: Biomicrofluidics Date: 2016-01-06 Impact factor: 2.800
Authors: Yuri I Golovin; Sergey L Gribanovsky; Dmitry Y Golovin; Natalia L Klyachko; Alexander G Majouga; Аlyssa M Master; Marina Sokolsky; Alexander V Kabanov Journal: J Control Release Date: 2015-09-25 Impact factor: 9.776
Authors: Syed I Hussain; Lamar O Mair; Alexander J Willis; Georgia Papavasiliou; Bing Liu; Irving N Weinberg; Herbert H Engelhard Journal: Nanotechnol Sci Appl Date: 2022-04-19
Authors: Soodabeh Hassanpour; Han-Jun Kim; Arezoo Saadati; Peyton Tebon; Chengbin Xue; Floor W van den Dolder; Jai Thakor; Behzad Baradaran; Jafar Mosafer; Amir Baghbanzadeh; Natan Roberto de Barros; Mahmoud Hashemzaei; Kang Ju Lee; Junmin Lee; Shiming Zhang; Wujin Sun; Hyun-Jong Cho; Samad Ahadian; Nureddin Ashammakhi; Mehmet R Dokmeci; Ahad Mokhtarzadeh; Ali Khademhosseini Journal: Small Date: 2020-08-12 Impact factor: 13.281
Authors: Alexander J Willis; Sebastian P Pernal; Zachary A Gaertner; Sajani S Lakka; Michael E Sabo; Francis M Creighton; Herbert H Engelhard Journal: Int J Nanomedicine Date: 2020-06-11
Authors: Herbert H Engelhard; Alexander J Willis; Syed I Hussain; Georgia Papavasiliou; David J Banner; Amanda Kwasnicki; Sajani S Lakka; Sangyeul Hwang; Tolou Shokuhfar; Sean C Morris; Bing Liu Journal: Front Neurol Date: 2020-11-27 Impact factor: 4.003