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Flow arrest intra-arterial delivery of small TAT-decorated and neutral micelles to gliomas

作者：Juliane Nguyen¹, Shaolie S. Hossain^2,3, Johann R. N. Cooke⁴, Jason A. Ellis⁵, Michael B. Deci¹, Charles W. Emala⁴, Jeffrey N. Bruce⁵, Irving J. Bigio^6,7, Robert M. Straubinger^1,8 ,Shailendra Joshi^4,9

    1.Department of Pharmaceutical SciencesUniversity at Buffalo, State University of New YorkBuffaloUSA

    2.Institute for Computational Engineering and SciencesUniversity of Texas at AustinAustinUSA

    3.Department of Molecular CardiologyTexas Heart InstituteHoustonUSA

    4.Department of AnesthesiologyColumbia University Medical CenterNew YorkUSA

    5.Department of Neurological SurgeryColumbia University Medical CenterNew YorkUSA

    6.Department of Electrical EngineeringBoston UniversityBostonUSA

    7.Department of Biomedical EngineeringBoston UniversityBostonUSA

    8.Department of Pharmacology & TherapeuticsRoswell Park Cancer InstituteBuffaloUSA

    9.Department of Anesthesiology, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA

摘要：The cell-penetrating trans-activator of transcription (TAT) is a cationic peptide derived from human immunodeficiency virus-1. It has been used to facilitate macromolecule delivery to various cell types. This cationic peptide is capable of crossing the blood–brain barrier and therefore might be useful for enhancing the delivery of drugs that target brain tumors. Here we test the efficiency with which relatively small (20 nm) micelles can be delivered by an intra-arterial route specifically to gliomas. Utilizing the well-established method of flow-arrest intra-arterial injection we compared the degree of brain tumor deposition of cationic TAT-decorated micelles versus neutral micelles. Our in vivo and post-mortem analyses confirm glioma-specific deposition of both TAT-decorated and neutral micelles. Increased tumor deposition conferred by the positive charge on the TAT-decorated micelles was modest. Computational modeling suggested a decreased relevance of particle charge at the small sizes tested but not for larger particles. We conclude that continued optimization of micelles may represent a viable strategy for targeting brain tumors after intra-arterial injection. Particle size and charge are important to consider during the directed development of nanoparticles for intra-arterial delivery to brain tumors.