title: Overcoming the blood-brain barrier to taxane delivery for neurodegenerative diseases and brain tumors.
abstract: The blood-brain barrier (BBB) effectively prevents microtubule (MT)-stabilizing drugs from readily entering the central nervous system (CNS). A major limiting factor for microtubule-stabilizing drug permeation across the BBB is the active efflux back into the circulation by the overexpression of the multidrug-resistant gene product 1 (MDR1) or P-glycoprotein (P-gp). This study has focused on strategies to overcome P-gp-mediated efflux of Taxol analogs, MT-stabilizing agents that could be used to treat brain tumors and, potentially, neurodegenerative diseases such as Alzheimer's disease. However, taxol is a strong P-gp substrate that limits its distribution across the BBB and therapeutic potential in the CNS. We have found that addition of a succinate group to the C-10 position of paclitaxel (Taxol) results in an agent, Tx-67, with reduced interactions with P-gp and enhanced permeation across the BBB in both in vitro and in situ models. Our studies demonstrate the feasibility of making small chemical modifications to Taxol to generate analogs with reduced affinity for the P-gp but retention of MT-stabilizing properties, i.e., a taxane that may reach and treat therapeutic targets in the CNS.
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D001932:Brain Neoplasms / Q000188:drug therapy*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods; D015195:Drug Design; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008968:Molecular Conformation; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123; D019802:Succinic Acid / Q000737:chemistry / Q000494:pharmacology; D043823:Taxoids / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D043823:Taxoids; D020112:Rhodamine 123; D019802:Succinic Acid; D017239:Paclitaxel