Promise of CNS drug delivery Immersion Studios, Inc. “Lung Nanorobots I” (2001) Alexander Kabanov Parke-Davis Professor of Pharmaceutical Sciences Director, Center for Drug Delivery and Nanomedicine

points of discussion vImproved therapeutic agent delivery to the brain vElimination of direct CNS drug administration vImproved pharmacokinetics vReduced systemic toxicity and increased therapeutic index vImproved therapeutic agent delivery to the brain vElimination of direct CNS drug administration vImproved pharmacokinetics vReduced systemic toxicity and increased therapeutic index

the blood brain barrier

Hydrophilic Protective Shell increased solubility shielding of toxic agents prevents interactions with plasma components Hydrophilic Protective Shell increased solubility shielding of toxic agents prevents interactions with plasma components Protected Core cargo for drugs, biomacromolecules and imaging agents triggered drug release due to pH-, salt-sensitive swelling behavior or biodegradation (e.g. degradable cross-links) Protected Core cargo for drugs, biomacromolecules and imaging agents triggered drug release due to pH-, salt-sensitive swelling behavior or biodegradation (e.g. degradable cross-links) Nanoscale Size essential to avoid renal excretion facilitate extravasation at the disease site Nanoscale Size essential to avoid renal excretion facilitate extravasation at the disease site Bar is 100 nm Surface Modification with Targeting Groups localized delivery of drugs and imaging agents Surface Modification with Targeting Groups localized delivery of drugs and imaging agents AFM TEM multifunctional nanomaterials

improved pharmacokinetics vlong circulation time: e.g. PEGylated (“stealth”) liposomes, polymeric micelles etc. vavoidance of excretion by reticuloendothelial system (RES) vactive targeting to/across the BBB (and potentially beyond) vpassive targeting to sites of disease vlong circulation time: e.g. PEGylated (“stealth”) liposomes, polymeric micelles etc. vavoidance of excretion by reticuloendothelial system (RES) vactive targeting to/across the BBB (and potentially beyond) vpassive targeting to sites of disease

Disease Endothelium “leaky” Normal Endothelium “tight” Normal Endothelium “tight” Renal Clearance Target Cell Nanomedicine No Clearance H. Maeda Adv. Enzyme Reg. 2001, 41: 189 passive targeting (EPR effect)

drug transport protein P-glycoprotein (Pgp) drug transport protein P-glycoprotein (Pgp) PO EO  HIV-1 protease inhibitors  Ritonavir, Nalfinavir, and Indinavir  anti-inflammatory agents  Prednesolone, Dexamethasone and Indomethacin  neuroleptics  Amitriptyline and Haloperidol  analgesics  Morphine, Beta-Endorphin, and Asimadoline  antiepileptic agents  Carbamazepine, Phenobarbital, Phenytoin, and Lamotrigine  antifungal agents  Itraconazole and Ketoconazole  HIV-1 protease inhibitors  Ritonavir, Nalfinavir, and Indinavir  anti-inflammatory agents  Prednesolone, Dexamethasone and Indomethacin  neuroleptics  Amitriptyline and Haloperidol  analgesics  Morphine, Beta-Endorphin, and Asimadoline  antiepileptic agents  Carbamazepine, Phenobarbital, Phenytoin, and Lamotrigine  antifungal agents  Itraconazole and Ketoconazole CNS drugs affected by Pgp in BBB improved CNS drug delivery by inhibiting drug efflux

cell-mediated delivery Howard Gendelman, 2006

benefits of improved CNS delivery vEnabled therapeutic effect vDecreased dose vReduced systemic toxicity  Increased therapeutic index vEnabled therapeutic effect vDecreased dose vReduced systemic toxicity  Increased therapeutic index