Delivery of Tenofovir to the Brain by Novel Nano-Vesicles for the Treatment of Neuro-HIV (S10.003)

OBJECTIVE: To demonstrate delivery of therapeutic amounts of tenofovir into the brain by novel nano-vesicles (V-Smart TM ) prepared from synthetic bolaamphiphiles for treatment of neuro-HIV. BACKGROUND: Many AIDS patients, on Highly Active Anti-Retroviral Treatment (HAART), have non-detectable HIV in the blood and, yet, measurable amounts in the CNS because of poor BBB penetrability of some HAART drugs, particularly tenofovir. Persistent HIV reservoirs in the CNS are considered responsible for neurological impairment in AIDS patients. We have synthesized novel bolaamphiphiles that form stable monolayer-membrane vesicles, characterized by high encapsulation efficiency, penetrability through the BBB and efficient release of the encapsulated material within the brain. Here we describe optimized V-Smart TM vesicles capable of delivering tenofovir into the brain to make HAART treatment more effective. DESIGN/METHODS Nano-vesicles were formed from various formulations that contain our novel bolaamphiphiles and tenofovir. Tenofovir encapsulation was determined following the removal of non-encapsulated tenofovir by size-exclusion chromatography. The vesicle formulation was optimized to achieve high tenofovir encapsulation and good BBB permeability. Optimized vesicles were administered to mice and at various times after vesicle administration, brain tenofovir levels were determined by LC/MS. RESULTS: Optimal vesicle formulations produced 20-40% tenofovir encapsulation. Incorporation of new bolaamphiphiles with chitosan head groups to the formulation increased significantly the penetration of the vesicles to the brain. A single injection (iv) of tenofovir-loaded vesicles (at a dose 10-fold below toxic levels) resulted in brain tenofovir concentration of ~6 ug/gm tissue, much higher than the therapeutic levels of ~ 100ng/gm, which is a typical blood level in HAART patients. CONCLUSIONS: V-Smart TM vesicles, optimized for brain delivery of tenofovir, successfully delivered therapeutic amounts of the drug into the brain after a single iv administration. The results indicate the feasibility of using the V-SmartTM vesicles for lowering viral load in the CNS of HIV patients. Study Supported by: The Campbell Foundation Disclosure: Dr. Heldman has received personal compensation for activities with Lauren Sciences. Dr. Heldman has received research support from Lauren Sciences. Dr. Linder has received personal compensation for activities with Lauren Sciences. Dr. Linder has received research support from Lauren Sciences. Dr. Grinberg has received personal compensation for activities with Lauren Sciences. Dr. Grinberg has received research support from Lauren Sciences. Dr. Popov has received personal compensation for activities with Lauren Sciences. Dr. Popov has received research support from Lauren Sciences. Dr. Hollander has received personal compensation for activities with Lauren Sciences. Dr. Hollander has received research support from Lauren Sciences.