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We have demonstrated that utilization of nano-sized micelles modified with Tat can facilitate direct intranasal brain delivery.

New therapeutic strategies are required to develop candidate drugs and ensure efficient delivery of these drugs to the brain and the central nervous system (CNS). Small interfering RNA (siRNA)-based therapies have been investigated as potential novel approaches for the treatment of brain disorders. Previously, we showed that Tat, a cell-penetrating peptide derived from HIV-Tat, and the modified block copolymers (MPEG-PCL-Tat) can form stable complexes with siRNA or can be loaded with an anticancer drug and efficiently deliver the drugs to the brain tissue via intranasal delivery. In this study, to develop a novel, efficient, and safe therapeutic strategy for managing brain disorders, we used MPEG-PCL-Tat micelles with a nose-to-brain delivery system to investigate its therapeutic effects on a rat model of malignant glioma using siRNA with a Raf-1 (siRaf-1)/camptothecin (CPT) codelivery system. MPEG-PCL-Tat and CPT-loaded MPEG-PCL-Tat can form a stable complex with siRNA with a particle size from 60 to 200 nm and a positive charge at N/P ratios up to 5. Additionally, MPEG-PCL-Tat/siRaf-1 and CPT-loaded MPEG-PCL-Tat/siRaf-1 have fostered cell death in rat glioma cells after the high cellular uptake of siRaf-1/drug by the MPEG-PCL-Tat carrier. Furthermore, compared to the unloaded MPEG-PCL-Tat/siRaf-1 complex, a CPT-loaded MPEG-PCL-Tat/siRaf-1 complex achieved the high therapeutic effect because of the additive effects of CPT and siRaf-1. These results indicate that drug/siRNA codelivery using MPEG-PCL-Tat nanomicelles with nose-to-brain delivery is an excellent therapeutic approach for brain and CNS diseases.

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Although the sartan family of angiotensin II type 1 (AT(1)) receptor blockers (ARBs), which includes valsartan, olmesartan, and losartan, have a common pharmacophore structure, their effectiveness in therapy differs. Although their efficacy may be related to their binding strength, this notion has changed with a better understanding of the molecular mechanism. Therefore, we hypothesized that each ARB differs with regard to its molecular interactions with AT(1) receptor in inducing inverse agonism. Interactions between valsartan and residues Ser(105), Ser(109), and Lys(199) were important for binding. Valsartan is a strong inverse agonist of constitutive inositol phosphate production by the wild-type and N111G mutant receptors. Substituted cysteine accessibility mapping studies indicated that valsartan, but not losartan, which has only weak inverse agonism, may stabilize the N111G receptor in an inactive state upon binding. In addition, the inverse agonism by valsatan was mostly abolished with S105A/S109A/K199Q substitutions in the N111G background. Molecular modeling suggested that Ser(109) and Lys(199) bind to phenyl and tetrazole groups of valsartan, respectively. Ser(105) is a candidate for binding to the carboxyl group of valsartan. Thus, the most critical interaction for inducing inverse agonism involves transmembrane (TM) V (Lys(199)) of AT(1) receptor although its inverse agonist potency is comparable to olmesartan, which bonds with TM III (Tyr(113)) and TM VI (His(256)). These results provide new insights into improving ARBs and development of new G protein-coupled receptor antagonists.

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