Dual-targeting for brain-specific drug delivery: synthesis and biological evaluation

Abstract

Ibuprofen is one of the most potent non-steroid anti-inflammatory drugs (NSAIDs) and plays an important role in the treatment of neurodegenerative diseases. However, its poor brain penetration and serious side effects at therapeutic doses, has hindered its further application. Thus, it is of great interest to develop a carrier-mediated transporter (CMT) system that is capable of more efficiently delivering ibuprofen into the brain at smaller doses to treat neurodegenerative diseases. In this study, a dual-mediated ibuprofen prodrug modified by glucose (Glu) and vitamin C (Vc) for central nervous system (CNS) drug delivery was designed and synthesized in order to effectively deliver ibuprofen to brain. Ibuprofen could be released from the prepared prodrugs when incubated with various buffers, mice plasma and brain homogenate. Also, the prodrug showed superior neuroprotective effect in vitro and in vivo than ibuprofen. Our results suggest that chemical modification of therapeutics with warheads of glucose and Vc represents a promising and efficient strategy for the development of brain-targeting prodrugs by utilizing the endogenous transportation mechanism of the warheads.

Liposomes actively recognizing the glucose transporter GLUT1 and integrin αvβ3 for dual‐targeting of glioma

“…Over the past years, our group has done a lot of researches on brain targeting and cancer targeting moieties specially based on glucose or peptides by active process . In addition to targeting the Warburg effect to deliver drugs to glioma, RGD sequence, an arginine‐glycine‐aspartic (Arg‐Gly‐Asp) tripeptide, has been shown to be another most promising ligand for targeting a range of malignant tumors, including glioma, osteocarcinoma, breast cancer and other human cancers, that are known to overexpress α v β 3 receptors .…”

Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and Neuroprotection

“…Sodium-dependent vitamin C transporter 2 (SVCT2), which is ubiquitously expressed in various brain tissues, including the cortex, cerebellar stem cells, neurons, and neuroblastoma cells, is a well-known transporter of ascorbic acid into the brain [ 55 ]. The conjugation of ascorbic acid to several drugs such as nipecotic, kynurenic, and diclophenamic acids and ibuprofen has demonstrated competitive binding with the SVCT2 receptor and increased drug penetration into the brain over nonconjugated drugs [ 56 , 57 ]. Thus, 2c and 5c were studied for their binding affinity with the SVCT2 receptor using molecular docking.…”

The Protective Effect of Aspirin Eugenol Ester on Paraquat-Induced Acute Liver Injury Rats

“…The elevated levels of AST and ALT in liver and serum may indicate PQ-induced ALI. MDA is the end product of lipid peroxidation and its level can be used to assess the extent of damage from peroxidative damage (45)(46)(47). Downregulation of AST, ALT, and MDA levels meant that AEE could reduce lipid peroxidation damage.…”