Loop 2 of Ophiophagus hannah toxin b binds with neuronal nicotinic acetylcholine receptors and enhances intracranial drug delivery.
Three-finger snake neurotoxins have been widely investigated for their high binding affinities with nicotinic acetylcholine receptors (nAChRs), which are widely expressed in the central nervous system including the blood-brain barrier and thus mediate intracranial drug delivery. The loop 2 segments of three-finger snake neurotoxins are considered as the binding domain with nAChRs, and thus, they may have the potential to enhance drug or drug delivery system intracranial transport. In the present work, binding of the synthetic peptides to the neuronal nAChRs was assessed by measuring their ability to inhibit the binding of (125)I-α-bungarotoxin to the receptor. The loop 2 segment of Ophiophagus hannah toxin b (KC2S) showed high binding affinity, and the competitive binding IC(50) value was 32.51 nM. Furthermore, the brain targeting efficiency of KC2S had been investigated in vitro and in vivo. The specific uptake by brain capillary endothelial cells (BCECs) demonstrated that KC2S could be endocytosized after binding with nAChRs. In vivo, the qualitative and quantitative biodistribution results of fluorescent dyes (DiR or coumarin-6) indicated that KC2S modified poly(ethylene glycol)-poly(lactic acid) micelles (KC2S-PEG-PLA micelles) could enhance intracranial drug delivery. Furthermore, intravenous treatment with paclitaxel-encapsulated KC2S-PEG-PLA micelles (KC2S-PEG-PLA-PTX micelles) afforded robust inhibition of intracranial glioblastoma. The median survival time of KC2S-PEG-PLA-PTX-micelle-treated mice (47.5 days) was significantly longer than that of mice treated by mPEG-PLA-PTX micelles (41.5 days), Taxol (38.5 days), or saline (34 days). Compared with the short peptide derived from rabies virus glycoprotein (RVG29) that has been previously reported as an excellent brain targeting ligand, KC2S has a similar binding affinity with neuronal nAChRs but fewer amino acid residues. Thus, we concluded that the loop 2 segment of Ophiophagus hannah toxin b could bind with neuronal nAChRs and thus enhance intracranial drug delivery for the treatment of central nervous system diseases.
School of Pharmacy, Fudan University, Shanghai 201203, China.
Changyou
C
Zhan
Zhiqiang
Z
Yan
Cao
C
Xie
Weiyue
W
Lu
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D016503:Drug Delivery Systems; D004546:Elapid Venoms / Q000737:chemistry / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy*; D006367:HeLa Cells; D006801:Humans; D007773:Lactates / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D009474:Neurons / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects*; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D004546:Elapid Venoms; D007773:Lactates; D008823:Micelles; D011978:Receptors, Nicotinic; C088513:poly(lactic acid-ethylene glycol); C105136:toxin b, king cobra; D011092:Polyethylene Glycols