Functionalized Ferritin As Targeted Drug Delivery Vehicles For Cerebral Ischemia Therapy

Stroke,which consists of 80%ischemic stroke,suffers the major cause of death worldwide.The only FDA approved treatment for ischemic stroke is tissue-plasminogen activator(t-PA).Nevertheless,the narrow window(4.5 h)and ischemia reperfusion injury present a great challenge.The blood brain barrier(BBB)is essential for protecting homeostasis of central nervous system and preventing neurotoxins flowing into the brain.At the same time,it poses a great challenge to deliver drug into the brain.To transport drugs across the BBB,active targeting is a promising strategy.The BBB endothelial cells are overexpressed with three receptors:insulin receptor,low-density lipoprotein receptor and transferrin receptor.Ferritin is a cage protein with an outside diameter about 12 nm and a hollow cavity of 8 nm.It can be found in a lot of living creatures.Ferritin has an important biological function:removing excess free irons from solution and storing irons within the interior cavity.With the instinct feature,each ferritin nano-cage can store over 4000 iron ions,and these ions can be easily removed by reducing agents and chelation.Additionally,the protein cage is very stable,even when heating to 85 ℃ and it tolerates harsh chemicals such as mild acid[8].The favorable characteristic of ferritin such as biodegradability and low toxicity have aroused quite interesting in the field of drug carriers.Interestingly,recent studies showed that heavy chain ferritin and transferrin would target to the transferrin receptor in the BBB.It showed that ferritin can not only act as a drug carrier,but also a targeting molecular.However,ferritin without any modification is easily cleared by reticuloendothelial system(RES)after intravenous injection.The targeting ability of ferritins can be improved by surface modifications such as biologic engineer.Besides to the traditional peptide that target to brain,we use a peptide from reported thesis by phage screening technique that targeted to ischemia stroke[9].Reactive oxygen species(ROS)is an important factor which involved in ischemic reperfusion injury.To reduce the oxidative stress induced by ROS,some antioxidants are applied as a potential therapeutic for ischemic reperfusion injury.Curcumin,a natural polyphenol found in the rhizomes of Curcuma longa,is yellow colored spice and possess remarkable medicinal properties.It inhibits inflammation in vascular smooth muscle cells through ROS-relative pathways.The therapeutic efficacy of curcumin has been extensively studied against ischemic stroke which is attributed by promoting free radical scavenging and anti-inflammatory.Extensive medicinal properties led curcumin towards clinical trials to prevent brain diseases;however,clinical trials had an unfavorable outcome because of its low bioavailability which owing to poor absorption,short circulation time,and rapid elimination by RES.These problems are a great challenge to overcome.Excitingly,curcumin loaded in functional ferritins was not only found more stable,but also appeared to show a good therapeutic effect.In conclusion,the paper systematically shows the application of functional ferritin loading with curcumin in the treatment of ischemic stroke.Our project developed a drug delivery system to e noninvasive enter the brain after ischemic stroke.