Neuroprotective NIRⅡ AIE Nanocomposites For AD Theranostics

As a serious threat to human health,Alzheimer’s disease(AD)is one of the most common neurodegenerative diseases characterized by some main pathological features,such as the excessive extracellular aggregation of amyloid β-protein(Aβ),mitochondrial dysfunction,oxidative stress and neuronal death.These generated a series of behavior disorder and cognitive impairment.Therefore,the Aβ fibril and oxidative stress could as two important AD therapeutic targets.However,the blood brain barrier(BBB)blocks most molecules into brain,and the lack of efficient targeted theranostics means induced late and lowefficiency treatment.Therefore,how to construct the brain-targeted theranostics probes with strong BBBpenetrating,high sensitivity,and therapeutic efficiency is the key in AD field.The rational molecular design and self-assembly technology offer an opportunity to fabricate dual functional nanotheranostics with degradative Aβ fiber and alleviating reactive oxygen species(ROS),which show a huge prospect for AD theranostics.Magnetic resonance imaging(MRI)and positron emission computed tomography(PET)are two main clinical imaging methods for AD.However,these methods are limited by the complicated operation,low specificity,short half-life,expensive,radiation risk,poor detection efficiency for Aβ.An emerging imaging method,near infrared(NIR)fluorescence imaging,was widely used for in vivo imaging application.However,the reported emission wavelength has only been extended to the NIR-I region(< 800 nm),easily quenching in aggregation,and induced low imaging sensitivity.Furthermore,the existing probes cannot effectively cross the BBB and degrade the Aβ fibers to reduce the harmful oxidative stress for neuron protection.Aggregation-induced emission(AIE)is an aggregation enhanced luminescence phenomenon based on the restriction of intramolecular motion(RIM)mechanism.Compared to the common probes,the AIE nano fluorophores have special luminescence and therapeutic advantages,such as the high resistance to aggregation quenching,excellent stability and biocompatibility,and are widely used in theranostics output.However,there are few reports on the AD theranostic because the molecule with molecular weight below to600 Da was unable to cross the BBB in the brain and induced a low signal-to-noise ratio.Simultaneously,the hydrophobic core of Aβ(Aβ16-20,KLVFF)poses a great challenge to the specific Aβ-binding and Aβ-degradation by NIR AIE molecules.Therefore,we focus on the design of a brain-targeted NIR AIE theranostic with excellent BBB penetration,high detected sensitivity and therapy function.Based on the advanced smart nanodrugs,we constructed a brain-targeted ROS responsive near infrared AIE nanocomposites via co-assembly of two AIE building blocks.One was an AIE molecule(termed as PTB)with alkyl thiophene as an electron donor together with multi rotors to achieve AIE characteristics through distort molecular skeleton.Benzene group increases electron conjugation and effectively broadens molecular absorption.Benzobisthiadiazole(BBTD)is the strong electron-withdrawing acceptor,for NIR absorption and emission.Besides BBTD interacts with hydrophobic Aβ,the hydroxy group also form the hydrogen bond with hydrophilic amino acid in Aβ to disassembly the Aβ fibril.Another AIE molecule(termed as Tp PTBCe)has same molecular backbone and Ce(Ⅲ)center.The reducing Ce(Ⅲ)has strong redox capacity to reduce oxidative stress in AD region and alleviate neuron damage.The brain targeted peptide(Angiopep-2,Ang-2)was modified onto the obtained nanocomposite to assist cross the BBB.Triggered by the high levels of ROS in the AD region,the responsive template(DSPE-TK-PEG)was in charge of the smart release of AIE nanotheranostic for the degradation of Aβ,redox equilibrium,and protect the activity of neurons.Then the UV absorption and fluorescence spectra were used to verify the optical performance of the nanocomposites.It showed a near-infrared absorption at 765 nm and near-infrared emission extended to 1550 nm.Elemental mapping analysis showed that two AIE components were uniformly doped in the whole nanocomposites.In vitro BBB-penetrating experiment results showed that the targeted modification effectively promoted the BBB penetration of nanocomposite(1.5-fold).Cytotoxicity experiments showed good biocompatibility and neuroprotective function of AIE nanocomposites,i.e.,effectively reverse the cytotoxicity of Aβ fibers.In hemolysis,blood routine and blood biochemical tests,the nanocomposites showed good biosafety.The pharmacokinetic data showed the target nanocomposites has a higher circulation time(5.82 h)than that of nontarget nanocomposites(elimination half-life 3.22 h).Benefited from the excellent NIR-Ⅱ imaging,it was effective for in vivo monitoring of nanocomposites crossing BBB.A series of behavioral experiments(water maze and nesting),and brain slices immunofluorescence observation verified the strong Aβ-disassembly,balancing the redox,effective neuron protection abilities of nanocomposites.The cognitive and behavioral functions improvement of AD mice also showed the effectiveness of the brain-targeted,ROS responsive,and near-infrared AIE nanotheranostics strategy,and provides a new idea for the clinical precise and visual theranostic of AD.