Engineering Theranostic Nanovehicles to Target Cerebrovascular Amyloid

1. Engineering TheranosticNanovehicles to Target Cerebrovascular Amyloid E. Agyare1; K.M. Jaruszewski2; G.L. Curran3; J.T. Rosenberg4; S.C. Grant4; V.J. Lowe3; S. Ramakrishnan4; Paravastu 4; J.F. Poduslo3; K.K. Kamdimalla2 1. Florida A&M University; 2. University of Minnesota; 3. Mayo Clinic; 4. National High Magnetic Field Laboratory Funding Grants:G.S. Boebinger (NSF DMR-1157490); S.C. Grant (User Collaboration Grants Program & AHA 10GRNT3860040) Cerebral amyloid angiopathy (CAA) results from the accumulation of Aβ proteins primarily within the media and adventitia of small arteries and capillaries of the cortex and leptomeninges. The CAA affects a majority of Alzheimer’s disease (AD) patients and is associated with a rapid decline in cognitive reserve. Unfortunately, there is no pre-mortem diagnosis available for CAA. Furthermore, treatment options are few and relatively ineffective. To combat this issue, we have designed nanovehicles (nanoparticles-IgG4.1) capable of targeting cerebrovascular amyloid and serve as early diagnostic and therapeutic agents. These nanovehicles(NVs) were loaded with Gadolinium (Gd) based magnetic resonance imaging contrast agents or single photon emission computerized tomography (SPECT) agents such as 125I. In addition, the NVs carry anti-inflammatory and anti-amyloidogenicagents, such as curcumin or dexamethasone. Theranostic NVs effectively marginate from the blood flow to the vascular wall. They demonstrated excellent distribution to the brain vasculature and targeting to CAA, thus providing multimodal MRI and SPECT contrast. In addition, they also displayed the potential to carry therapeutic agents to reduce cerebrovascular inflammation associated with CAA, which is believed to trigger hemorrhage in CAA patients. (A) AlexaFluor647 (AF647)-nanovehicles (NVs) in brain arteriole of a wild type mouse. (B) Uptake of AF647-NV in brain arteriole of an APP transgenic mouse model of Alzheimer’s disease. Blue fluorescence visualizes structure, AF647-NVs emits red fluorescence and Thioflavin S emits green fluorescence. (C and D) MRI of Gd-DTPA-NVs in wild type (WT) miceand APP transgenic mice, respectively. Yellow arrows indicate GdDTPA-NV contrast. (E) Uptake of 125I-nanovehicles in APP transgenic mice vs WT mice as determined by SPECT. Facilities: NMR Facility, Tallahassee, FL Instrument/Magnet: 21.1 Tesla Magnet Citation: Multimodal nanoprobes to target cerebrovascular amyloid in Alzheimer's disease brain. Jaruszewski KM, Curran GL, Swaminathan SK, Rosenberg JT, Grant SC, Ramakrishnan S, Lowe VJ, Poduslo JF, KandimallaKK. Biomaterials. 2014. 35(6):1967-76.

2. Engineering TheranosticNanovehicles to Target Cerebrovascular Amyloid E. Agyare1; K.M. Jaruszewski2; G.L. Curran3; J.T. Rosenberg4; S.C. Grant4; V.J. Lowe3; S. Ramakrishnan4; Paravastu 4; J.F. Poduslo3; K.K. Kamdimalla2 1. Florida A&M University; 2. University of Minnesota; 3. Mayo Clinic; 4. National High Magnetic Field Laboratory Funding Grants:G.S. Boebinger (NSF DMR-1157490); S.C. Grant (User Collaboration Grants Program); AHA (10GRNT3860040) Cerebral amyloid angiopathy (CAA) results from the accumulation of Aβ proteins primarily within the media and adventitia of small arteries and capillaries of the cortex and leptomeninges. The CAA affects a majority of Alzheimer’s disease (AD) patients and is associated with a rapid decline in cognitive reserve. Unfortunately, there is no pre-mortem diagnosis available for CAA. Furthermore, treatment options are few and relatively ineffective. To combat this issue, we have designed nanovehicles (nanoparticles-IgG4.1) capable of targeting cerebrovascular amyloid and serve as early diagnostic and therapeutic agents. These nanovehicles were loaded with Gadolinium (Gd) based magnetic resonance imaging contrast agents or single photon emission computerized tomography (SPECT) agents such as 125I. In addition, the nanovehicles carry anti-inflammatory and anti-amyloidogenicagents, such as curcumin, or immunosuppressants such as dexamethasone. The nanovehicles effectively marginate from the blood flow to the vascular wall. They demonstrated excellent distribution to the brain vasculature and targeting to CAA, thus providing MRI and SPECT contrast. In addition, they also displayed the potential to carry therapeutic agents to reduce cerebrovascular inflammation associated with CAA, which is believed to trigger hemorrhage in CAA patients. T1 and T2 weighted MRI contrast and relaxivitymeasurements (table) of the targeted nanovehicle agent. High resolution ex vivo imaging of the CAA animal model (yellow frame) showing its ability to target amyloid plaques for detection with MRI. Facilities: NMR Facility, Tallahassee, FL Instrument/Magnet: 21.1 Tesla Magnet Citation: Multimodal nanoprobes to target cerebrovascular amyloid in Alzheimer's disease brain. Jaruszewski KM, Curran GL, Swaminathan SK, Rosenberg JT, Grant SC, Ramakrishnan S, Lowe VJ, Poduslo JF, KandimallaKK. Biomaterials. 2014. 35(6):1967-76.