Recent studies indicate that M13 bacteriophage, a very large nanoparticle, binds to β-amyloid and α-synuclein proteins, leading to plaque disaggregation in models of Alzheimer and Parkinson disease. To determine the feasibility, safety, and characteristics of convection-enhanced delivery (CED) of M13 bacteriophage to the brain, the authors perfused primate brains with bacteriophage.
Four nonhuman primates underwent CED of M13 bacteriophage (900 nm) to thalamic gray matter (4 infusions) and frontal white matter (3 infusions). Bacteriophage was coinfused with Gd-DTPA (1 mM), and serial MRI studies were performed during infusion. Animals were monitored for neurological deficits and were killed 3 days after infusion. Tissues were analyzed for bacteriophage distribution.
Real-time T1-weighted MRI studies of coinfused Gd-DTPA during infusion demonstrated a discrete region of perfusion in both thalamic gray and frontal white matter. An MRI-volumetric analysis revealed that the mean volume of distribution (Vd) to volume of infusion (Vi) ratio of M13 bacteriophage was 2.3 ± 0.2 in gray matter and 1.9 ± 0.3 in white matter. The mean values are expressed ± SD. Immunohistochemical analysis demonstrated mean Vd:Vi ratios of 2.9 ± 0.2 in gray matter and 2.1 ± 0.3 in white matter. The Gd-DTPA accurately tracked M13 bacteriophage distribution (the mean difference between imaging and actual bacteriophage Vd was insignificant [p > 0.05], and was –2.2% ± 9.9% in thalamic gray matter and 9.1% ± 9.5% in frontal white matter). Immunohistochemical analysis revealed evidence of additional spread from the initial delivery site in white matter (mean Vd:Vi, 16.1 ± 9.1). All animals remained neurologically intact after infusion during the observation period, and histological studies revealed no evidence of toxicity.
The CED method can be used successfully and safely to distribute M13 bacteriophage in the brain. Furthermore, additional white matter spread after infusion cessation enhances distribution of this large nanoparticle. Real-time MRI studies of coinfused Gd-DTPA (1 mM) can be used for accurate tracking of distribution during infusion of M13 bacteriophage.
Abbreviations used in this paper:AAV = adenoma-associated virus; AD = Alzheimer disease; CED = convection-enhanced delivery; PBS = phosphate-buffered saline; PD = Parkinson disease; Vd = volume of distribution; Vi = volume of infusion.
Address correspondence to: Russell R. Lonser, M.D., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Building 10, Room 3D20, Bethesda, Maryland 20892-1414. email: firstname.lastname@example.org.
Please include this information when citing this paper: published online May 18, 2012; DOI: 10.3171/.2012.4.JNS111528.
Alzheimer's and Parkinson's diseases: advances, concepts and new challenges. Proceedings of the 9th International Conference on Alzheimer's and Parkinson's Diseases. Prague, Czech Republic March 11–15, 2009. Neurodegener Dis7:5–2152010
AsthagiriARWalbridgeSHeissJDLonserRR: Effect of concentration on the accuracy of convective imaging distribution of a gadolinium-based surrogate tracer. Laboratory investigation. J Neurosurg115:467–4732011
BankiewiczKSEberlingJLKohutnickaMJagustWPivirottoPBringasJ: Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach. Exp Neurol164:2–142000
ChenMYHofferAMorrisonPFHamiltonJFHughesJSchlageterKS: Surface properties, more than size, limiting convective distribution of virus-sized particles and viruses in the central nervous system. J Neurosurg103:311–3192005
HadaczekPKohutnickaMKrauzeMTBringasJPivirottoPCunninghamJ: Convection-enhanced delivery of adeno-associated virus type 2 (AAV2) into the striatum and transport of AAV2 within monkey brain. Hum Gene Ther17:291–3022006
MacKayJADeenDFSzokaFCJr: Distribution in brain of liposomes after convection enhanced delivery; modulation by particle charge, particle diameter, and presence of steric coating. Brain Res1035:139–1532005
SaitoRKrauzeMTBringasJRNobleCMcKnightTRJacksonP: Gadolinium-loaded liposomes allow for realtime magnetic resonance imaging of convection-enhanced delivery in the primate brain. Exp Neurol196:381–3892005