Proton spectral editing for discrimination of lactate and threonine 1.31 ppm resonances in human brain in vivo

The complexities of human neurodevelopment have historically been challenging to decipher but continue to be of great interest in the contexts of healthy neurobiology and disease. The classic animal models and monolayer in vitro systems have limited the types of questions scientists can strive to answer in addition to the technical ability to answer them. However, the tridimensional human stem cell-derived organoid system provides the unique opportunity to model human development and mimic the diverse cellular composition of human organs. This strategy is adaptable and malleable, and these neural organoids possess the morphogenic sensitivity to be patterned in various ways to generate the different regions of the human brain. Furthermore, recapitulating human development provides a platform for disease modeling. One master regulator of human neurodevelopment in many regions of the human brain is sonic hedgehog (SHH), whose expression gradient and pathway activation are responsible for conferring ventral identity and shaping cellular phenotypes throughout the neural axis. This review first discusses the benefits, challenges, and limitations of using organoids for studying human neurodevelopment and disease, comparing advantages and disadvantages with other in vivo and in vitro model systems. Next, we explore the range of control that SHH exhibits on human neurodevelopment, and the application of SHH to various stem cell methodologies, including organoids, to expand our understanding of human development and disease. We outline how this strategy will eventually bring us much closer to uncovering the intricacies of human neurodevelopment and biology.

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EFFECTS OF POLYMERIC NANOPARTICLE SURFACE PROPERTIES ON INTERACTION WITH BRAIN TUMOR ENVIRONMENT

Nano LIFE ◽

10.1142/s1793984413430034 ◽

2013 ◽

Vol 03 (04) ◽

pp. 1343003 ◽

Cited By ~ 7

Author(s):

BRANDON MATTIX ◽

THOMAS MOORE ◽

OLGA UVAROV ◽

SAMUEL POLLARD ◽

LAUREN O'DONNELL ◽

...

Keyword(s):

Human Brain ◽

Surface Charge ◽

Cellular Uptake ◽

Drug Clearance ◽

Cellular Interaction ◽

Normal Tissues ◽

Poly Ethylene ◽

Uptake Studies ◽

Effect Of Surface

Current chemotherapy treatments are limited by poor drug solubility, rapid drug clearance and systemic side effects. Additionally, drug penetration into solid tumors is limited by physical diffusion barriers [e.g., extracellular matrix (ECM)]. Nanoparticle (NP) blood circulation half-life, biodistribution and ability to cross extracellular and cellular barriers will be dictated by NP composition, size, shape and surface functionality. Here, we investigated the effect of surface charge of poly(lactide)-poly(ethylene glycol) NPs on mediating cellular interaction. Polymeric NPs of equal sizes were used that had two different surface functionalities: negatively charged carboxyl ( COOH ) and neutral charged methoxy ( OCH 3). Cellular uptake studies showed significantly higher uptake in human brain cancer cells compared to noncancerous human brain cells, and negatively charged COOH NPs were uptaken more than neutral OCH 3 NPs in 2D culture. NPs were also able to load and control the release of paclitaxel (PTX) over 19 days. Toxicity studies in U-87 glioblastoma cells showed that PTX-loaded NPs were effective drug delivery vehicles. Effect of surface charge on NP interaction with the ECM was investigated using collagen in a 3D cellular uptake model, as collagen content varies with the type of cancer and the stage of the disease compared to normal tissues. Results demonstrated that NPs can effectively diffuse across an ECM barrier and into cells, but NP mobility is dictated by surface charge. In vivo biodistribution of OCH 3 NPs in intracranial tumor xenografts showed that NPs more easily accumulated in tumors with less collagen. These results indicate that a robust understanding of NP interaction with various tumor environments can lead to more effective patient-tailored therapies.

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Molar quantitation of in vivo proton metabolites in human brain with 3D magnetic resonance spectroscopic imaging

Magnetic Resonance Imaging ◽

10.1016/0730-725x(94)92461-9 ◽

1994 ◽

Vol 12 (4) ◽

pp. 661-667 ◽

Cited By ~ 27

Author(s):

C.A. Husted ◽

J.H. Duijn ◽

G.B. Matson ◽

A.A. Maudsley ◽

M.W. Weiner

Keyword(s):

Magnetic Resonance ◽

Human Brain ◽

Spectroscopic Imaging ◽

Magnetic Resonance Spectroscopic Imaging

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Imaging Muscarinic Cholinergic Receptors in Human Brain in vivo with SPECT, [123I]4-Iododexetimide, and [123I]4-Iodolevetimide

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1992.80 ◽

1992 ◽

Vol 12 (4) ◽

pp. 562-570 ◽

Cited By ~ 48

Author(s):

Hans W. Müller-Gärtner ◽

Alan A. Wilson ◽

Robert F. Dannals ◽

Henry N. Wagner ◽

J. James Frost

Keyword(s):

Human Brain ◽

Muscarinic Receptor ◽

Muscarinic Receptors ◽

Acetylcholine Receptors ◽

Brain Regions ◽

Muscarinic Acetylcholine Receptors ◽

Emission Computed Tomography ◽

Nonspecific Binding ◽

Muscarinic Acetylcholine

A method to image muscarinic acetylcholine receptors (muscarinic receptors) noninvasively in human brain in vivo was developed using [123I]4-iododexetimide ([123I]IDex), [123I]4-iodolevetimide ([123I]ILev), and single photon emission computed tomography (SPECT). [123I]IDex is a high-affinity muscarinic receptor antagonist. [123I]ILev is its pharmacologically inactive enantiomer and measures nonspecific binding of [123I]IDex in vitro. Regional brain activity after tracer injection was measured in four young normal volunteers for 24 h. Regional [123I]IDex and [123I]ILev activities were correlated early after injection, but not after 1.5 h. [123I]IDex activity increased over 7–12 h in neocortex, neostriatum, and thalamus, but decreased immediately after the injection peak in cerebellum. [123I]IDex activity was highest in neostriatum, followed in rank order by neocortex, thalamus, and cerebellum. [123I]IDex activity correlated with muscarinic receptor concentrations in matching brain regions. In contrast, [123I]ILev activity decreased immediately after the injection peak in all brain regions and did not correspond to muscarinic receptor concentrations. [123I]IDex activity in neocortex and neostriatum during equilibrium was six to seven times higher than [123I]ILev activity. The data demonstrate that [123I]IDex binds specifically to muscarinic receptors in vivo, whereas [123I]ILev represents the nonspecific part of [123I]IDex binding. Subtraction of [123I]ILev from [123I]IDex images on a pixel-by-pixel basis therefore reflects specific [123I]IDex binding to muscarinic receptors. Owing to its high specific binding, [123I]IDex has the potential to measure small changes in muscarinic receptor characteristics in vivo with SPECT. The use of stereoisomerism directly to measure nonspecific binding of [123I]IDex in vivo may reduce complexity in modeling approaches to muscarinic acetylcholine receptors in human brain.

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