Functionalized Nanomaterials Capable of Crossing the Blood-Brain Barrier.

The blood-brain barrier (BBB) is a specialized semipermeable structure that highly regulates exchanges between the central nervous system parenchyma and blood vessels. Thus, the BBB also prevents the passage of various forms of therapeutic agents, nanocarriers, and their cargos. Recently, many multidisciplinary studies focus on developing cargo-loaded nanoparticles (NPs) to overcome these challenges, which are emerging as safe and effective vehicles in neurotheranostics. In this Review, first we introduce the anatomical structure and physiological functions of the BBB. Second, we present the endogenous and exogenous transport mechanisms by which NPs cross the BBB. We report various forms of nanomaterials, carriers, and their cargos, with their detailed BBB uptake and permeability characteristics. Third, we describe the effect of regulating the size, shape, charge, and surface ligands of NPs that affect their BBB permeability, which can be exploited to enhance and promote neurotheranostics. We classify typical functionalized nanomaterials developed for BBB crossing. Fourth, we provide a comprehensive review of the recent progress in developing functional polymeric nanomaterials for applications in multimodal bioimaging, therapeutics, and drug delivery. Finally, we conclude by discussing existing challenges, directions, and future perspectives in employing functionalized nanomaterials for BBB crossing.

Expanding the Toolbox of Upconversion Nanoparticles for In Vivo Optogenetics and Neuromodulation.

Optogenetics is an optical technique that exploits visible light for selective neuromodulation with spatio-temporal precision. Despite enormous effort, the effective stimulation of targeted neurons, which are located in deeper structures of the nervous system, by visible light, remains a technical challenge. Compared to visible light, near-infrared illumination offers a higher depth of tissue penetration owing to a lower degree of light attenuation. Herein, an overview of advances in developing new modalities for neural circuitry modulation utilizing upconversion-nanoparticle-mediated optogenetics is presented. These developments have led to minimally invasive optical stimulation and inhibition of neurons with substantially improved selectivity, sensitivity, and spatial resolution. The focus is to provide a comprehensive review of the mechanistic basis for evaluating upconversion parameters, which will be useful in designing, executing, and reporting optogenetic experiments.

Neuroprotective assessment of prolonged local hypothermia post contusive spinal cord injury in rodent model.

BACKGROUND CONTEXT: Although general hypothermia is recognized as a clinically applicable neuroprotective intervention, acute moderate local hypothermia post contusive spinal cord injury (SCI) is being considered a more effective approach. Previously, we have investigated the feasibility and safety of inducing prolonged local hypothermia in the central nervous system of a rodent model. PURPOSE: Here, we aimed to verify the efficacy and neuroprotective effects of 5 and 8 hours of local moderate hypothermia (30±0.5°C) induced 2 hours after moderate thoracic contusive SCI in rats. STUDY DESIGN: Rats were induced with moderate SCI (12.5 mm) at its T8 section. Local hypothermia (30±0.5°C) was induced 2 hours after injury induction with an M-shaped copper tube with flow of cold water (12°C), from the T6 to the T10 region. Experiment groups were divided into 5-hour and 8-hour hypothermia treatment groups, respectively, whereas the normothermia control group underwent no hypothermia treatment. METHODS: The neuroprotective effects were assessed through objective weekly somatosensory evoked potential (SSEP) and motor behavior (basso, beattie and bresnahan Basso, Beattie and Bresnahan (BBB) scoring) monitoring. Histology on spinal cord was performed until at the end of day 56. All authors declared no conflict of interest. This work was supported by the Singapore Institute for Neurotechnology Seed Fund (R-175-000-121-733), National University of Singapore, Ministry of Education, Tier 1 (R-172-000-414-112.). RESULTS: Our results show significant SSEP amplitudes recovery in local hypothermia groups starting from day 14 post-injury onward for the 8-hour treatment group, which persisted up to days 28 and 42, whereas the 5-hour group showed significant improvement only at day 42. The functional improvement plateaued after day 42 as compared with control group of SCI with normothermia. This was supported by both 5-hour and 8-hour improvement in locomotion as measured by BBB scores. Local hypothermia also observed insignificant changes in its SSEP latency, as compared with the control. In addition, 5- and 8-hour hypothermia rats' spinal cord showed higher percentage of parenchyma preservation. CONCLUSIONS: Early local moderate hypothermia can be induced for extended periods of time post SCI in the rodent model. Such intervention improves functional electrophysiological outcome and motor behavior recovery for a long time, lasting until 8 weeks.

Gold and Hairpin DNA Functionalization of Upconversion Nanocrystals for Imaging and In Vivo Drug Delivery.

Although multifunctional upconversion imaging probes have recently attracted considerable interest in biomedical research, there are currently few methods for stabilizing these luminescent nanoprobes with oligonucleotides in biological systems. Herein, a method to robustly disperse upconversion nanoprobes in physiological buffers based on rational design and synthesis of nanoconjugates comprising hairpin-DNA-modified gold nanoparticles is presented. This approach imparts the upconversion nanoprobes with excellent biocompatibility and circumvents the problem of particle agglomeration. By combining single-band anti-Stokes near-infrared emission and the photothermal effect mediated by the coupling of gold to upconversion nanoparticles, a simple, versatile nanoparticulate system for simultaneous deep-tissue imaging and drug molecule release in vivo is demonstrated.

Real-Time In†Vivo Hepatotoxicity Monitoring through Chromophore-Conjugated Photon-Upconverting Nanoprobes.

Drug toxicity is a long-standing concern of modern medicine. A typical anti-pain/fever drug paracetamol often causes hepatotoxicity due to peroxynitrite ONOO- . Conventional blood tests fail to offer real-time unambiguous visualization of such hepatotoxicity in vivo. Here we report a luminescent approach to evaluate acute hepatotoxicity in vivo by chromophore-conjugated upconversion nanoparticles. Upon injection, these nanoprobes mainly accumulate in the liver and the luminescence of nanoparticles remains suppressed owing to energy transfer to the chromophore. ONOO- can readily bleach the chromophore and thus recover the luminescence, the presence of ONOO- in the liver leads to fast restoring of the near-infrared emission. Taking advantages of the high tissue-penetration capability of near-infrared excitation/emission, these nanoprobes achieve real-time monitoring of hepatotoxicity in living animals, thereby providing a convenient screening strategy for assessing hepatotoxicity of synthetic drugs.

Designing Upconversion Nanocrystals Capable of 745†nm Sensitization and 803†nm Emission for Deep-Tissue Imaging.

A crystal design strategy is described that generates hexagonal-phased NaYF4 :Nd/Yb@NaYF4 :Yb/Tm luminescent nanocrystals with the ability to emit light at 803 nm when illuminated at 745 nm. This is accomplished by taking advantage of the large absorption cross-section of Nd(3+) between 720 and 760 nm plus efficient spatial energy transfer and migration through Nd(3+) →Yb(3+) →Yb(3+) →Tm(3+) . Mechanistic investigations suggest that a cascaded two-photon energy transfer upconversion process underlies the emission mechanism. This protocol enables deep-tissue imaging to be achieved while mitigating the attenuation effect associated with the visible emission and the overheating constraint imposed by conventional 980 nm excitation.