Functionalized Nanomaterials as Tailored Theranostic Agents in Brain Imaging

Abstract

Functionalized nanomaterials of various categories are essential for developing cancer nano-theranostics for brain diseases; however, some limitations exist in their effectiveness and clinical translation, such as toxicity, limited tumor penetration, and inability to cross blood-brain and blood-tumor barriers. Metal nanomaterials with functional fluorescent tags possess unique properties in improving their functional properties, including surface plasmon resonance (SPR), superparamagnetism, and photo/bioluminescence, which facilitates imaging applications in addition to their deliveries. Moreover, these multifunctional nanomaterials could be synthesized through various chemical modifications on their physical surfaces via attaching targeting peptides, fluorophores, and quantum dots (QD), which could improve the application of these nanomaterials by facilitating theranostic modalities. In addition to their inherent CT (Computed Tomography), MRI (Magnetic Resonance Imaging), PAI (Photo-acoustic imaging), and X-ray contrast imaging, various multifunctional nanoparticles with imaging probes serve as brain-targeted imaging candidates in several imaging modalities. The primary criteria of these functional nanomaterials for translational application to the brain must be zero toxicity. Moreover, the beneficial aspects of nano-theranostics of nanoparticles are their multifunctional systems proportioned towards personalized disease management via comprising diagnostic and therapeutic abilities in a single biodegradable nanomaterial. This review highlights the emerging aspects of engineered nanomaterials to reach and deliver therapeutics to the brain and how to improve this by adopting the imaging modalities for theranostic applications.

Keywords: contrast agents; delivery; functionalized nanomaterials; imaging; theranostics.

Figure 1

Scheme identifies the emerging different kinds of nanomaterial formulations attempted for the improved drug delivery approaches in neurological diseases. Reprinted with permission from Ref. [8]. Copyright 2021 John Wiley and Sons.

Figure 2

Triple-modality nanoparticle delivery and imaging concept to the brain tumor model. (a) Delivery of nanoparticles circulates in the bloodstream; they diffuse through the disrupted blood–brain barrier and are then sequestered and retained by the tumor; upon employing photoacoustic imaging, the high resolution, and deep tissue penetration guide tumor resection intraoperatively in the surgical room. Following imaging strategies of the brain specimen can subsequently be examined as an imaging probe ex vivo to validate clear tumor margins. (b) Immunohistochemistry of the tissue sections from the margin of the brain tumor stained for glial cells under confocal laser scanning microscopy. Scanning transmission electron microscope (STEM) images validated the presence of delivered nanoparticles in the brain tissue, whereas no such nanoparticles were seen in the healthy brain tissue. (c) Two-dimensional axial MRI, Photoacoustic, and Raman images; (d) three-dimensional (3D) rendering of magnetic resonance images with the tumor segmented overlay of the three-dimensional photoacoustic images. (e) Corresponding quantitative signals of the nanoparticles from images shown in (c,d). Shown data represents mean ± S.E.M; *** p < 0.001, ** p < 0.01. Reprinted with permission from Ref. [43].Copyright 2021 Springer Nature.

Figure 3

(a) Schematic illustration of the synthesis of Poly-gold-iron oxide nanoparticles (polyGIONs) system and in vitro fluorescence images of Cy5 labeled miR-100 and antimiR-21 loaded cyclodextrin-chitosan (CD-CS) hybrid polymer complexes. (b) Schematic of the as-prepared polyGION nanoparticle structure and the associated compositions. (c) TEM micrograph of GIONs. (d) In vivo treatment flow chart of the therapeutic design and imaging timelines; fluorescence (Cy5-miRNA loaded nanoparticles) and bioluminescence (FLuc-EGFP expressing glioblastoma model); quantitative measurements for the tumor bioluminescence measured concerning treatment duration; mice body weight profiles over the treatment duration and their survival curve indicates the intranasally delivered nanoparticles towards the theranostic efficacy. (e) 3T MRI scanning (coronal and axial) of the polyGIONs-miRNAs treated mice brain imaging; biodistribution; ex vivo fluorescence imaging, and qRT-PCR of antimiR-21 and miR-100 expression levels. Reprinted (adapted) with permission from Reference [51]. (f) H&E-stained histological image shows the nasal epithelium, followed by iron-specific Prussian blue staining (inset figure) to trace the accumulation of polyGION nanoparticles in mice intranasal cavities. (g) microCT imaging of mice head scan shows the non-treated (control) and T7-polyGION-CD-CS NPs administered in vivo. Corresponding microCT scan images depict the migration of IN administered T7-polyGION-CD-CS NPs nanoparticles movements through the olfactory nerve pathway into the olfactory bulb and passing into trigeminal nerve pathway, thereby entering the pons and medulla of the mice brain. Shown data represents mean ± S.E.M; *** p < 0.001, ** p < 0.01. Adapted with permission from Ref. [51], with permission. Copyright 2021 Elsevier.

Figure 4

Schematic representations of the growing contributing fields of theranostics. Representative illustration showing the contributing interdisciplinary fields of nanomaterials associated with theranostics. Via adopting these multidisciplinary fields, the innovative nanomaterial formulations aim to involve disease monitoring, diagnosis, and therapy through the researcher’s intersections of multiple scientific fields.

Figure 5

(a) Schematic illustration explains the microfluidic reconstruction of miRNA-loaded extracellular vesicles (EVs) for intranasal delivery towards the enhancements of theranostic imaging in glioblastoma tumor-bearing mice model. (b) H&E and confocal laser scanning immunohistochemical images of cranial sections of animals treated with IN delivered EVs and (c) corresponding therapeutic monitoring of IN delivered EVs associated targeted nanomaterial platform with respective control groups, in co-treatment with temozolomide in vivo. (d) Diagrammatic and sagittal views of the brain delivered with EVs associated nanomaterials by ex vivo bioluminescence and fluorescence imaging showing intranasal administration at varied time-points in vivo. Shown data represents mean ± S.E.M; *** p < 0.001, ** p < 0.01. Reprinted with permission from Ref. [68]. Copyright 2021 American Chemical Society.

Figure 6

(a). Scheme with representative images shows the functional polymer associated PAI nanomaterials. (b) TEM morphology, size, and absorption (UV) features, (c) PAI scanning of the mice brain under the pulsed field lasers and corresponding quantification analysis, and (d) bioluminescence, MRI, and PA imaging conditions of the mice brain shows the ultrasound and PA signals produced by the nanoparticles with grey and green color, respectively. Reprinted with permission from Ref. [124]. Copyright 2021 Royal Society of Chemistry.