Functionalized Nanomaterials as Theranostic Agents in Brain Imaging

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Ramar Thangam	--	3489	2022-04-06 10:36:05	\|
2	format change	Peter Tang	-30 word(s)	3459	2022-04-08 05:46:54	\| \|
3	format change	Peter Tang	Meta information modification	3459	2022-04-08 05:47:22	\|

This entry is adapted from the peer-reviewed paper 10.3390/nano12010018

functionalized nanomaterials contrast agents imaging theranostics neuroimaging neurosciences molecular imaging nanotechnology cell biology MRI

1. Introduction

The remarkable developments in multimodal molecular imaging methods using various functional nanomaterials have led to the translation of many novel materials into the clinic. These nanomaterials are established to confront the crucial problems encountered by diagnostic imaging techniques ^[1]^[2]. Theranostic imaging adopting nanomaterials presents significant improvements over the traditional approaches via increasing blood circulation times, enhanced diagnostic specificity, and organ-specific delivery ^[3]. Theranostic imaging modalities improve the understanding of various biological processes via direct observation of available events in real-time. In recent years, growing interests in image-guided theranostics have elevated the researchers’ directions to study and understand the mechanistic aspects of multiple disease-related signaling to recognize and enable easy and early diagnosis ^[4]. This further helped them to identify the complex neural networks in the brain process of cognitive therapies. Imaging techniques, such as MRI, fluorescence, bioluminescence, FRET (Förster (or Fluorescence) Resonance Energy Transfer), BRET (Bioluminescence resonance energy transfer), US (Ultra-sound), and PAI, provide necessary information about brain functions at anatomical, cellular, and molecular levels ^[5]^[6]. Furthermore, the image-guided biological studies facilitate researchers to better understand the detailed biochemical processes involved in metabolic and functional physiological events (the macromolecular interaction in cells at healthy or diseased states) and translate them into pathologic functions associated with the disease to establish independent research directions ^[7]. Abilities of engineered nanomaterials generated in theranostics ensure the dual capacity of therapeutic delivery ^[8] and diagnosis to a preponderance of personalized medicine in clinical conditions to target different neurological diseases (Figure 1). In spite of all these, the nanomaterials produce the imaging signals of delivered molecules which could carry the essential features of molecular imaging and which further translate the imaging signals towards image acquisition. Several nanostructured materials ^[9] with magnetic properties ^[10]^[11] are emerging due to their functional properties towards biomedical applications with reduced toxicity. However, these nanostructures could be regulated via external stimuli-based magnetic fields that could regulate a variety of tissue modulatory potentials in vivo ^[12]^[13]^[14]. This functionalization could improve the target functions, biocompatibility, and surface area modifications in biological and clinical translations ^[15]^[16]^[17]. One of the major criteria for any molecular imaging in brain theranostics would be the target-specificity of the delivery method with improved biocompatibility at the delivered site without much toxicity. The principal imaging associated factors, such as high sensitivity, non-invasive imaging detection systems, signal penetration without attenuation, and temporal and spatial resolution, are the significant factors that are critical for ensuring the clinical potential of the developed methods ^[18]. These factors should be carefully included while making the functional nanoparticles for imaging applications of the brain. In addition, these nanoparticles should possess properties that enhance image quality, contrast, and targeting features during their modifications, which could play prominent roles in target-specific molecular screening ^[19]^[20].

Figure 1. Scheme identifies the emerging different kinds of nanomaterial formulations attempted for the improved drug delivery approaches in neurological diseases ^[8].

Brain with its complex neural network is difficult to study using various biochemical techniques. Non-invasive molecular imaging techniques with the potential to monitor dynamic physiological events in the brain could be an effective strategy for studying the complex processes of the nervous system ^[21]. One of the significant breakthroughs in the longitudinal image monitoring of animals is molecular imaging, which allows researchers to observe biological events at physiological conditions without the need for sacrificing the animals ^[22]. Gold nanoparticles with various surface modifications using imaging probes/candidates have allowed X-ray contrast imaging in disease diagnosis, including cancer. These innovative strategies might be applicable to detect tiny tumors in multiple organs, including the brain, for glioma, when they are a few-millimeter in size in vivo ^[23]^[24]. In addition, the enzyme-modified functional gold nanoparticles systems were applied to make nanoparticles with the property of self-assembly and disassembly in vivo at the delivered target sites ^[25]^[26]^[27]. Moreover, novel nanomaterials functionalized with fluorescent probes can be used for image-guided disease theranostics of the brain, while the coupled chemical agents functionalized at the surface of the nanoparticles could enhance the targeted delivery and therapy during theranostic applications ^[28]^[29]. These contrast agents further help the researchers to get more detailed information via delivered functional nanomaterial systems to understand the biological systems and their interrelationship much better than the conventional methods ^[30]^[31].

In view of the perspective, the blood–brain barrier (BBB), which interfaces between the central nervous system (CNS) and the vascular compartment, can block the delivery of administered nanoparticles circulating in the body to the brain’s extravascular cells. BBB is critical in protecting brain cells from the vascular contents to maintain homeostasis; in contrast, it represents an intense challenge in drug delivery applications. The permeability modulations of BBB can be graded by light-laser intensity ^[32]. The permeability of BBB is entirely reversible and involves increased paracellular diffusion or opening at the delivered sites without leading to a significant disruption in the structure of neurovascular units of the brain. This strategy allows the delivery and entry of multiple therapeutic agents, such as immunoglobulins and viral gene therapy vectors, cargo-laden liposomes, functionalized nanomaterials, peptide conjugates, and nanomaterials with small molecules ^[33]. The researchers anticipate this theranostic nanotechnology development might be helpful in tissue regions accessible to novel imaging applications and open novel venues in screening and therapeutic interventions in CNS diseases. Thus, the recent emergence of nanomaterial systems could be applied for disease or cellular pathway imaging at the molecular level by linking with theranostic imaging fields via providing potentials to grow molecular imaging field both in vitro and in vivo applications ^[34]^[35]^[36]. Furthermore, various imaging methods, such as optical/magnetic resonance, have been achieved via developing shape-tuned nanomaterials, such as nanospheres, nanorods, nanocoils, and nanoclusters, to test under various physiological conditions ^[9]^[14]^[37]^[38]. Moreover, the currently used nanoparticles for MRI imaging have broader magnetic properties, and most of them are paramagnetic or super-paramagnetic in nature ^[39]^[40]. In addition, the other oxidized forms of metal nanomaterials (i.e., MnO and SPIONs, etc.) carry the MR-imaging (Figure 2) features have been applied in brain theranostics ^[41]^[42]^[43]. There has been the emergence of gold nanoparticles, nanorods, carbon nanoparticles or nanotubes, and graphene oxide nanomaterials, which are being translated to photoacoustic and other functional imaging modalities in neurological disorders, including brain cancers.

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 ^[43].

To further envisage the importance of nanomaterials in brain theranostics, functional nanomaterials with the widespread application have been developed with significant roles in the field of emerging nano-theranostics of molecular imaging. Nanotechnology is an engineering discipline that comprises the characterization and application of nanoscale (1–999 nm) materials in a single structural dimension for disease diagnosis applications. Most of the engineered nanomaterials are designed to display various functional features, such as high sensitivity, selectivity, and tunable properties, that are absent, or their properties vary from other bulk materials ^[44]^[45]. In addition, these nanoscale materials can be modified to possess novel features, such as optical, magnetic, structural, and electronic properties, which are not originally present in the bulked materials. These utilizations of nanomaterials are attracting their applications in various aspects of drug delivery, molecular diagnosis, theranostics, and improved cancer therapies, including brain cancer or other neurological disorders, such as Alzheimer’s and Parkinson diseases. However, before the researchers apply these nanomaterials for brain theranostics of nanotechnology in novel drug delivery and imaging, there must be several aspects that should be considered for better outcomes, which include improved biocompatibility, less or no toxicity, non-agglomeration in the body upon injection, longer half-life, and in vivo stability and improved target specificity with enhanced imaging qualities at the target sites ^[46]. As shown in Table 1, several forms of nanomaterials have been engineered and applied for the brain targeting functions with improved therapeutic outcomes. In addition to that, Zhang et.al. developed an engineered nanomaterial platform to act as disease contrast agents in brain imaging. These materials showed less toxicity and a prolonged circulation time upon delivery ^[47]. In addition, the potentialities of nanomaterials associated toxicities could be escaped via certain structural modifications in the shape or properties, whereas the nanomaterials controlled to show slow and sustained release at the delivery site of the brain upon linked using targeting receptors/ligands involved to suppress the associated toxicities in vitro and in vivo ^[48]^[49]^[50]. Recently, Sukumar et.al. developed a multifunctional nanosystem using gold iron oxide nanoparticles (GIONs) conjugated with receptor targeting peptides with less toxicity for targeting glioblastoma via intranasal administration to overcome BBB ^[51]. This smart construct delivered the small therapeutic microRNAs that altered gene expression while facilitating contrast CT and MR-imaging of the glioma cells. The delivered microRNA further sensitized the tumor cells to the delivered Temozolomide (TMZ) anticancer agent in vivo (Figure 3). Similarly, Zhou et.al. developed a non-toxic nanoimaging material that specifically measured angiogenesis in glioblastoma ^[52]. Thus, the emerging nanomaterials platforms to brain theranostics would emphasize this field upon using their distinctive characteristics, further supporting them for biomedical imaging modalities, including drug delivery and therapeutics ^[53].

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 ^[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 ^[51].

Table 1. A list of functionalized theranostic nanoformulations developed to deliver therapeutics for brain-related diseases intranasally.

Target Disease	Nanoformulation	Model Organism	Therapeutic Outcome	Ref. No.
Parkinsons	Selegiline nanoemulsion	Rat	Intranasally administered selegiline nanoemulsion improved the behavioral activities in comparison to oral administration.	^[54]
Parkinsons	Resveratrol and curcumin nanoemulsion	Sheep	Intranasal delivery of hyaluronic acid-based lipidic nanoemulsion proven as a successful carrier to enhance the solubility, stability, and brain targetability of polyphenols.	^[55]
Alzheimer’s disease	Rivastigmine-loaded nanoemulsion	Rat	Achieved higher drug delivery to the brain with enhanced safety, non-toxic and non-irritating to the nasal mucosa.	^[56]
Alzheimer’s disease	Donepezil nanoemulsion	Pig	Effective strategy using polymers improved the adhesion and penetration of the drug through the nasal mucosa.	^[57]
Alzheimer’s disease	Cholera Toxin B subunit-based nanoparticles	Mice	Delivered nanosystem exhibited a notable performance in accumulating in the hippocampus that further showed an excellent magnetic resonance imaging (MRI) potential in vivo.	^[3]
Epilepsy	Letrozole loaded nanoemulsion	Mice	Intranasal administration of nanoemulsion improved the prolonged drug release profile in brain as compared to suspension.	^[58]
Migraine	Zolmitriptan mucoadhesive nanoemulsion	Rat	In vivo delivery showed higher permeability through the nasal mucosa.	^[59]
Neuroprotective	Kaempferol loaded chitosan nanoemulsion	Rat	In vivo delivery and biodistribution studies exhibited a higher drug concentration in the brain upon intranasal administration.	^[60]
Glioblastoma	Bevacizumab-PLGA NPs	Mice	Bevacizumab-loaded PLGA NPs showed effective tumor reductions as accompanied by higher anti-angiogenic potentials than free drug.	^[61]
Glioma	Ecto-50-nucleotidase (CD73 siRNA) nanoemulsion	Rat	Intranasal nasal administration of cationic nanoemulsion with CD73 siRNA delivery system improved glioblastoma therapy.	^[62]
Glioma	Temozolomide-Anti-EPHA3 PLGA NPs	Rat	Study results indicated that anti-EPHA3-decorated PLGA NPs targeted the Glioma via a nose-to-brain drug delivery approach.	^[63]
Glioblastoma	Farnesylthiosalicylicacid (FTA) loaded hybrid NPs	Rat	Intranasal delivery of FTA-NPs improved the glioblastoma therapy in vivo.	^[64]
Glioblastoma	miR-100 and antimiR-21 loaded PolyGIONS	Mice	Intranasal delivery of NPs strategy potentiated the nano-theranostic effects in vivo.	^[51]
Glioblastoma	siRNA + TMZ loaded chitosan NPs	Mice	Intranasal delivery of nanoparticle adjuvants increase the efficiency of immune-checkpoint blockade and chemotherapy in vivo.	^[65]
Glioblastoma	Self-assembled BMP4 plasmid DNA with poly(beta-amino ester) NPs	Rat	Intransally administered NPs could target brain tumors to enhance targeted therapies.	^[66]
Gliobastoma	Self-assembly of MPEG-PCL-Tat with siRaf-1/ Camptothecin	Rat	Nose-to-brain delivery proved the excellent therapeutic functions for treating glioblastoma.	^[67]
Glioblastoma	Extracellular vesicles (EVs) loaded with CXCR4 receptor, antimiRNA-21 and miRNA-100 biomaterials	Mice	Intranasally delivered EVs with miRNA sensitized the tumor cells to treat temozolomide, thereby improving mice’s survival rate.	^[68]
Epilepsy	Carbamazepine loaded carboxymethyl chitosan nanoparticles	Mice	Enhanced drug bioavailability and brain targeting was achieved via nasal administration.	^[69]
Central nervous systems disorders	Rabies Virus Glycoprotein (RVG29)-Modified PLGA Nanoparticles	Mice	Engineered nanoparticulate systems proved the viral delivery vectors to target and treat CNS via intranasal delivery.	^[70]
Huntington’s disease	Chitosan nanoparticles loaded with anti-HTT siRNA	Mice	Intranasal delivery proved the promising therapeutic alternative for safe and effective which further decreases the mutant HTT expression.	^[71]
Ischemic stroke	17β-estradiol (E2) loaded gelatin nanoparticles	Mice	The intranasally administered nanoparticles achieved higher delivery efficacy in vivo.	^[72]
Newcastle disease and infectious bronchitis	Chitosan nanoparticles loaded with the combined attenuated live vaccine	Chicken	Intranasal adjuvant and delivery carrier made a mucosal vaccine and delivery of drugs for enhanced immune functions.	^[73]
SARS-CoV-2	Receptor-binding domain (RBD) of SARS-CoV-2 spike glycoprotein loaded chitosan nanoparticles	Mice	An alternative route of intranasal vaccination mimics the natural route of SARS-CoV-2 infection and stimulates both mucosal and systemic compartments of the immune responses.	^[74]
SARS-CoV2 vaccine mucosal immunization	Au-nanostar-chitosan loaded with SARS CoV-2 DNA vaccine	Mice	Intranasal administered SARS-CoV2 DNA vaccines encoded the spike protein antigen loaded nanomaterial achieved the humoral antibody responses and providing long-lasting immunity.	^[75]
Respiratory infection	Chitosan Nanoparticles–Adjuvanted Chlamydia Vaccine	Mice	Intranasal adjuvants induced the humoral, mucosal, cell-mediated immunity against bacterial infections in vivo by acting as nano vaccines.	^[76]

2. Nanomaterials Improving Theranostic Imaging Modalities

Theranostic nanoparticles in molecular imaging significantly impact non-invasive strategies to understand biological and biochemical events in intact cells within living subjects. It plays a prominent role in disease diagnosis and therapeutic monitoring outcomes in vivo ^[27]. The theranostic application of nanomaterials can be classified into morphological and functional imaging based on their roles in image contrast abilities during applicable imaging methods. A wide range of multifunctional nanoparticles have been extensively proven for their properties as an agent for both therapeutic and diagnostic applications (theranostics). Promoting newer research directions are shown to explore those novel materials function in relevant animal disease models via improving their qualities towards clinical translations—recent approaches in non-invasive disease monitoring, biomarkers, and therapeutic drug deliveries are under investigation in advanced theranostics. In addition, some of the biomaterials, including magnetic NPs, QDs (Quantum dots), UCNPs (Upconverting nanoparticles), SLNs (silica nanomaterials), carbon nanoparticles, and organic dye coupled materials, have shown a significant role in theranostics with wide ranges of clinical translations. Variations in size and surface changes could modulate biocompatibility and interactions of these nanomaterials with target tissues. Hence, developing the contracted interest for improved disease monitoring/detections with improved chemotherapies along with clinically translatable innovative nanomaterials can be a significant driving force for theranostic agent research in the near future. The advancements made in, and the tie between, interdisciplinary scientific disciplines, such as nanotechnology, biology, pharmacology, chemistry, medicine, and imaging fields involving developing theranostics, have been significantly designed and evaluated over the past few years in clinical conditions, for growing nano-theranostics (Figure 4).

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.

The development of novel nanoparticles consisting of both diagnostic and therapeutic components has increased over the past decade. These theranostic nanoparticles have been tailored toward one or more types of imaging modalities. They have been developed as imaging probes in optical imaging, magnetic resonance imaging (MRI), photoacoustic imaging (PAI), computed tomography (CT), and nuclear imaging comprising both single-photon computed tomography (SPECT) and positron emission tomography (PET). Here, the researchers focused on the brain theranostic nanoparticles capable of both delivering therapy and self-reporting/tracking disease through imaging. Generally, imaging modalities, such as optical imaging, SPECT, and PET, are performed using a broad range of probes with high sensitivity ^[77]. The other primary imaging modalities, CT and MRI, are also reduced by image contrast properties during the probe conjugation or the tailored agents in the surface modification to impact resolution and sensitivity further. The growing interest in applying CQD (carbon quantum dots) with functionalized nanomaterials attention to various brain-related drug delivery approaches is emerging towards the clinical need of the situation. Utilizing these types of nanomaterials in combination with external stimuli, such as light or photoacoustic waves, at the delivery site, could efficiently modulate the functional properties of chemotherapeutic agents with diagnostic abilities ^[78]^[79]. The broader utilization of CQD in clinical applications is increasing because of their role in various aspects, including imaging and drug/gene delivery with therapeutics. The use of CQD in drug delivery across the BBB was achieved via nanoparticles after several functionalization processes in their structure that further internalized to the glioma cells, thereby envisaging their potentials in theranostic modalities in vitro and in vivo ^[80]^[81]^[82]. Thus, the novel nanomaterials in various categories could overcome these limitations by enhancing the tissue penetration, biodistribution at the desired sites, and the target specificity while adopting them in molecular imaging application ^[83]. Moreover, the nanomaterials are economically affordable and accurately deliverable for molecular-level quantitative imaging information towards translational approaches. Several interdisciplinary areas that range from novel targeting strategies, combination therapies, and unique imaging prospects via multiple multidisciplinary fields are emerging in recent decades to enhance theranostics (Figure 4). Despite significant progresses in developing MRI-targeted nanotheranostic platforms and their undeniable potential in predictive, preventive, and personalized medicine, gaps in knowledge continue to hinder their translations from bench to bedside, and a few nanotheranostic systems have undergone clinical trials ^[84]. This can be due to several factors, including the complexity of the developed hybrid nanosystems, difficulty in predicting their complex effects and interactions with biological systems, species-dependent immune responses and toxicity profiles, difficulty in controlling the pharmacokinetics and biodistribution properties, premature release of the therapeutic cargos in blood and healthy tissues, toxicity concerns, and the significant differences between animal models and humans. Recent research has focused on using imaging data to understand better the interactions between nanoparticles and biological systems to optimize tumor targeting and biodistribution ^[85].

In recent years, the growing interest in multimodal theranostics has been getting broader to overcome most contrast-associated limitations; nanomaterials with image contrast functions can provide more optimal materials to study the physiological and anatomical data retrieval in disease diagnosis with treatments (theragnosis). Hence, molecular engineers and nanotechnologists are trying to improve the existing nanomaterials contrast in disease detections in several human diseases, including neurological disorders ^[86]. Furthermore, various research groups work towards brain targeting and imaging with multifunctional nanomaterials strategies for suitable optical and MR-imaging modalities ^[24]^[87]^[88]. In practice, the multimodal targeting of tumors in the brains or the microenvironments could reach via engineered nanomaterials to enhance their theranostic functions (Table 1). In addition to integrating the disparity of dosage requirement between diagnostic and therapeutic entities within a single nanoparticle platform, the emerging tailored theranostic technologies could be applied to optimize the differences by estimating their circulation times that will further necessitate to realize the potentialities.

References

Menon, J.U.; Jadeja, P.; Tambe, P.; Vu, K.; Yuan, B.; Nguyen, K.T. Nanomaterials for photo-based diagnostic and therapeutic applications. Theranostics 2013, 3, 152.
Burgos-Ravanal, R.; Campos, A.; Díaz-Vesga, M.C.; González, M.F.; León, D.; Lobos-González, L.; Leyton, L.; Kogan, M.J.; Quest, A.F. Extracellular vesicles as mediators of cancer disease and as nanosystems in theranostic applications. Cancers 2021, 13, 3324.
Chen, Y.; Fan, H.; Xu, C.; Hu, W.; Yu, B. Efficient cholera toxin B subunit-based nanoparticles with MRI capability for drug delivery to the brain following intranasal administration. Macromol. Biosci. 2019, 19, 1800340.
Gu, X.; Kwok, R.T.; Lam, J.W.; Tang, B.Z. AIEgens for biological process monitoring and disease theranostics. Biomaterials 2017, 146, 115–135.
Weissleder, R.; Pittet, M.J. Imaging in the era of molecular oncology. Nature 2008, 452, 580–589.
Pirovano, G.; Roberts, S.; Kossatz, S.; Reiner, T. Optical imaging modalities: Principles and applications in preclinical research and clinical settings. J. Nucl. Med. 2020, 61, 1419–1427.
James, M.L.; Gambhir, S.S. A molecular imaging primer: Modalities, imaging agents, and applications. Physiol. Rev. 2012, 92, 897–965.
Mukherjee, S.; Madamsetty, V.S.; Bhattacharya, D.; Roy Chowdhury, S.; Paul, M.K.; Mukherjee, A. Recent advancements of nanomedicine in neurodegenerative disorders theranostics. Adv. Funct. Mater. 2020, 30, 2003054.
Kang, H.; Wong, S.H.D.; Pan, Q.; Li, G.; Bian, L. Anisotropic ligand nanogeometry modulates the adhesion and polarization state of macrophages. Nano Lett. 2019, 19, 1963–1975.
Kang, H.; Jung, H.J.; Wong, D.S.H.; Kim, S.K.; Lin, S.; Chan, K.F.; Zhang, L.; Li, G.; Dravid, V.P.; Bian, L. Remote control of heterodimeric magnetic nanoswitch regulates the adhesion and differentiation of stem cells. J. Am. Chem. Soc. 2018, 140, 5909–5913.
Min, S.; Jeon, Y.S.; Jung, H.J.; Khatua, C.; Li, N.; Bae, G.; Choi, H.; Hong, H.; Shin, J.E.; Ko, M.J. Independent tuning of nano-ligand frequency and sequences regulates the adhesion and differentiation of stem cells. Adv. Mater. 2020, 32, 2004300.
Kang, H.; Jung, H.J.; Kim, S.K.; Wong, D.S.H.; Lin, S.; Li, G.; Dravid, V.P.; Bian, L. Magnetic manipulation of reversible nanocaging controls in vivo adhesion and polarization of macrophages. ACS Nano 2018, 12, 5978–5994.
Thangam, R.; Kim, M.S.; Bae, G.; Kim, Y.; Kang, N.; Lee, S.; Jung, H.J.; Jang, J.; Choi, H.; Li, N. Remote switching of elastic movement of decorated ligand nanostructures controls the adhesion-regulated polarization of host macrophages. Adv. Funct. Mater. 2021, 31, 2008698.
Hong, H.; Min, S.; Koo, S.; Lee, Y.; Yoon, J.; Jang, W.Y.; Kang, N.; Thangam, R.; Choi, H.; Jung, H.J. Dynamic ligand screening by magnetic nanoassembly modulates stem cell differentiation. Adv. Mater. 2021, 2105460.
Kang, H.; Kim, S.; Wong, D.S.H.; Jung, H.J.; Lin, S.; Zou, K.; Li, R.; Li, G.; Dravid, V.P.; Bian, L. Remote manipulation of ligand nano-oscillations regulates adhesion and polarization of macrophages in vivo. Nano Lett. 2017, 17, 6415–6427.
Kang, H.; Zhang, K.; Jung, H.J.; Yang, B.; Chen, X.; Pan, Q.; Li, R.; Xu, X.; Li, G.; Dravid, V.P. An in situ reversible heterodimeric nanoswitch controlled by metal-ion–ligand coordination regulates the mechanosensing and differentiation of stem cells. Adv. Mater. 2018, 30, 1803591.
Kim, Y.; Choi, H.; Shin, J.E.; Bae, G.; Thangam, R.; Kang, H. Remote active control of nanoengineered materials for dynamic nanobiomedical engineering. View 2020, 1, 20200029.
Cheng, Z.; Yan, X.; Sun, X.; Shen, B.; Gambhir, S.S. Tumor molecular imaging with nanoparticles. Engineering 2016, 2, 132–140.
Cherry, S.R. Multimodality in vivo imaging systems: Twice the power or double the trouble? Annu. Rev. Biomed. Eng. 2006, 8, 35–62.
Smith, B.R.; Gambhir, S.S. Nanomaterials for in vivo imaging. Chem. Rev. 2017, 117, 901–986.
Fan, W.; Yung, B.; Huang, P.; Chen, X. Nanotechnology for multimodal synergistic cancer therapy. Chem. Rev. 2017, 117, 13566–13638.
Bjornmalm, M.; Thurecht, K.J.; Michael, M.; Scott, A.M.; Caruso, F. Bridging bio–nano science and cancer nanomedicine. ACS Nano 2017, 11, 9594–9613.
Hainfeld, J.; Slatkin, D.; Focella, T.; Smilowitz, H. Gold nanoparticles: A new X-ray contrast agent. Br. J. Radiol. Suppl. 2006, 79, 248–253.
Zhao, W.; Yu, X.; Peng, S.; Luo, Y.; Li, J.; Lu, L. Construction of nanomaterials as contrast agents or probes for glioma imaging. J. Nanobiotechnol. 2021, 19, 1–31.
Rangnekar, A.; Sarma, T.K.; Singh, A.K.; Deka, J.; Ramesh, A.; Chattopadhyay, A. Retention of enzymatic activity of α-amylase in the reductive synthesis of gold nanoparticles. Langmuir 2007, 23, 5700–5706.
Liu, T.; Jin, R.; Yuan, P.; Bai, Y.; Cai, B.; Chen, X. Intracellular enzyme-triggered assembly of amino acid-modified gold nanoparticles for accurate cancer therapy with multimode. ACS Appl. Mater. Interfaces 2019, 11, 28621–28630.
Hainfeld, J.F.; Smilowitz, H.M.; O’Connor, M.J.; Dilmanian, F.A.; Slatkin, D.N. Gold nanoparticle imaging and radiotherapy of brain tumors in mice. Nanomedicine 2013, 8, 1601–1609.
Liu, Y.; Bhattarai, P.; Dai, Z.; Chen, X. Photothermal therapy and photoacoustic imaging via nanotheranostics in fighting cancer. Chem. Soc. Rev. 2019, 48, 2053–2108.
Jia, X.; Han, Y.; Pei, M.; Zhao, X.; Tian, K.; Zhou, T.; Liu, P. Multi-functionalized hyaluronic acid nanogels crosslinked with carbon dots as dual receptor-mediated targeting tumor theranostics. Carbohydr. Polym. 2016, 152, 391–397.
Mu, J.; Lin, J.; Huang, P.; Chen, X. Development of endogenous enzyme-responsive nanomaterials for theranostics. Chem. Soc. Rev. 2018, 47, 5554–5573.
Song, N.; Zhang, Z.; Liu, P.; Yang, Y.W.; Wang, L.; Wang, D.; Tang, B.Z. Nanomaterials with supramolecular assembly based on AIE luminogens for theranostic applications. Adv. Mater. 2020, 32, 2004208.
Kreuter, J. Drug delivery to the central nervous system by polymeric nanoparticles: What do we know? Adv. Drug Deliv. Rev. 2014, 71, 2–14.
Rabanel, J.-M.; Delbreil, P.; Banquy, X.; Brambilla, D.; Ramassamy, C. Periphery-confined particulate systems for the management of neurodegenerative diseases and toxicity: Avoiding the blood-brain-barrier challenge. J. Control. Release 2020, 322, 286–299.
Li, X.; Vemireddy, V.; Cai, Q.; Xiong, H.; Kang, P.; Li, X.; Giannotta, M.; Hayenga, H.N.; Pan, E.; Sirsi, S.R. Reversibly modulating the blood–brain barrier by laser stimulation of molecular-targeted nanoparticles. Nano Lett. 2021, 21, 9805–9815.
Pandit, R.; Chen, L.; Götz, J. The blood-brain barrier: Physiology and strategies for drug delivery. Adv. Drug Deliv. Rev. 2020, 165, 1–14.
Gao, H. Progress and perspectives on targeting nanoparticles for brain drug delivery. Acta Pharm. Sin. B 2016, 6, 268–286.
Poulose, A.C.; Veeranarayanan, S.; Mohamed, M.S.; Nagaoka, Y.; Aburto, R.R.; Mitcham, T.; Ajayan, P.M.; Bouchard, R.R.; Sakamoto, Y.; Yoshida, Y. Multi-stimuli responsive Cu2S nanocrystals as trimodal imaging and synergistic chemo-photothermal therapy agents. Nanoscale 2015, 7, 8378–8388.
Gai, S.; Yang, G.; Yang, P.; He, F.; Lin, J.; Jin, D.; Xing, B. Recent advances in functional nanomaterials for light–triggered cancer therapy. Nano Today 2018, 19, 146–187.
Banerjee, R.; Katsenovich, Y.; Lagos, L.; McIintosh, M.; Zhang, X.; Li, C.-Z. Nanomedicine: Magnetic nanoparticles and their biomedical applications. Curr. Med. Chem. 2010, 17, 3120–3141.
Gelmi, A.; Schutt, C.E. Stimuli-responsive biomaterials: Scaffolds for stem cell control. Adv. Healthc. Mater. 2021, 10, 2001125.
Kim, J.; Piao, Y.; Hyeon, T. Multifunctional nanostructured materials for multimodal imaging, and simultaneous imaging and therapy. Chem. Soc. Rev. 2009, 38, 372–390.
Na, H.B.; Song, I.C.; Hyeon, T. Inorganic nanoparticles for MRI contrast agents. Adv. Mater. 2009, 21, 2133–2148.
Kircher, M.F.; De La Zerda, A.; Jokerst, J.V.; Zavaleta, C.L.; Kempen, P.J.; Mittra, E.; Pitter, K.; Huang, R.; Campos, C.; Habte, F. A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nat. Med. 2012, 18, 829–834.
Jeon, M.; Halbert, M.V.; Stephen, Z.R.; Zhang, M. Iron oxide nanoparticles as T1 contrast agents for magnetic resonance imaging: Fundamentals, challenges, applications, and prospectives. Adv. Mater. 2021, 33, 1906539.
Zhang, J.; Ning, L.; Huang, J.; Zhang, C.; Pu, K. Activatable molecular agents for cancer theranostics. Chem. Sci. 2020, 11, 618–630.
Medintz, I.L.; Uyeda, H.T.; Goldman, E.R.; Mattoussi, H. Quantum dot bioconjugates for imaging, labelling and sensing. Nat. Mater. 2005, 4, 435–446.
Zhang, H.; Li, L.; Liu, X.L.; Jiao, J.; Ng, C.-T.; Yi, J.B.; Luo, Y.E.; Bay, B.-H.; Zhao, L.Y.; Peng, M.L. Ultrasmall ferrite nanoparticles synthesized via dynamic simultaneous thermal decomposition for high-performance and multifunctional T 1 magnetic resonance imaging contrast agent. ACS Nano 2017, 11, 3614–3631.
Nowak, M.; Helgeson, M.E.; Mitragotri, S. Delivery of nanoparticles and macromolecules across the blood–brain barrier. Adv. Ther. 2020, 3, 1900073.
Muthuraman, A.; Rishitha, N.; Mehdi, S. Role of nanoparticles in bioimaging, diagnosis and treatment of cancer disorder. In Design of Nanostructures for Theranostics Applications; Elsevier: Amsterdam, The Netherlands, 2018; pp. 529–562.
Mukhtar, M.; Bilal, M.; Rahdar, A.; Barani, M.; Arshad, R.; Behl, T.; Brisc, C.; Banica, F.; Bungau, S. Nanomaterials for diagnosis and treatment of brain cancer: Recent updates. Chemosensors 2020, 8, 117.
Sukumar, U.K.; Bose, R.J.; Malhotra, M.; Babikir, H.A.; Afjei, R.; Robinson, E.; Zeng, Y.; Chang, E.; Habte, F.; Sinclair, R. Intranasal delivery of targeted polyfunctional gold–iron oxide nanoparticles loaded with therapeutic microRNAs for combined theranostic multimodality imaging and presensitization of glioblastoma to temozolomide. Biomaterials 2019, 218, 119342.
Zhou, Z.; Qutaish, M.; Han, Z.; Schur, R.M.; Liu, Y.; Wilson, D.L.; Lu, Z.-R. MRI detection of breast cancer micrometastases with a fibronectin-targeting contrast agent. Nat. Commun. 2015, 6, 1–11.
Wu, C.; Muroski, M.E.; Miska, J.; Lee-Chang, C.; Shen, Y.; Rashidi, A.; Zhang, P.; Xiao, T.; Han, Y.; Lopez-Rosas, A. Repolarization of myeloid derived suppressor cells via magnetic nanoparticles to promote radiotherapy for glioma treatment. Nanomed. Nanotechnol. Biol. Med. 2019, 16, 126–137.
Kumar, S.; Ali, J.; Baboota, S. Design Expert® supported optimization and predictive analysis of selegiline nanoemulsion via the olfactory region with enhanced behavioural performance in Parkinson’s disease. Nanotechnology 2016, 27, 435101.
Nasr, M. Development of an optimized hyaluronic acid-based lipidic nanoemulsion co-encapsulating two polyphenols for nose to brain delivery. Drug Deliv. 2016, 23, 1444–1452.
Haider, M.F.; Khan, S.; Gaba, B.; Alam, T.; Baboota, S.; Ali, J.; Ali, A. Optimization of rivastigmine nanoemulsion for enhanced brain delivery: In-vivo and toxicity evaluation. J. Mol. Liq. 2018, 255, 384–396.
Espinoza, L.C.; Silva-Abreu, M.; Clares, B.; Rodríguez-Lagunas, M.J.; Halbaut, L.; Cañas, M.-A.; Calpena, A.C. Formulation strategies to improve nose-to-brain delivery of donepezil. Pharmaceutics 2019, 11, 64.
Iqbal, R.; Ahmed, S.; Jain, G.K.; Vohora, D. Design and development of letrozole nanoemulsion: A comparative evaluation of brain targeted nanoemulsion with free letrozole against status epilepticus and neurodegeneration in mice. Int. J. Pharmaceut. 2019, 565, 20–32.
Abdou, E.M.; Kandil, S.M.; El Miniawy, H.M. Brain targeting efficiency of antimigrain drug loaded mucoadhesive intranasal nanoemulsion. Int. J. Pharmaceut. 2017, 529, 667–677.
Colombo, M.; de Lima Melchiades, G.; Figueiró, F.; Battastini, A.M.O.; Teixeira, H.F.; Koester, L.S. Validation of an HPLC-UV method for analysis of Kaempferol-loaded nanoemulsion and its application to in vitro and in vivo tests. J. Pharm. Biomed. Anal. 2017, 145, 831–837.
Sousa, F.; Dhaliwal, H.K.; Gattacceca, F.; Sarmento, B.; Amiji, M.M. Enhanced anti-angiogenic effects of bevacizumab in glioblastoma treatment upon intranasal administration in polymeric nanoparticles. J. Control. Release 2019, 309, 37–47.
Azambuja, J.; Schuh, R.; Michels, L.; Gelsleichter, N.; Beckenkamp, L.; Iser, I.; Lenz, G.; De Oliveira, F.; Venturin, G.; Greggio, S. Nasal administration of cationic nanoemulsions as CD73-siRNA delivery system for glioblastoma treatment: A new therapeutical approach. Mol. Neurobiol. 2020, 57, 635–649.
Chu, L.; Wang, A.; Ni, L.; Yan, X.; Song, Y.; Zhao, M.; Sun, K.; Mu, H.; Liu, S.; Wu, Z. Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting. Drug Deliv. 2018, 25, 1634–1641.
Sekerdag, E.; Lüle, S.; Pehlivan, S.B.; Öztürk, N.; Kara, A.; Kaffashi, A.; Vural, I.; Işıkay, I.; Yavuz, B.; Oguz, K.K. A potential non-invasive glioblastoma treatment: Nose-to-brain delivery of farnesylthiosalicylic acid incorporated hybrid nanoparticles. J. Control. Release 2017, 261, 187–198.
Van Woensel, M.; Mathivet, T.; Wauthoz, N.; Rosière, R.; Garg, A.D.; Agostinis, P.; Mathieu, V.; Kiss, R.; Lefranc, F.; Boon, L. Sensitization of glioblastoma tumor micro-environment to chemo-and immunotherapy by Galectin-1 intranasal knock-down strategy. Sci. Rep. 2017, 7, 1–14.
Mangraviti, A.; Tzeng, S.Y.; Gullotti, D.; Kozielski, K.L.; Kim, J.E.; Seng, M.; Abbadi, S.; Schiapparelli, P.; Sarabia-Estrada, R.; Vescovi, A. Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival. Biomaterials 2016, 100, 53–66.
Kanazawa, T.; Morisaki, K.; Suzuki, S.; Takashima, Y. Prolongation of life in rats with malignant glioma by intranasal siRNA/drug codelivery to the brain with cell-penetrating peptide-modified micelles. Mol. Pharm. 2014, 11, 1471–1478.
Wang, K.; Kumar, U.S.; Sadeghipour, N.; Massoud, T.F.; Paulmurugan, R. A microfluidics-based scalable approach to generate extracellular vesicles with enhanced therapeutic microRNA loading for intranasal delivery to mouse glioblastomas. ACS Nano 2021, 15, 18327–18346.
Liu, S.; Yang, S.; Ho, P.C. Intranasal administration of carbamazepine-loaded carboxymethyl chitosan nanoparticles for drug delivery to the brain. Asian J. Pharm. Sci. 2018, 13, 72–81.
Chung, E.P.; Cotter, J.D.; Prakapenka, A.V.; Cook, R.L.; DiPerna, D.M.; Sirianni, R.W. Targeting small molecule delivery to the brain and spinal cord via intranasal administration of rabies virus glycoprotein (RVG29)-modified PLGA nanoparticles. Pharmaceutics 2020, 12, 93.
Sava, V.; Fihurka, O.; Khvorova, A.; Sanchez-Ramos, J. Enriched chitosan nanoparticles loaded with siRNA are effective in lowering Huntington’s disease gene expression following intranasal administration. Nanomed. Nanotechnol. Biol. Med. 2020, 24, 102119.
Joachim, E.; Barakat, R.; Lew, B.; Kim, K.K.; Ko, C.; Choi, H. Single intranasal administration of 17β-estradiol loaded gelatin nanoparticles confers neuroprotection in the post-ischemic brain. Nanomed. Nanotechnol. Biol. Med. 2020, 29, 102246.
Zhao, K.; Li, S.; Li, W.; Yu, L.; Duan, X.; Han, J.; Wang, X.; Jin, Z. Quaternized chitosan nanoparticles loaded with the combined attenuated live vaccine against Newcastle disease and infectious bronchitis elicit immune response in chicken after intranasal administration. Drug Deliv. 2017, 24, 1574–1586.
Jearanaiwitayakul, T.; Seesen, M.; Chawengkirttikul, R.; Limthongkul, J.; Apichirapokey, S.; Sapsutthipas, S.; Phumiamorn, S.; Sunintaboon, P.; Ubol, S. Intranasal administration of RBD nanoparticles confers induction of mucosal and systemic immunity against SARS-CoV-2. Vaccines 2021, 9, 768.
Kumar, U.S.; Afjei, R.; Ferrara, K.; Massoud, T.F.; Paulmurugan, R. Gold-nanostar-chitosan-mediated delivery of SARS-CoV-2 DNA vaccine for respiratory mucosal immunization: Development and proof-of-principle. ACS Nano 2021, 15, 17582–17601.
Li, Y.; Wang, C.; Sun, Z.; Xiao, J.; Yan, X.; Chen, Y.; Yu, J.; Wu, Y. Simultaneous intramuscular and intranasal administration of chitosan nanoparticles–Adjuvanted Chlamydia vaccine elicits elevated protective responses in the lung. Int. J. Nanomed. 2019, 14, 8179.
Cheng, L.; Wang, X.; Gong, F.; Liu, T.; Liu, Z. 2D nanomaterials for cancer theranostic applications. Adv. Mater. 2020, 32, 1902333.
Li, S.; Su, W.; Wu, H.; Yuan, T.; Yuan, C.; Liu, J.; Deng, G.; Gao, X.; Chen, Z.; Bao, Y. Targeted tumour theranostics in mice via carbon quantum dots structurally mimicking large amino acids. Nat. Biomed. Eng. 2020, 4, 704–716.
Molaei, M.J. Carbon quantum dots and their biomedical and therapeutic applications: A review. RSC Adv. 2019, 9, 6460–6481.
Li, N.; Liang, X.; Wang, L.; Li, Z.; Li, P.; Zhu, Y.; Song, J. Biodistribution study of carbogenic dots in cells and in vivo for optical imaging. J. Nanopart. Res. 2012, 14, 1–9.
Huang, N.; Cheng, S.; Zhang, X.; Tian, Q.; Pi, J.; Tang, J.; Huang, Q.; Wang, F.; Chen, J.; Xie, Z. Efficacy of NGR peptide-modified PEGylated quantum dots for crossing the blood–brain barrier and targeted fluorescence imaging of glioma and tumor vasculature. Nanomed. Nanotechnol. Biol. Med. 2017, 13, 83–93.
Kabanov, A.V.; Batrakova, E.V. Polymer nanomaterials for drug delivery across the blood brain barrier. In Neuroimmune Pharmacology; Springer: Berlin/Heidelberg, Germany, 2017; pp. 847–868.
Huang, H.; Lovell, J.F. Advanced functional nanomaterials for theranostics. Adv. Funct. Mater. 2017, 27, 1603524.
Van der Meel, R.; Sulheim, E.; Shi, Y.; Kiessling, F.; Mulder, W.J.; Lammers, T. Smart cancer nanomedicine. Nat. Nanotechnol. 2019, 14, 1007–1017.
Toy, R.; Bauer, L.; Hoimes, C.; Ghaghada, K.B.; Karathanasis, E. Targeted nanotechnology for cancer imaging. Adv. Drug Deliv. Rev. 2014, 76, 79–97.
Kevadiya, B.D.; Ottemann, B.M.; Thomas, M.B.; Mukadam, I.; Nigam, S.; McMillan, J.; Gorantla, S.; Bronich, T.K.; Edagwa, B.; Gendelman, H.E. Neurotheranostics as personalized medicines. Adv. Drug Deliv. Rev. 2019, 148, 252–289.
Ehlerding, E.B.; Grodzinski, P.; Cai, W.; Liu, C.H. Big potential from small agents: Nanoparticles for imaging-based companion diagnostics. ACS Nano 2018, 12, 2106–2121.
Chen, J.; Li, J.; Zhou, J.; Lin, Z.; Cavalieri, F.; Czuba-Wojnilowicz, E.; Hu, Y.; Glab, A.; Ju, Y.; Richardson, J.J. Metal–phenolic coatings as a platform to trigger endosomal escape of nanoparticles. ACS Nano 2019, 13, 11653–11664.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Neuroimaging; Neurosciences; Cell & Tissue Engineering

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Ramar Thangam

Ramasamy Paulmurugan

Heemin Kang

View Times: 420

Update Date: 08 Apr 2022

Table of Contents

Video Upload Options

Confirm

1. Introduction

2. Nanomaterials Improving Theranostic Imaging Modalities

References