Nat Med — MRI is a powerful, non-invasive in vivo imaging tool based on the alignment of protons in a strong magnetic field. Contrast agents are typically used to increase the brightness of the image, and hence the sensitivity of the technique.
Contrast agents such as gadolinium increase the relaxation time of protons in water, lengthening the period during which nuclear magnetization the alignment of protons returns to equilibrium distribution.
Also, because they are polyvalent they can carry several hundred chelated Gd-complexes, which can be covalently attached to the exterior or interior surfaces.
Targeted therapy requires that drugs interact specifically with disease tissue, while avoiding healthy cells. The targeted delivery of imaging and therapeutic molecules will make diagnosis more accurate and will reduce off-target effects associated with drugs. The development of phage-display technologies has led to the identification of tumor-specific markers and their ligands, as well as vascular homing peptides. The discovery of these ligands has revolutionized the field and opened the door for the development of specifically targeted reagents.
Opaque object is a nylon mesh grid used for quantification of angiogenesis. C High magnification image of tumor interior shown in b; tumor microvasculature is clearly observed. Right, merge. Scale bar, mm. E Left, visualization of pre-existing CAM vasculature and neovasculature arising from tumor angiogenesis 24 h after tumor-cell injection.
The extensive migration over 24 h indicates a high level of tumor-cell viability. Natural interactions between CPMV and mammalian cells have also been demonstrated using an animal model of the human demyelinating disease multiple sclerosis, by targeting the VNPs to sites of inflammation in the central nervous system CNS. In inflammatory lesions containing macrophages, microglia, and immunoglobulins indicative of barrier failure , CPMV was also detected in the brain parenchyma.
This provides opportunities for the targeted treatment of inflammatory disease of the CNS. Certain disease tissues express different receptors to the corresponding healthy tissues and such receptors can be targeted specifically using appropriate ligands to deliver therapeutic or imaging reagents. For example, the receptor for the iron storage protein transferrin Tf is overexpressed on several tumor cells. VNPs have been designed for the targeted delivery of drugs and also for targeted photodynamic therapy PDT , in which a photosoensitizer is excited by specific wavelengths of light to generate reactive oxygen species, killing the target cells.
Biochemical and biophysical data have shown that approximately 40 C 60 molecules can be displayed per VNP, and in vitro studies have confirmed the efficient delivery of the hybrid material into cells Figure 5. A HeLa cells only. D Z-section image 1. E, F Same cell as shown in D , image reconstructions using Imaris software. Reproduced from Steinmetz NF et al. JACS — When the VNP-targeted bacteria were exposed to light emitting diodes at a wavelength of nm they were killed by the resulting burst of reactive oxygen species.
Bacteriophages M13 and fd have also been developed as antimicrobial agents using antibodies against S. Small drug molecules can be covalently attached to VNPs, or encapsulated within them, and used for targeted therapies.
The chemotherapeutic molecules hygromycin and doxorubicin have each been covalently attached to M13 and targeted successfully to cancer cells in vitro resulting in targeted cytotoxicity. When VNPs were infused with the RNA operator, it diffused into the particles and bound to all 90 copies of the coat protein dimer, allowing 90 molecules of the cargo to be encapsulated.
Recent advances in nanotechnology have led to the development of VNPs for potential applications in targeted imaging and therapy. Most of the studies conducted so far have focused on the in vitro behavior of functionalized VNPs, either in biochemical assays or using cultured cells, and there is only limited data on the performance of specifically engineered VNPs in vivo. Many of the studies reported thus far have demonstrated proof of concept, to underline the strong potential of VNPs as novel candidate materials for medical devices.
The next hurdle will be to gain a better understanding of the fate and potential long-term side effects of VNPs in vivo. Targeting VNPs to specific receptors has been achieved in tissue culture but replicating these results in vivo will require greater insight into the way VNPs are processed by the body. The studies carried out thus far suggest that VNPs are indeed promising candidates for the development of next-generation targeted imaging reagents and drugs.
The virus-chemistry interface remains an exciting place to be! I would like to thank Prof. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form.
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Potential conflict of interest: none. National Center for Biotechnology Information , U. Author manuscript; available in PMC Oct 1. Nicole F. Steinmetz , Ph. Author information Copyright and License information Disclaimer. Steinmetz, PhD. Copyright notice. The publisher's final edited version of this article is available at Nanomedicine. See other articles in PMC that cite the published article.
Abstract Nanomaterials have been developed for potential applications in biomedicine, such as tissue-specific imaging and drug delivery. Open in a separate window. Figure 1. Figure 2. Viral nanotechnology — the assembly line 1. The toxicity, biodistribution and pharmacokinetics of VNPs When developing novel materials for applications in biomedicine it is essential to understand their in vivo properties, particularly any potential toxic effects.
PEGylation to reduce biospecific interactions and immunogenicity PEGylation, the attachment of polyethylene glycol PEG , is a common strategy in biomedicine to reduce or eliminate biospecific interactions. Hybrid VNP complexes for biomedical imaging A broad range of design principles have been established to formulate hybrid VNP systems for imaging applications.
Figure 3. Targeted VNPs Targeted therapy requires that drugs interact specifically with disease tissue, while avoiding healthy cells. Figure 4. Designing receptor-targeted VNP formulations Certain disease tissues express different receptors to the corresponding healthy tissues and such receptors can be targeted specifically using appropriate ligands to deliver therapeutic or imaging reagents. Targeted therapeutic VNP formulations VNPs have been designed for the targeted delivery of drugs and also for targeted photodynamic therapy PDT , in which a photosoensitizer is excited by specific wavelengths of light to generate reactive oxygen species, killing the target cells.
Figure 5. Conclusions and outlook Recent advances in nanotechnology have led to the development of VNPs for potential applications in targeted imaging and therapy. Acknowledgements I would like to thank Prof. Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. References 1. Current dendrimer applications in cancer diagnosis and therapy. Curr Top Med Chem. Manchester M, Singh P.
Virus-based nanoparticles VNPs : platform technologies for diagnostic imaging. Adv Drug Deliv Rev. Drug delivery by soft matter: matrix and vesicular carriers. A Scheme of a color transition of PDA vesicles by their structure change on target binding. Although highly sensitive detection e. Thus, further studies are required to significantly reduce the assay time while maintaining or further improving the sensitivity. Here, we have reviewed recent studies on colorimetric diagnostics of pathogenic bacteria and viruses utilizing various NMs with unique optical, electrical, and catalytic properties.
As described above, sensitivity and specificity of colorimetric pathogen diagnostics can be enhanced by employing NMs as signal transduction and amplification tools. First, various NMs of low cost need to be investigated. As not all NMs exhibit the unique optical properties required for colorimetric responses, testing of various NMs for their suitability will be the first step.
For example, white or colorless silicon Si NPs are not suitable for use in colorimetric detection, although Si is one of the most abundant elements on the Earth. For making colorless Si NPs colorful, doping of various organic dyes on Si NPs has recently been reported and utilized in colorimetric diagnostics. Second, optimizing the size and shape of NMs needs to be performed for enhancing the sensitivity and selectivity of colorimetric pathogenic diagnostics.
Properties of NMs, such as catalytic properties, are often dependent on the size and shape of NMs. Third, simple methods for fabricating colorimetric diagnostic systems need to be developed for facilitating commercialization. However, methods for modifying NMs and bioreceptors and also conjugation are time consuming and labor intensive. Modification of NMs with small molecules e.
However, NM synthesis is mostly performed under rather harsh conditions, which can denature or degrade such bioreceptor molecules of interest. The authors thank Seung Min Yoo for her advice in planning the manuscript. Yoojin Choi is a Ph. She is working on biological synthesis of nanomaterials and their applications in various fields. Prior to undertaking her Ph. Ji Hyeon Hwang is an M. She is working on biosensors and pathogen diagnostics. Prior to undertaking her M. His research interests are metabolic engineering, systems biology and biotechnology, industrial biotechnology, synthetic biology, and nanobiotechnology.
Choi Y. National Center for Biotechnology Information , U. Small Methods. Published online Mar 8. Author information Article notes Copyright and License information Disclaimer. Sang Yup Lee, Email: rk. Corresponding author. Received Nov 2. KGaA, Weinheim. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
This article has been cited by other articles in PMC. Keywords: bacteria, colorimetric biosensors, nanomaterials, pathogens, viruses. Abstract Colorimetric diagnostic systems for detecting pathogenic bacteria and viruses using various nanomaterials are reviewed.
Table 1 Summary of recent studies on colorimetric detection of pathogenic bacteria and viruses using various NMs. Open in a separate window. Figure 1. Colorimetric Detection Based on Aggregation of NMs As another approach to using NMs in colorimetric methods, direct use of NMs has been investigated by taking advantage of their unique optical properties. Figure 2. Colorimetric Detection Based on Destabilization of NM Structure Methods for colorimetric detection of pathogens based on the change and destabilization of NM structure have also been developed.
Figure 3. Conclusion and Future Perspectives Here, we have reviewed recent studies on colorimetric diagnostics of pathogenic bacteria and viruses utilizing various NMs with unique optical, electrical, and catalytic properties. Conflict of Interest The authors declare no conflict of interest. Acknowledgements Y. Notes Choi Y. References 1. Yoo S. Singh R.
Actuators, B , , Lifson M. Drug Delivery Rev. Bridle H. Vidic J. Velusamy V. Ahmed A. Because many viruses rely on glycoproteins on their surface to bind to molecules on host cells, nanomaterials that mimic these cellular attachment points can potentially act as antivirals.
After removing the contents of the cell to leave only the membrane, they break the membrane into thousands of tiny vesicles roughly nanometers wide. Then they add nanoparticles made from a biocompatible and biodegradable polymer, such as poly lactic-co-glycolic acid. Each nanoparticle becomes coated with a cell membrane, forming a stable core-shell structure that acts as a decoy of a human cell. The nanosponges then use binding points on their membranes to surround a virus and prevent it from entering host cells.
Cellics is also using macrophage membranes to develop similar nanosponges with antiviral activity. Last year, Zhang found that a cellular nanosponge coated in membranes derived from human lung epithelial type II cells or human macrophages were both able to trap SARS-CoV-2 and prevent infection in vitro. Starpharma, headquartered in Abbotsford, Melbourne, Australia, is also mimicking host cells to combat viruses.
It makes synthetic polymers with a branched structure, known as dendrimers, that are roughly 3—4 nanometers wide. The outer surface of each dendrimer is covered in naphthalene disulfonate groups, similar to the heparan sulfate proteoglycans found on host cell membranes, which many viruses stick to. Starpharma already has products on the market that employ a dendrimer called SPL as an external barrier against viruses and bacteria.
SPL is used in VivaGel, a lubricant in condoms, for example. Earlier this year, Starpharma launched Viraleze, a broad-spectrum antiviral nasal spray containing SPL, which is registered for sale as a medical device in Europe and India.
The company says that a clinical safety study, which has not yet been peer reviewed, showed that the dendrimer in Viraleze was not absorbed in the body and caused no significant side effects. Some antiviral nanomaterials are precisely shaped to trap viruses. The spikes can be decorated with sialic acid sugars to enhance binding, or with antiviral compounds such as zanamivir. In vitro experiments showed that the particles prevented infection of cells with influenza A virus, and the team now hopes to design spiky nanoparticles with activity against SARS-CoV Star-shaped DNA scaffolds offer another potential approach.
Xing Wang at the University of Illinois at Urbana-Champaign has built such structures carrying DNA aptamers capable of binding to antigens at multiple points on the surface of dengue fever virus. The physical bulk of the DNA star, and its negative charge, prevent the virus from latching on to host cells, shutting down infection. The team has developed shells made from DNA that are large enough to swallow an entire virus whole.
The interior of the self-assembling icosahedral shells can be lined with binders, such as antibodies, to hold onto trapped viruses. Dietz says that the nanoshells could potentially decrease viral load during acute infections. The researchers designed triangular DNA structures that assemble into shells of various shapes and sizes, from 90 to nanometers wide. By tweaking the DNA sequences in the triangular building blocks, they created virus-sized openings in the side of a shell. In vitro experiments showed that these shells could bind viruses such as adeno-associated virus serotype 2 and prevent them from infecting human cells.
This means the shells could in principle be tailored to bind any virus, he says. Some nanomaterials go beyond simply binding viruses—instead, they disrupt the viral membrane to prevent infection.
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