How could gold nanourchins be applied in the clinic?

NanomedicineVol. 15, No. 9 EditorialFree AccessHow could gold nanourchins be applied in the clinic?Dana M Samhadaneh, Siwei Chu, Dusica Maysinger & Ursula StochajDana M SamhadanehDepartment of Physiology, McGill University, Montreal, QC, H3G, Canada, Siwei ChuDepartment of Physiology, McGill University, Montreal, QC, H3G, Canada, Dusica MaysingerDepartment of Pharmacology & Therapeutics, McGill University, Montreal, QC, H3G, Canada & Ursula Stochaj*Author for correspondence: E-mail Address: ursula.stochaj@mcgill.caDepartment of Physiology, McGill University, Montreal, QC, H3G, CanadaPublished Online:17 Feb 2020https://doi.org/10.2217/nnm-2019-0438AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: cancerdiagnosticsgold nanoparticlesgold nanourchinsmedical imagingnanomaterialsnanoparticle imagingpathogenstherapeuticsThe physicochemical characteristics of nanoparticles, including gold nanoparticles (AuNPs), depend on their composition, shape, size and surface modification. These features contribute to the photophysical properties, reactivity and toxicity of nanomaterials in biological systems [1–3]. The excellent biocompatibility and colloidal stability are critical attributes that propelled AuNPs to the forefront of research and development [1,2].Gold nanourchins (AuNUs), also termed gold nanoflowers or gold nanostars [4], are multibranched nanoparticles. The spikes on the AuNU surface are the basis for unique optical features that can be exploited for basic research, sensor development, theranostics and other applications. Of particular importance is the surface plasmon resonance (SPR) peak of AuNUs; it is tunable and can be adjusted to emit in the near-infrared spectral regions. For most AuNUs studied to date, SPR peaks are between 550 and 800 nm [1]. This is crucial for in vivo use, because tissue absorption is low in the near-infrared, while penetration is deep. Moreover, the electromagnetic field increases profoundly at the tips of AuNU spikes. The resulting surface-enhanced Raman scattering (SERS) has been used for AuNU-mediated Raman imaging with excellent sensitivities [5].AuNUs can support diverse functions that are relevant to human health. They include biosensing, catalysis, in vivo imaging, drug delivery, photothermal therapy (PTT), photodynamic therapy (PDT) and immunotherapy. Here, we briefly summarize the production of AuNUs and discuss present theranostic applications. We conclude with bottlenecks that currently limit the widespread clinical use of AuNUs and provide an outlook on future developments.AuNU synthesisContinuous progress in recent years improved the methods for AuNU synthesis. For instance, AuNUs can be produced by green-chemistry synthesis [6], and they have been incorporated into composite nanomaterials [1]. Furthermore, protocols have been developed to advance the reproducibility and quality control for AuNU production [1]. Knowledge on the AuNP-related bio–nano interactions promoted the production of AuNUs that display low toxicity and optimal performance in living cells.AuNUs for research & clinical applicationsAuNPs serve as multifunctional nanoplatforms, and AuNU-based tools have been established for basic research. Some of these protocols are highly suitable for diagnostic applications, such as imaging and biomarker detection. By contrast, the therapeutic use of AuNUs still faces substantial obstacles.Biomedical imaging with AuNUsBiological imaging is a major field of application for AuNUs. It takes advantage of the unique AuNU features described above. As such, AuNUs are photostable, suitable for long-term tracking, multiplexing and noninvasive imaging in living organisms.A wide variety of imaging methods rely on the SPR properties of AuNUs. Accordingly, AuNUs are ideal for imaging that is based on SERS, two-photon photoluminescence, magnetic resonance (MR), positron emission tomography (PET), x-ray computed tomography, single-photon emission computed tomography (SPECT), ultrasound and optical imaging [7]. Important for the killing of cells, the high photon-to-heat conversion efficiency of AuNUs outperforms the photothermal ablation capabilities of AuNPs with more regular shapes (e.g., gold nanospheres).Ex vivo techniques were applied for the AuNU-based evaluation of alkaline phosphatase activity in situ [8], cell tracking and photothermal ablation (e.g., PTT) [9]. AuNUs also function as sensors for biomolecules and disease biomarkers [7]. Biosensing is achieved by ligand-induced changes in AuNU properties [1,10]; the detection method is based on alterations in SERS or color. SERS-based immunoassays are especially valuable for the detection of low abundance biomarkers. AuNUs and SERS-dependent methods have been used to assess extracellular kinases, such as protein kinase A, plasma markers of brain damage (neuron-specific enolase), antibiotic resistant Enterobacteriaceae (carbapenemase activity), virus infection (enterovirus 71) and tumor therapy markers (PD-L1, EGFR) [7]. More recently, AuNU-based SERS technology was employed to discover Pseudomonas aeruginosa and Staphylococcus aureus in burn wounds of the skin [11], whereas AuNU-based colorimetric assays detected influenza virus [7].Other protocols employed AuNUs to measure a wide variety of pharmacological compounds and biomolecules. Examples are the antimalarial drug mefloquine [12], the neurotransmitter dopamine [13], hydrogen peroxide [14], the pregnancy hormone chorionic gonadotropin [15] or leptin, a hormone regulating satiety [16]. The diversity of imaging techniques and biosensor analytes demonstrate that AuNUs can contribute to the diagnosis of a wide variety of health conditions.Diseases & disorders that could benefit from AuNU-based therapyTo date, nanotherapeutic applications focus predominantly on different forms of cancer. AuNUs are particularly promising tools for PDT, immunotherapy and drug delivery [17–25]. In the context of cancer, AuNUs could also be part of multimodal therapy to overcome treatment resistance. Different AuNU-dependent strategies have been designed to surmount the multidrug resistance of cancer cells [23,26]. In addition to PTT [27], the inhibition or downregulation of P-glycoprotein and anti-angiogenic approaches [28] could be incorporated in future treatment strategies as well.The application of AuNUs is not limited to cancer therapy, but may also help to eradicate various pathogens that are linked to tumorigenesis or other health conditions. For instance, antibiotic-resistant Helicobacter pylori represents a potential clinical target for AuNUs [29]. This pathogen promotes inflammation and increases the risk for gastric cancer. When administered orally, pH-sensitive AuNUs can eliminate H. pylori in the stomach of living experimental mice [29]. The AuNUs were excreted within 7 days, suggesting a safe route to prevent AuNU accumulation [29]. P. aeruginosa and S. aureus represent other possible targets for AuNU-induced elimination [30]. Taken together, the AuNU-mediated killing of pathogens merits further development for treatment and prevention of several infectious diseases.AuNP-based diagnosis & treatmentAuNUs can measure a wide variety of disease biomarkers, and their therapeutic applications have been evaluated in experimental animals ([1] and references therein). Gold nanoparticles have been used in clinical trials that are relevant to cancer therapy, thermal ablation of atherosclerotic plaques and biomarker detection for Parkinson's disease [31]. The properties of AuNPs employed in these trials are not always described in detail. To the best of our knowledge, information on the assessment of AuNUs in clinical trials is not available. By contrast, patent applications have been filed for the synthesis and diagnostic use of AuNUs (see US Patent and Trademark Office [32]).What are the current bottlenecks for the clinical use of AuNUs?Gold nanourchins are clearly outstanding candidates for theranostics and disease prevention. Nevertheless, there are obstacles that limit their clinical applications. At the synthesis stage, both cost–effectiveness and reproducibility need to be improved. It has to be demonstrated that protocols are scalable to ensure adequate AuNU supplies for therapeutic interventions. Quality control is particularly important for AuNUs. Slight diversions from the synthesis method can have profound effects on the 'spiky' AuNU surface, which in turn will alter their physicochemical properties. Standardization of AuNU preparation is currently not available.For use in living cells, AuNUs have to be safe with low or no toxicity, even when repeated exposures to the AuNUs are required. Although many studies evaluate the toxicity of AuNUs in cultured cells, the examination of diverse cell types or healthy cells is often missing. Notably, sublethal AuNU effects are only beginning to emerge [33]. Thus, many aspects of AuNU-dependent bio–nano interactions remain to be characterized.The targeting of tumor cells is the most commonly proposed application for AuNUs in living organisms. As for all NPs, the AuNU biodistribution and proper accumulation at tumor sites in vivo remain challenging, especially if injection close to the tumor is not possible. Interestingly, AuNUs can be produced on wafers [4] or immobilized on adhesive tape [11]. Therefore, future applications may take advantage of AuNUs that are immobilized on biocompatible support.For all therapeutic applications, the optimal route of AuNU administration, pharmacokinetics, pharmacodynamics, biodistribution and long-term effects have to be explored. Additional questions need to be answered; for example, how do AuNUs affect the homeostasis of immune cells? Aside from oral administration [29], what other route(s) ensure the safe excretion of AuNUs? Are there cell type- and sex-specific differences in the response to therapeutic AuNUs? Can these differences be incorporated in therapeutic strategies?ConclusionAuNUs have ideal properties for diverse applications in the clinic; they range from biomedical imaging to diagnostics and therapeutics. However, the knowledge gaps that relate to the bio–nano interactions and effects of AuNPs on living cells and organisms currently restrict their therapeutic use. These gaps have to be filled to ensure that AuNUs can be optimized for safe and efficient treatment.Future perspectiveAlthough it is difficult to predict future developments, we anticipate that AuNUs will become firmly established as diagnostic tools that detect health-relevant biomolecules and pathogens. In addition, therapeutic applications that involve oral or topical AuNU administration may be fast-tracked to the clinic. In this scenario, nanoparticle accumulation in the patient and associated side effects will be low. Long-term, AuNU-based particles with multimodal and multiplexing capabilities could be applied to detect, image and kill selected patient cells or pathogens that are targeted for elimination.Author contributionsDM Samhadaneh, S Chu and D Maysinger contributed to the writing and editing, and U Stochaj drafted, wrote and edited the manuscript.Financial & competing interest disclosureThe authors acknowledge funding and fellowships from Natural Sciences and Engineering Research Council of Canada (NSERC) and Mitacs. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was used in the production of this manuscript.References1. Falahati M , Attar F , Sharifi M et al. Gold nanomaterials as key suppliers in biological and chemical sensing, catalysis, and medicine. Biochim. 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The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was used in the production of this manuscript.PDF download