pH-responsive polyelectrolyte complexation on upconversion nanoparticles: a multifunctional nanocarrier for protection, delivery, and 3D-imaging of therapeutic protein.

The delicate tertiary structure of proteins, their susceptibility to heat- and enzyme-induced irreversible denaturation, and their tendency to get accumulated at the cell membrane during uptake are daunting challenges in proteinaceous therapeutic delivery. Herein, a polyelectrolyte complex having encapsulated therapeutic protein has been designed on the surface of upconverting luminescent nanoparticles (NaYF4:20%Yb3+,2%Er3+). This nanosized complex system has been found to overcome the challenges of protein aggregation at the cell membrane. It has also defended the cargo from denaturation against (a) enzymatic action of proteinase K and (b) heat (up to 60 °C). Additionally, the nanoparticles at the core of the loaded carrier served as near-infrared (980 nm) responsive probe to accomplish extended-duration 3D imaging during protein delivery. The outer layer of polymer played pivotal role to protect/retrieve the protein structure from denaturation as investigated by circular dichroism studies. Both the masked surface-charges of protein and the nanoscale size of the loaded carrier have facilitated their efficient passage through the cell membrane as observed through 3D images/videos. This nanocarrier is the first of its kind for direct delivery of protein. Thus, the findings can be useful to protect and transport various proteinaceous materials to overcome challenges of accumulation at the cell-membrane and low-temperature storage, as nature does.

Structure-Based Varieties of Polymeric Nanocarriers and Influences of Their Physicochemical Properties on Drug Delivery Profiles.

Carriers are equally important as drugs. They can substantially improve bioavailability of cargos and safeguard healthy cells from toxic effects of certain therapeutics. Recently, polymeric nanocarriers (PNCs) have achieved significant success in delivering drugs not only to cells but also to subcellular organelles. Variety of natural sources, availability of different synthetic routes, versatile molecular architectures, exploitable physicochemical properties, biocompatibility, and biodegradability have presented polymers as one of the most desired materials for nanocarrier design. Recent innovative concepts and advances in PNC-associated nanotechnology are providing unprecedented opportunities to engineer nanocarriers and their functions. The efficiency of therapeutic loading has got considerably increased. Structural design-based varieties of PNCs are widely employed for the delivery of small therapeutic molecules to genes, and proteins. PNCs have gained ever-increasing attention and certainly paves the way to develop advanced nanomedicines. This article presents a comprehensive investigation of structural design-based varieties of PNCs and the influences of their physicochemical properties on drug delivery profiles with perspectives highlighting the inevitability of incorporating both the multi-stimuli-responsive and multi-drug delivery properties in a single carrier to design intelligent PNCs as new and emerging research directions in this rapidly developing area.

Near-Infrared-Triggered Upconverting Nanoparticles for Biomedicine Applications.

Due to the unique properties of lanthanide-doped upconverting nanoparticles (UCNP) under near-infrared (NIR) light, the last decade has shown a sharp progress in their biomedicine applications. Advances in the techniques for polymer, dye, and bio-molecule conjugation on the surface of the nanoparticles has further expanded their dynamic opportunities for optogenetics, oncotherapy and bioimaging. In this account, considering the primary benefits such as the absence of photobleaching, photoblinking, and autofluorescence of UCNPs not only facilitate the construction of accurate, sensitive and multifunctional nanoprobes, but also improve therapeutic and diagnostic results. We introduce, with the basic knowledge of upconversion, unique properties of UCNPs and the mechanisms involved in photon upconversion and discuss how UCNPs can be implemented in biological practices. In this focused review, we categorize the applications of UCNP-based various strategies into the following domains: neuromodulation, immunotherapy, drug delivery, photodynamic and photothermal therapy, bioimaging and biosensing. Herein, we also discuss the current emerging bioapplications with cutting edge nano-/biointerfacing of UCNPs. Finally, this review provides concluding remarks on future opportunities and challenges on clinical translation of UCNPs-based nanotechnology research.

Acute Neurological Care in the COVID-19 Era: The Pandemic Health System REsilience PROGRAM (REPROGRAM) Consortium Pathway.

The management of acute neurological conditions, particularly acute ischemic stroke, in the context of Coronavirus disease 2019 (COVID-19), is of importance, considering the risk of infection to the healthcare workers and patients and emerging evidence of the neuroinvasive potential of the virus. There are variations in expert guidelines further complicating the picture for clinicians in acute settings. In this light, there is a compelling need for further formulation of recommendations that compile these variations seen in the numerous guidelines present. Health system protocols for managing ongoing acute neurological care and intervention need consideration of safety and well-being of the frontline healthcare workers and the patients. We examine existing pathways and their efficacy to mitigate viral exposure to the healthcare workers and patients and synthesize a systemic approach to manage patients with acute neurological conditions in the COVID-19 scenario. Early experiences with a COVID-19 positive stroke patient treated with endovascular thrombectomy is presented to highlight the urgent need for adequate personal protective equipment (PPE) during acute neuro-interventional procedures.

Upconversion photoluminescence of Ho3+-Yb3+ doped barium titanate nanocrystallites: Optical tools for structural phase detection and temperature probing.

Authors have explored the photo-physical properties of Ho3+-Yb3+ doped BaTiO3 nanocrystals and proposed an intuitive method to probe temperature and crystal phase structure of the matrix. Structural phase change of doped crystals was analyzed in terms of their X-ray diffraction, and it was confirmed through second harmonic generation. We give insights on upconversion of energy of light-emission in Ho3+-Yb3+: BaTiO3 nanocrystals upon a 980 nm laser-light excitation and subsequently, the excited state dynamics were studied with the help of dependence of upconversion luminescence on excitation power and measuring-temperature. To understand the nature of occupancies of the Ho3+ ions at the Ti- and Ba-sites, we performed site-selective, time-resolved spectroscopic measurements at various crystal phases. Based on the lifetime analysis, it is inferred that the Ho3+ ions are present at two types of sites in barium titanate lattice. One of those is the 6-coordinated Ti-site of low symmetry, while the other one is the 12-coordinated Ba-site of higher symmetry. The upconversion emission of the nanocrystals are found to be temperature-sensitive (12 to 300 K), indicating possible use as a self-referenced temperature probe. An analysis of the temperature dependent emissions from 5F4 and 5S2 levels of Ho3+ ions, gives a maximum value of temperature sensitivity ~ 0.0095 K-1 at 12 K. Furthermore, we observe a sharp change in the luminescence intensity at ~180 K due to a ferroelectric phase change of the sample. The correlation of upconversion luminescence with the results of X-ray diffraction and second harmonic generation at different crystal phases implies that the frequency upconversion may be used as a probe of structural change of the lattice.

Crystal phase induced upconversion enhancement in Er3+/Yb3+ doped SrTiO3 ceramic and its temperature sensing studies.

Through doping of Er3+/Yb3+ ions the SrTiO3 perovskite ceramic is turned into an optically active material keeping its ferroelectric property intact. A huge enhancement of around 20 times in upconversion (UC) emission intensity is observed due to the transformation of cubic crystal structure to tetragonal phase. The intensity ratio of green to red band is found too high to neglect the contribution from the red emission band, which is not observed normally in such type of relatively moderate phonon frequency materials containing Yb3+/Er3+ ions. The change in emission intensity is reflected in the decay time measurement. Optical temperature sensing behavior based on FIR technique also has been discussed for Er3+/Yb3+ doped SrTiO3 ceramic.

Development of near-infrared sensitized core-shell-shell upconverting nanoparticles as pH-responsive probes.

Recently, the functionalization of nanoparticles, either within themselves or on the outer surface and its application in medicine, turned out to be the ultimate goal of nanotechnology. By providing these nanoparticles with chemical functional groups, one can force the nanoparticles to target the markers of the particular diseases or to measure the quantity and distribution of various intracellular species. In this paper, we report our development of a pH-responsive nanocomposite based on lanthanide-doped upconverting nanoparticles (UCNPs). Through multiphoton absorption and energy migration between spatially separated Nd3+, Yb3+, and Tm3+ in a three-layered NaYF4 host coated with FITC (fluorescein-5-isothiocyanate), this nanocomposite can measure the pH with high sensitivity. The fundamental acidity measurement is based on the pH-dependent equilibrium of the bright and dark states of FITC. The tremendous advantages of this system, regarding the pH measurement, come from the fact that the versatility of UCNP-imaging can fully be exploited. This includes the fact that (a) the optical wavelengths for the sensitization (980 nm and/or 808 nm) and the emission bands (UV, visible) are well separated, (b) the spectral overlap between FITC (absorption) and Tm3+ (emission) is substantially high, (c) there is no background signal due to the near-infrared laser, and (d) the signals are consistent regardless of the fluctuations by monitoring the ratio of blue band with respect to the unaffected self-reference (red and near-infrared bands). Moreover, the double shell structure is obviously superior to the core-shell structure in that it enhances the spectral separation between the sensitizer and the emitter in the upconversion process, inhibiting any unnecessary contamination in the spectra. Finally, it is noteworthy that Yb3+ plays crucial roles as a sensitizer at 980 nm excitation and a bridge above which 808 nm excitation migrates from Nd3+ to Tm3+ via the Yb3+ excited state.

Cellular uptake efficiency of nanoparticles investigated by three-dimensional imaging.

Understanding the interaction of nanoparticles with living cells on the basis of cellular uptake efficiency is a fundamental requisite in biomedical research. Cellular internalization of nanoparticles takes place by mechanisms like ATP hydrolysis-driven endocytosis that deliver nanoparticles to the cytoplasm, organelles and nuclei. Despite its importance in nanomedicine, this uptake procedure is not understood in-depth because of the complexity of the biochemical mechanisms and the lack of available experimental methods for quantitative analysis. The only breakthrough is likely to be the development of imaging techniques that can visualize, monitor and even count the number of nanoparticles inside the cell. To this end, we report here a new, fast and background-free three-dimensional (3-D) imaging technique with quantitative evaluation of the uptake efficiency for NaYF4:Yb3+,Er3+/NaYF4 core/shell upconversion nanoparticles (UCNPs) functionalized with different chemical and biological groups. Furthermore, the multiple 3-D trajectories of the UCNPs have been analyzed to investigate the cellular dynamics. This study reveals the nuclear uptake of UCNPs to be dependent on the specific chemical groups conjugated to the UCNPs. The developed 3-D imaging technique is of great significance for exploring complex biological systems.

Upconversion Luminescence Sensitized pH-Nanoprobes.

Photon upconversion materials, featuring excellent photophysical properties, are promising for bio-medical research due to their low autofluorescence, non-cytotoxicity, low photobleaching and high photostability. Upconversion based pH-nanoprobes are attracting considerable interest due to their superiority over pH-sensitive molecular indicators and metal nanoparticles. Herein, we review the advances in upconversion based pH-nanoprobes, the first time in the seven years since their discovery in 2009. With a brief discussion on the upconversion materials and upconversion processes, the progress in this field has been overviewed, along with the toxicity and biodistribution of upconversion materials for intracellular application. We strongly believe that this survey will encourage the further pursuit of intense research for designing molecular pH-sensors.

Dualistic temperature sensing in Er3+/Yb3+ doped CaMoO4 upconversion phosphor.

Temperature sensing performance of Er3+/Yb3+ doped CaMoO4 phosphor prepared via polyol method is reported herein. The X-ray diffraction, Fourier transform infrared spectroscopy and field emission scanning electron microscopy are done to confirm the phase, structure and purity of the synthesized phosphor. The infrared to green upconversion emission is investigated using 980nm diode laser excitation along with its dependence on input pump power and external temperature. The temperature dependent fluorescence intensity ratio of two upconversion emission bands assigned to 2H11/2→4I15/2 (530nm) and 4S3/2→4I15/2 (552nm) transitions has shown two distinct slopes in the studied temperature range - 300 to 760K and therefore, dual nature of temperature sensitivity is observed in this phosphor. This phenomenon in rare earth doped materials is either scarcely reported or overlooked. The material has shown higher sensitivity in the high temperature region (535K

Incorporation of Zn(2+) ions into BaTiO3:Er(3+)/Yb(3+) nanophosphor: an effective way to enhance upconversion, defect luminescence and temperature sensing.

Ferroelectric BaTiO3 became a multifunctional material via doping of lanthanide ions (0.3 mol% Er(3+)/3.0 mol% Yb(3+)) and subsequently upconversion luminescence was enhanced by incorporation of Zn(2+) ions. Upconversion luminescence of BaTiO3:Er(3+)/Yb(3+) perovskite nanophosphor has been studied using 800 and 980 nm laser excitations. The emission dynamics is studied with respect to its dependence on input power and external temperature including lifetime. Based on time-resolved spectroscopy, it is inferred that two types of Er(3+) sites are present in the barium titanate lattice. The first one is a short lived component (minor species) present at 6-coordinated Ti-sites of low symmetry while the second one is a long lived component (major species), present at 12-coordinated Ba-sites with high symmetry. The influence of the introduction of Zn(2+) ions on the lifetime of (4)S3/2 and (4)F9/2 levels of Er(3+) ions is also investigated. Enhanced temperature sensing performance (120 K to 505 K) of the material is observed using the fluorescence intensity ratio technique, employing the emission from the thermally coupled, (2)H11/2 and (4)S3/2 energy levels of Er(3+) ions. The defect luminescence of the material is also found to increase upon Zn-doping.

Structural and optical properties of Er3+/Yb3+ doped barium titanate phosphor prepared by co-precipitation method.

In the present work we have synthesized the Er(3+)/Yb(3+) codoped barium titanate phosphor via co-precipitation method and studied its upconversion emission properties. The prepared BaTiO3 powder was found in cubic phase as a major component and having good crystallinity revealed by the XRD analysis. Optical band gap of the cubic barium titanate was calculated using the diffuse reflectance absorption spectrum. Good green upconversion emission is observed from the samples when excited by 980 nm diode laser. The variation in upconversion emission intensity is studied with the increase in excitation power as well as temperature of the sample. It is found that the emission bands centred at 524 and 548 nm are thermally coupled and can act as a temperature sensor in the 300-480 K temperature range.