Niagara Muhammad Idris

In vivo photodynamic therapy using upconversion nanoparticles as remote-controlled nanotransducers

Conventional photodynamic therapy (PDT) is limited by the penetration depth of visible light needed for its activation. Here we used mesoporous-silica–coated upconversion fluorescent nanoparticles (UCNs) as a nanotransducer to convert deeply penetrating near-infrared light to visible wavelengths and a carrier of photosensitizers. We also used the multicolor-emission capability of the UCNs at a single excitation wavelength for simultaneous activation of two photosensitizers for enhanced PDT. We showed a greater PDT efficacy with the dual-photosensitizer approach compared to approaches using a single photosensitizer, as determined by enhanced generation of singlet oxygen and reduced cell viability. In vivo studies also showed tumor growth inhibition in PDT-treated mice by direct injection of UCNs into melanoma tumors or intravenous injection of UCNs conjugated with a tumor-targeting agent into tumor-bearing mice. As the first demonstration, to the best of our knowledge, of the photosensitizer-loaded UCN as an in vivo–targeted PDT agent, this finding may serve as a platform for future noninvasive deep-cancer therapy.

Remote activation of biomolecules in deep tissues using near-infrared-to-UV upconversion nanotransducers

Controlled activation or release of biomolecules is very crucial in various biological applications. Controlling the activity of biomolecules have been attempted by various means and controlling the activity by light has gained popularity in the past decade. The major hurdle in this process is that photoactivable compounds mostly respond to UV radiation and not to visible or near-infrared (NIR) light. The use of UV irradiation is limited by its toxicity and very low tissue penetration power. In this study, we report the exploitation of the potential of NIR-to-UV upconversion nanoparticles (UCNs), which act as nanotransducers to absorb NIR light having high tissue penetration power and negligible phototoxicity and emit UV light locally, for photoactivation of caged compounds and, in particular, used for photo-controlled gene expression. Both activation and knockdown of GFP was performed in both solution and cells, and patterned activation of GFP was achieved successfully by using upconverted UV light produced by NIR-to-UV UCNs. In-depth photoactivation through tissue phantoms and in vivo activation of caged nucleic acids were also accomplished. The success of this methodology has defined a unique level in the field of photo-controlled activation and delivery of molecules.

Tracking transplanted cells in live animal using upconversion fluorescent nanoparticles

With the emergence of cell transplant as an attractive treatment modality for various diseases, there is a parallel need to track the fate of these cells to assess their therapeutic effectiveness. Here, we report the use of upconversion fluorescent nanoparticles, silica/NaYF(4):Yb,Er, to dynamically track live myoblast cells in vitro and in a living mouse model of cryoinjured hind limb. Nanoparticles loaded into cells were confirmed for its intracellular uptake by confocal imaging, spectrophotometry and inductively coupled plasma analysis. Loaded nanoparticles demonstrated absolute resistance to photobleaching and were applied for dynamic imaging to real time track in vitro cell migratory activity for a continuous 5 h duration using a time-lapse confocal microscope. Direct observation on the direction, speed and cell-cell interaction of migrating cells was clearly visualized. In vivo confocal imaging of nanoparticle-loaded cells intravenously injected into a mouse tail vein showed them flowing in the ear blood vessels. Nanoparticle-loaded cells were also unambiguously identified with superior contrast against a negligible background at least 1300 microm deep in a fully vascularized living tissue upon intramuscular injection. Spatiotemporal migratory activity of the transplanted cells within the three-dimensional living tissue was captured for at least 7 days post-delivery. Direct in vivo visualization of cell dynamics in the native tissue was unobtrusively followed over a 4 h time course and revealed subtle migratory activity of the transplanted cells. With these unique optical properties, we present silica/NaYF(4):Yb,Er nanoparticles as a new fluorescent live cell tracker probe for superior in vitro and in vivo dynamic imaging.

Singlet oxygen-induced apoptosis of cancer cells using upconversion fluorescent nanoparticles as a carrier of photosensitizer

UNLABELLED The photodynamic effect of upconversion nanoparticles loaded with a photosensitizer was studied on murine bladder cancer cells (MB49). Mesoporous silica was coated onto sodium yttrium fluoride upconversion nanocrystals to form a core-shell structure and then loaded with the photosensitizer zinc (II)-phthalocyanine into the porous silica. The nanoparticles displayed a uniform spherical shape with an average diameter of about 50 nm and showed good dispersibility in water. Intracellular uptake study in MB49 cells revealed a time- and concentration-dependent accumulation of these nanoparticles. Upon irradiation with 980-nm near-infrared light, their efficiency in activating the loaded zinc (II)-phthalocyanine to generate singlet oxygen molecules was confirmed in live cells. The cytotoxic effect of the released singlet oxygen from the nanoplatform was proven by cell viability assay, confocal microscopy, DNA agarose gel electrophoresis, cytochrome c-releasing assay, and prostate-specific antigen-enzyme-linked immunosorbent assay, all of which showed a strong photodynamic effect of the nanoparticles on MB49 cells. This suggests the efficacy of sodium yttrium fluoride upconversion nanoparticles as a carrier for photosensitizers and their use in photodynamic therapy of cancer and some other diseases. FROM THE CLINICAL EDITOR In this study, the photodynamic effect of upconversion nanoparticles loaded with a photosensitizer was investigated on murine bladder cancer cells, with strongly positive results, which may pave its way to future clinical use in malignant tumors and potentially other diseases.

Gold nanoshell coated NaYF4 nanoparticles for simultaneously enhanced upconversion fluorescence and darkfield imaging

Lanthanide-doped upconversion nanocrystals (UCN) converting low energy photons to high energy photons have emerged as an efficient and versatile bioimaging and therapeutic tool. However, the upconversion efficiency of the UCNs is low, which limits their applications. Plasmonic modulation makes it possible to enhance the luminescence of these nanocrystals. We hypothesize that the enhancement of the upconversion luminescence for all the emission peaks simultaneously could be achieved if the UCNs are coated with a gold nanoshell and the surface plasmon resonance (SPR) peak is tuned to the near-infrared (NIR) region and made resonant with the absorption of the UCNs, thereby substantially increasing the excitation flux via local field enhancement (LFE) effect. Furthermore, the nanoparticles could be used for darkfield imaging due to the light scattering caused by the gold nanoshell. Herein, we report a poly-(amino acid)-templated gold-shell encapsulation of the silica coated NaYF4:Yb,Er UCNs and show how a deft tuning of the SPR peak from visible to NIR region dramatically transforms the luminescence quenching into an enhancement effect and how the nanoparticles are used for combined upconversion fluorescence and darkfield light scattering imaging.

Titania Coated Upconversion Nanoparticles for Near-Infrared Light Triggered Photodynamic Therapy

Because of the limited penetration depth of visible light that generally excites most of the available photosensitizers (PSs), conventional photodynamic therapy (PDT) is limited to the treatment of superficial and flat lesions. Recently, the application of deep penetrating near-infrared (NIR) light excitable upconversion nanoparticles (UCNs) in conjunction with PDT has shown to have clear potential in the treatment of solid tumors due to its ability to penetrate thick tissue. However, various constructs developed so far have certain limitations such as poor or unstable PS loading, reducing their therapeutic efficacy and limiting their application to solution or cell-based studies. In this work, we present a method to fabricate uniform core-shell structured nanoconstruct with a thin layer of photocatalyst or PS-titanium dioxide (TiO2) stably coated on individual UCN core. Our design allows controllable and highly reproducible PS loading, preventing any leakage of PS compared to previously developed nanoconstructs, thus ensuring repeatable PDT results. Further surface modification of the developed nanoconstructs with polyethylene glycol (PEG) rendered them biocompatible, demonstrating good therapeutic efficacy both in vitro and in vivo.

Sandwich-structured upconversion nanoparticles with tunable color for multiplexed cell labeling

The need for a more efficient biological label to meet their burgeoning utility in rapidly developing multiplexing applications may be realized through the recent advent of upconversion nanoparticles (UCNs). UCNs fabricated to-date, however, are either not displaying strong fluorescence or have limited available colors. Here, we report on fabricating sandwich-structured UCNs with a NaYbF(4) matrix sandwiched between two NaYF(4) layers. Such sandwich design allows for efficient absorption of the excitation energy by the absorber ion-rich NaYbF(4) layer that then transfers it to the adjacent NaYF(4) layers on either side for an improved fluorescence efficiency. By doping different emitters into each of the shells and adjusting their thickness, different color output tunable based on the RGB color model were obtained. In this study, multicolor UCNs with strong emission intensity have been facilely synthesized and used for multiplex detection of three subcellular targets with a single near-infrared excitation wavelength.

Hybrid Lanthanide Nanoparticles with Paramagnetic Shell Coated on Upconversion Fluorescent Nanocrystals

Nanoparticles comprising of fluorescent probes and MRI contrast agents are highly desirable for biomedical applications due to their ability to be detected at different modes, optically and magnetically. However, most fluorescent probes in such nanoparticles synthesized so far are down-conversion phosphors such as organic dyes and quantum dots, which are known to display many intrinsic limitations. Here, we report a core-shell hybrid lanthanide nanoparticle consisting of an upconverting lanthanide nanocrystal core and a paramagnetic lanthanide complex shell. These nanoparticles are uniform in size, stable in water, and show both high MR relaxivities and upconversion fluorescence, which may have the potential to serve as a versatile imaging tool for smart detection or diagnosis in future biomedical engineering.

LRET-based biodetection of DNA release in live cells using surface-modified upconverting fluorescent nanoparticles.

In this work, we demonstrate near-infrared-to-visible upconverting fluorescent nanoparticles as a promising platform for lanthanide-based or luminescence resonance energy transfer (LRET)-based biodetection of DNA release in live cells. Highly monodispersed, stable aqueous suspension of nanoparticles, surface-functionalized with amino groups for binding to DNA, were prepared and characterized. These amino-functionalized nanoparticles were able to electrostatically bind to DNA and protect it from DNaseI degradation as shown by gel electrophoresis. Attachment of DNA to the nanoparticles was also confirmed by LRET, which was observed to occur between the donor nanoparticle and acceptor POPO-3 dye intercalating the DNA. The intrinsic fluorescence property of upconverting fluorescent nanoparticles makes them useful for tracking their cellular localization without the use of any additional fluorescent tag. We were able to track the movement of these DNA-loaded nanoparticles into the cell cytoplasm where they successfully released their genetic cargo. Successful transfection of the loaded DNA material in vitro and in vivo was confirmed by expression of its encoded green fluorescent protein (GFP) in Hela cells and induction of specific antibody in mice, respectively.

Engineering of Lanthanide-Doped Upconversion Nanoparticles for Optical Encoding.

Lanthanide-doped upconversion nanoparticles (UCNPs) are an emerging class of luminescent materials that emit UV or visible light under near infra-red (NIR) excitations, thereby possessing a large anti-Stokes shift property. Due to their sharp excitation and emission bands, excellent photo- and chemical stability, low autofluorescence, and high tissue penetration depth of the NIR light used for excitation, UCNPs have surpassed conventional fluorophores in many bioapplications. A better understanding of the mechanism of upconversion, as well as the development of better approaches to preparing UCNPs, have provided more opportunities to explore their use for optical encoding, which has the potential for applications in multiplex detection and imaging. With the current ability to precisely control the microstructure and properties of UCNPs to produce particles of tunable emission, excitation, luminescence lifetime, and size, various strategies for optical encoding based on UCNPs can now be developed. These optical properties of UCNPs (such as emission and excitation wavelengths, ratiometric intensity, luminescence lifetime, and multicolor patterns), and the strategies employed to engineer these properties for optical encoding of UCNPs through homogeneous ion doping, heterogeneous structure fabrication and microbead encapsulation are reviewed. The challenges and potential solutions faced by UCNP optical encoding are also discussed.