Singapore

Inspired by Natural biomineralization processes, our research focuses on the rational design of peptide- and nucleic acid-based biomolecular templates for the synthesis of multifunctional metallic and carbon-based nanomaterials with tunable optical properties and biofunctionalities for sensing, imaging, drug/gene delivery and therapy. Such bio-hybrid nanomaterials exhibit synergistic combination of biological functions and chemical properties resulting from the hard nanocore and soft biomolecular shell. For example, we have developed a series of metallic nanobiosensors with target specific bio-shell to detect wide range of analytes in solution from small molecule drugs, protein biomarkers to cancer and bacteria cells [1-4]. Recently, we have exploited the use of designer DNA and peptide templates to synthesize a palette of photoluminescent metal nanoclusters (NCs &lt; 2nm in core size) which could be used as multicolour probes for bioimaging, image-guided photodynamic therapy and multiplexed sensing [5-7]. We also take this biomimetic approach to ‘turn’ the native protein into bioactive fluorescent nanosensor for rapid drug screening without tedious genetic engineering. To enable greener synthesis with good biocompatibility and sustainability, pure organic resources and biomass wastes were utilized to synthesize carbon dots from biomolecules (biodots) and metal-enhanced fluorescent nanodots with tailored functionalities for a range of biomedical applications [8-12]. For instance, bioinspired antimicrobial biodots has been successfully developed for ultrasensitive pathogen detection (1 cfu/ml in &lt; 0.5 hour) as well as to combat broad spectrum multi-drug resistant bacteria [11]. With further understanding in biotemplates design, we expect a far more extensive applications of bioinspired hybrid nanomaterials for the advanced biomedical diagnostic and treatment towards personalized nanomedicine in future.

MATERIALS FOR HUMANITY (MH 21)

Bioinspired Nanomaterials for Biomedical Diagnostics and Treatment Towards Personalized Nanomedicine

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MH 21 is arranged around 6 themes that focus attention on pressing needs that should be addressed to enhance the well-being of communities and provide a forum for presenting breakthrough discoveries.

Inspired by Natural biomineralization processes, our research focuses on the rational design of peptide- and nucleic acid-based biomolecular templates for the synthesis of multifunctional metallic and carbon-based nanomaterials with tunable optical properties and biofunctionalities for sensing, imaging, drug/gene delivery and therapy. Such bio-hybrid nanomaterials exhibit synergistic combination of biological functions and chemical properties resulting from the hard nanocore and soft biomolecular shell. For example, we have developed a series of metallic nanobiosensors with target specific bio-shell to detect wide range of analytes in solution from small molecule drugs, protein biomarkers to cancer and bacteria cells [1-4]. Recently, we have exploited the use of designer DNA and peptide templates to synthesize a palette of photoluminescent metal nanoclusters (NCs < 2nm in core size) which could be used as multicolour probes for bioimaging, image-guided photodynamic therapy and multiplexed sensing [5-7]. We also take this biomimetic approach to ‘turn’ the native protein into bioactive fluorescent nanosensor for rapid drug screening without tedious genetic engineering. To enable greener synthesis with good biocompatibility and sustainability, pure organic resources and biomass wastes were utilized to synthesize carbon dots from biomolecules (biodots) and metal-enhanced fluorescent nanodots with tailored functionalities for a range of biomedical applications [8-12]. For instance, bioinspired antimicrobial biodots has been successfully developed for ultrasensitive pathogen detection (1 cfu/ml in < 0.5 hour) as well as to combat broad spectrum multi-drug resistant bacteria [11]. With further understanding in biotemplates design, we expect a far more extensive applications of bioinspired hybrid nanomaterials for the advanced biomedical diagnostic and treatment towards personalized nanomedicine in future.

technical paper

Seeing the Sound: Optical Neural Interfaces for In Vivo Neuromodulation

Light plays vital roles in organisms for manipulating a variety of important biological processes because of its high degree of spatiotemporal resolution and ease of precisely regulating parameters. Studying biological pathways underlying diseased states always requires bidirectional controlling over the signal processes. To allow programmable or bidirectional regulations of multiple biological pathways, probes should exhibit orthogonal emission properties with modulation of external stimuli such as excitation wavelength. The complicated energy level structure of lanthanide ions can be an asset to achieve such multi-coloured emission, if one can precisely navigate the energy transfer pathways within single lanthanide ions to favour discrete energy transitions. This challenge once overcome would eliminate the need for using multiple lanthanide ions for obtaining orthogonal emissive properties. For example, Er3+ ions are able to produce green color luminescence through the 2H11/2, 4S3/2→4I15/2 transition, and red emission from the 4F9/2→4I15/2 transition. We have explored cross-relaxation to manipulate energy migration within the same lanthanide activator ion (Er3+) in upconversion nanoparticles (UCNPs) to produce orthogonal red and green emissions, simply by adjusting the excitation wavelength from 980 nm to 808 nm. These UCNPs offer a powerful tool for programmable activation of two synergistic light gated ion channels VChR1 and Jaws in the same cell to manipulate membrane depolarization and hyperpolarization for a multitude of disease therapies, demonstrated here for cardiac pacing. Moreover, this orthogonal emissive UCNP was designed to develop single-line based test strip, in which one emission can be used as reporting signal, and another one as calibrating signal. Due to the removal of control lines, such novel strategy greatly reduces strip size, facilitating design a testing array for multiple detections of different samples.

Orthogonal Upconversion Luminescence from Single Lanthanide Activator Ion for Disease Diagnosis

Dental caries remains a persistent major oral healthcare burden worldwide with little significant improvement in dental healthcare in the last 30 years. Intraoral/biofilm-tooth pH is the single parameter that has demonstrated accurate assessment of the caries risk, reflecting the summative integrated outcome of the complicated interactions between the three etiological factors, namely microorganisms/biofilm, diet/carbohydrates, and tooth/saliva/host. However, there is no technology/system capable of probing both the micro-pH profile in dentin tissue and acidogenic oral biofilm simultaneously, with high spatial/temporal resolution of pathophysiologic acid attacks. Herein, a highly sensitive pH-responsive Hybrid NanoParticle (pH-NP) is developed coupled with an ex vivo tooth-biofilm caries model to simulate key cariogenic determinants/steps in a well-controlled platform to decipher the mechanistic complexity of caries initiation/formation. The pH-NP emits two fluorescence intensities that can change in opposite directions with pH to measure with a ratiometric output sensitivity of 13.4-fold a broad clinically-relevant pH range of 3.0–8.0. Using [H+], in addition to pH, to calculate the “area-under-curve” corroborates with the “minimum-pH” in semi-quantifying the demineralizing potential in each biofilm-dentin zones/depth. The data mechanistically elucidates a two-pronged cariogenic effect of a popular-acidic-sweet-drink, in inundating the biofilm/tooth-system with H+ from both the drink and the metabolic by-products of biofilm.

Imaging Spatiotemporal pH Changes in Biofilm-Dentin Microenvironments using pH-Responsive Hybrid Nanoparticles

Targeting Inflammatory Macrophages with Polysaccharide Nanocarriers

Thermogels are valuable soft materials for biomedical applications. At low temperatures, they remain as solutions which can be used to entrap therapeutic payloads such as drugs and proteins within their solvated polymer matrices. Upon injection into the body, higher body temperatures cause the solutions to gelate in situ at the site of injection, allowing localized placement for applications such as drug delivery. Herein, we present our three-component thermogelling polyurethane technology comprising of biocompatible polyethylene glycol (PEG), poly(propylene glycol) (PPG) and a third component, which can be poly(caprolactone) (PCL), poly(tetrahydrofuran) carbonate (PTHF) or poly[(R)-3-hydroxybutyrate-(R)-3-hydroxyhexanoate] (PHBHx), as a unique platform for biomedical applications. Our thermogels loaded with anticancer drugs were highly effective for inhibition of tumour growth in vivo using mice models. Docetaxel-loaded PEG-PPG-PHBHx thermogels showed enhanced anti-melanoma effects on solid melanoma tumours compared with the free drug, whilst exhibiting excellent biosafety and no apparent harm to organs. With doxorubicin-loaded PEG-PPG-PTHF thermogels, sustained drug release for 16 days in vivo successfully inhibited growth of hepatocellular carcinoma. Impressively, incorporating a dye capable of aggregation-induced emission into the polymer structure allowed it to be used to track in-vivo doxorubicin release status and gel degradation, revealing valuable insights on the drug transportation pathways. Recent efforts on PEG-PPG-PCL thermogels are concentrated on their unprecedented use in vitreoretinal surgery as a vitreous substitute and an internal tamponading agent. The thermogel showed long-term biocompatibility in rabbit vitrectomy models, and was an effective endotamponade in a non-human primate surgical retinal detachment model. This is likely attributed to the thermogel providing support for the retina and preventing subsequent re-detachments.

Thermogels for Biomedical Applications

Subcellular compartmentalization is a key feature of eukaryotic cells. Selectively targeting subcellular compartments, though holding many exciting opportunities for biomedicine, remains rather underdeveloped. Enzyme noncovalent synthesis (ENS), an approach that integrate enzymatic reactions and self-assembly, provides a new way for subcellular targeting. In this talk, we briefly introduce the development of supramolecular self-assemblies for targeting mitochondria, endoplasmic reticulum, Golgi apparatus, and cell membrane. We mainly focus on the use ENS, which spatiotemporally controls the formation of supramolecular assemblies, for subcellular targeting and its applications, such as developing novel cancer therapeutics.

Enzymatic Noncovalent Synthesis for Targeting Subcellular Organelles

Fluorescence imaging in the second near-infrared window (NIR-II, 1,000-1,700 nm) demonstrates unique advantages of high sensitivity, high temporal and spatial resolution, and excellent image quality in comparison to that in the first near-infrared window (NIR-I, 650-950 nm) due to low scattering of photons and zero background fluorescence in the NIR-II region. Currently, a variety of NIR-II fluorescence imaging probes, such as single-wall carbon nanotubes, quantum dots, rare-earth-doped nanoparticles, conjugated polymer nanoparticles, small molecules, and AIEgens, have been developed as significant imaging tools for basic and clinical research. In this report, we begin with briefly introducing the advances of NIR-II fluorescence molecular probes in the last 10 years, including the design, preparation, and NIR-II fluorescence molecular imaging applications of AIEgens and indocyanine green (ICG). Subsequently, we highlight the large-scale preparation of NIR-II imaging probes and their applications in large animals, including New Zealand white rabbits and cynomolgus monkeys. Finally, we prospect the opportunities and challenges of NIR-II fluorescent molecular imaging probes in basic and translational studies.

Advances in NIR-II Fluorescence Imaging Probes

It is well-known that luminescent materials have found applications in many fields, such as lighting, display, biomedical analysis and solar energy light conversion and so on. The NIR excitation light for upconversion nanoparticles have many advantages in biomedical application, such as good photostability, low or zero background luminescence, higher penetration depth and so on. NIR light can be used to excite upconversion nanoparticles to produce UV-vis light, which can be further employed to excite the prodrugs or photosensitizers to kill cancer cells. Various of therapy processes can be combined together in one system under NIR irradiation, thus increasing the treatment efficacy.



Rare Earth Up-conversion Luminescent Nanomaterials: Controllable Synthesis, Property Modification and Biomedical Application

Cancer, a major public health problem worldwide, is a death causing disease. Chemotherapy and radiotherapy are main treatments for cancer. However, their side effects and resistance limited their clinical use. On the other hand, nanomedicine, the area of interdisciplinary science, applies nanotechnology to health and medicine [1]. First, we demonstrate that how nanotechnology overcomes platinum drug resistance [2]. The platinum prodrug was designed and tethered onto surface of gold nanorods. The designed delivery system can overcome resistance through increasing drug uptake and decreasing drug deactivation. We also used nanomedicine strategy to deliver chemotherapy drugs, such as Histone deacetylase (HDAC) inhibitor, to sensitize radiotherapy through inhibiting DNA repair [3]. Second, we developed a multifunctional platform with controlled activation of platinum prodrug using near infrared (NIR) light and with real-time evaluation of drug efficacy [4]. The ultraviolet (UV) light sensitive platinum prodrug was synthesized and conjugated onto surface of upconversion nanoparticles (UCNPs). Upon absorbing NIR light, UCNPs convert it into UV light, which activates platinum prodrug, release active components and then induce cancer cells apoptosis. Meanwhile, an apoptosis-imaging probe was also conjugated onto UCNPs. Once NIR light irradiated UCNPs, cancer cells apoptosis was triggered, which unleashed the release of enzyme, caspase-3 and subsequently activate the imaging probe. Therefore, the direct imaging of apoptosis in living cells can be for real-time evaluation of drug efficacy. Finally, yet importantly, nowadays immunotherapy generates promising clinical data that have not seen before. It showed that combining radiotherapy and immunotherapy can enhance immune responses and can boost ‘abscopal effect’. Unfortunately, response rates for this strategy remain low. Herein we utilizes antigen-capturing nanoparticles (AC-NPs) to improve this strategy [5]. Our engineered AC-NPs can capture a set of protein antigens released post radiotherapy and it helped antigen presentation, which eventually induce enhanced immune responses and enhance ‘abscopal effect’.

Nanomedicine Strategies for Improving Chemoradiotherapy, Real-time Evaluating Drug Efficacy, and Enhancing Immunotherapy in Cancer Treatment

The unique optical properties of lanthanide-doped inorganic nanocrystals have rendered their potential usefulness as novel nanodrugs for many applications. Surface modification with organic dye molecules is a useful strategy to manipulate the optical properties of lanthanide-doped nanocrystals. The interaction between dye molecules and nanocrystals provides unprecedented possibilities to gain new optical phenomena from the organic-inorganic composite systems. The development of highly efficient lanthanide-based organic-inorganic nanoconjugates may overcome the existing limitations to the lanthanide-doped nanomaterials and stimulate applications in area such as light energy harvesting, light emission, biosensing, therapeutics and photocatalysis. Driven by this motivation, our group has recently devoted to the fabrication and mechanical studies of lanthanide nanocrystals with either unique crystal lattice structures or novel core-shell heterogeneous structures. We are trying to understand the energy transfer through the surface of lanthanide-doped nanocrystals for applying these materials in nanomaterial therapeutics.

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Seeing the Sound: Optical Neural Interfaces for In Vivo Neuromodulation

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