Synthesis of self-assembled organic-inorganic hybrid nanomaterials for cancer diagnostics and photo-induced therapeutic applications

Correct clinical evaluation and diagnosis are crucial for effective treatment of cancer to develop and evolve cancer theranostics for personalized cancer therapy. Owing to the rapid advancement and development in the field of nanotechnology, various kinds of nanoparticles are explored for cancer therapy. Organic-inorganic hybrid nanoparticles have attracted vast interest due to their promising physicochemical properties, which make them suitable for biomedical applications. In this work, hybrid nanoparticles are prepared through different kinds of supramolecular interactions using self-assembly of small molecules or polymers with inorganic nanoparticles or salts. By combining both organic and inorganic components, we envisaged that we could circumvent the typical limitations of organic molecules such as low resistance to photobleaching and poor degradability of the inorganic nanoparticles. Utilizing the organic component scaffolds as the carrier or direct therapeutic agent and inorganic nanoparticles as the imaging agents or the direct therapeutic agents, we could attain hybrid nanostructures that are biocompatible, stable, and highly efficient. We employed strategies such as surface functionalization, one-pot synthesis, and wrapping techniques to bring all the components together.Doctor of Philosoph

Metal–organic frameworks meet polymers: from synthesis strategies to healthcare applications

Metal–organic frameworks (MOFs) have been at the forefront of nanotechnological research for the past decade owing to their high porosity, high surface area, diverse configurations, and controllable chemical structures. They are a rapidly developing class of nanomaterials that are predominantly applied in batteries, supercapacitors, electrocatalysis, photocatalysis, sensors, drug delivery, gas separation, adsorption, and storage. However, the limited functions and unsatisfactory performance of MOFs resulting from their low chemical and mechanical stability hamper further development. Hybridizing MOFs with polymers is an excellent solution to these problems, because polymers—which are soft, flexible, malleable, and processable—can induce unique properties in the hybrids based on those of the two disparate components while retaining their individuality. This review highlights recent advances in the preparation of MOF–polymer nanomaterials. Furthermore, several applications wherein the incorporation of polymers enhances the MOF performance are discussed, such as anticancer therapy, bacterial elimination, imaging, therapeutics, protection from oxidative stress and inflammation, and environmental remediation. Finally, insights from the focus of existing research and design principles for mitigating future challenges are presented.Agency for Science, Technology and Research (A*STAR)National Research Foundation (NRF)Submitted/Accepted versionThis research work was supported by the Singapore Agency for Sci-ence, Technology and Research (A*STAR) AME IRG grant (A20E5c0081)and the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03)

Degradability and clearance of inorganic nanoparticles for biomedical applications

Inorganic nanoparticles with tunable and diverse properties hold tremendous potential in the field of nanomedicine, while having non-negligible toxicity concerns in healthy tissues/organs that have resulted in their restricted clinical translation to date. In the past decade, the emergence of biodegradable or clearable inorganic nanoparticles has made it possible to completely solve this long-standing conundrum. A comprehensive understanding of the design of these inorganic nanoparticles with their metabolic performance in the body is of crucial importance to advance clinical trials and expand their biological applications in disease diagnosis. Here, a diverse variety of biodegradable or clearable inorganic nanoparticles regarding considerations of the size, morphology, surface chemistry, and doping strategy are highlighted. Their pharmacokinetics, pathways of metabolism in the body, and time required for excretion are discussed. Some inorganic materials intrinsically responsive to various conditions in the tumor microenvironment are also introduced. Finally, an overview of the encountered challenges is provided along with an outlook for applying these inorganic nanoparticles toward future clinical translations.NRF (Natl Research Foundation, S’pore)ASTAR (Agency for Sci., Tech. and Research, S’pore)MOE (Min. of Education, S’pore)Accepted versio

Clearable black phosphorus nanoconjugate for targeted cancer phototheranostics

Therapeutic efficacy of synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) is limited by complex conjugation chemistry, absorption wavelength mismatch and inadequate biodegradability of the PDT-PTT agents. Herein, we designed biocompatible copper sulfide nanodot anchored folic acid-modified black phosphorus nanosheets (BP-CuS-FA) to overcome these limitations, consequently enhancing the therapeutic efficiency of PDT-PTT. In vitro and in vivo assays reveal good biocompatibility and commendable tumor inhibition efficacy of the BP-CuS-FA nanoconjugate owing to synergistic PTT-PDT mediated by near-infrared laser irradiation. Importantly, folic acid unit could target folate receptor overexpressed cancer cells, leading to enhanced cellular uptake of BP-CuS-FA. BP-CuS-FA also exhibits significant contrast effect for photoacoustic imaging, permitting its in vivo tracking. The photodegradable character of BP-CuS-FA is associated with better renal clearance after the antitumor therapy in vivo. The present research may facilitate further development on straightforward approaches for targeted and imaging-guided synergistic PDT-PTT of cancer.Agency for Science, Technology and Research (A*STAR)National Research Foundation (NRF)Accepted versionThis research is supported by the Singapore Agency for Science, Technology and Research (A*STAR) AME IRG grant (No. A1883c0005), and the Singapore National Research Foundation Investigatorship (No. NRF-NRFI2018-03)

Ultrasmall alloy nanozyme for ultrasound- and near-infrared light-promoted tumor ablation

The therapeutic effect of chemodynamic therapy (CDT) is significantly restricted by the stern reaction conditions and slow reaction rate of the Fenton reaction (pH 3-4). Herein, we report an ultrasmall trimetallic (Pd, Cu and Fe) alloy nanozyme (PCF-a NEs) possessing dynamic active-site synergism, thus exhibiting a cascade glutathione peroxidase and peroxidase (POD) mimicking activities in circumneutral pH. PCF-a NEs exhibit photothermally augmented POD property and high photothermal conversion efficiency (62%) for synergistic tumor cell apoptosis. In addition, ultrasound can also enhance the mass transfer at active catalytic sites of PCF-a NEs, in turn accelerating Fenton-like reaction for tumor-specific CDT. This work provides a strategy for engineering alloy nanozymes in a bioinspired way for the amplification of intratumor reactive oxygen species in response to external stimuli, demonstrating enhanced efficiency for the inhibition of tumor growth in vitro and in vivo.Agency for Science, Technology and Research (A*STAR)National Research Foundation (NRF)Submitted/Accepted versionThis research is supported by the Singapore Agency for Science, Technology and Research (A*STAR) AME IRG grant (A20E5c0081), the Singapore Academic Research Fund (RT12/19), and the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03)

Morphology-dependent resonance enhanced nonlinear photoacoustic effect in nanoparticle suspension: a temporal-spatial model

The morphology-dependent resonances (MDRs) hotspot, ubiquity formed between the pairs of nanoparticles in close vicinity, has garnered considerable recent attention. By extending this phenomenon to pulse-laser irradiated nanoparticle suspension, we demonstrate that such collective optical/thermal enhancement can give rise to the nonlinear photoacoustic (PA) generation. In this study, a temporal-spatial analytical expression is derived to quantitatively describe the nonlinear PA signal generation from nanoparticles, incorporating the Grüneisen increase at the microscopic individual particle level and MRDs enhancement at the macroscopic suspension level. The dependence of PA nonlinearity on the critical contributors, including the laser pulse width, the particle size, and the statistical interparticle spacing, is quantitatively discussed. The theory is well validated with the finite element method (FEM) and experimentally proved with semiconducting polymer nanoparticles (SPN) suspension. This work may pave a new direction towards effective MDR based nonlinear PA contract agent design.Ministry of Education (MOE)Published versionMinistry of Education - Singapore (AcRF Tier 2: MOE2019-T2-2-179)

Hybrid carbon dot assembly as a reactive oxygen species nanogenerator for ultrasound-assisted tumor ablation

The efficacy of reactive oxygen species (ROS)-based therapy is substantially constrained by the limited ROS generation, stern activation conditions, and lack of a straightforward reaction paradigm. Carbon dots (CDs) have been highly sought after for therapeutic applications for their biocompatibility and intrinsic fluorescence imaging capabilities, making them suitable for ROS generation. Herein, we synthesized a CD-based ultrasmall hybrid nanostructure possessing active sites of Mo, Cu, and IR-780 dye. After cooperative self-assembly with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol), the obtained assembly (CMIR-CDa) exhibits near-infrared fluorescence imaging and photoacoustic tomography. Interestingly, CMIR-CDa can generate singlet oxygen (1O2), hydroxyl radical (·OH), and superoxide radical anion (O2 • -) upon ultrasound stimulus owing to its sonosensitizing and enzyme-mimicking properties, showing an enhanced efficacy for tumor ablation in vivo. The collective in vitro and in vivo results indicate that CMIR-CDa has a high potency as an ROS nanogenerator under US irradiation, even at a low concentration. The present study offers an approach for engineering hybrid CDs in a bioinspired way for intratumoral ROS augmentation in response to deep tissue penetrable external stimuli.Agency for Science, Technology and Research (A*STAR)National Research Foundation (NRF)Published versionThis research was supported by the Singapore Agency for Science, Technology and Research (A*STAR) AME IRG grant (A20E5c0081) and the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03)

Self-assembled semiconducting polymer based hybrid nanoagents for synergistic tumor treatment

There is an impending need for the development of carrier-free nanosystems for single laser triggered activation of phototherapy, as such approach can overcome the drawbacks associated with irradiation by two distinct laser sources for avoiding prolonged treatment time and complex treatment protocols. Herein, we developed a self-assembled nanosystem (SCP-CS) consisting of a new semiconducting polymer (SCP) and encapsulated ultrasmall CuS (CS) nanoparticles. The SCP component displays remarkable near infrared (NIR) induced photothermal ability, enhanced reactive oxygen species (ROS) generation, and incredible photoacoustic (PA) signals upon activation by 808 nm laser for phototherapy mediated cancer ablation. The CuS component improves the PA imaging ability of SCP-CS, and also enhances photo-induced chemodynamic efficacy. Attributed to promoted single laser-triggered hyperthermia and enhanced ROS generation, the SCP-CS nanosystem shows effective intracellular uptake and intratumoral accumulation, enhanced tumor suppression with reduced treatment time, and devoid of any noticeable toxicity.Agency for Science, Technology and Research (A*STAR)National Research Foundation (NRF)Submitted/Accepted versionThe work was supported by the Singapore Agency for Science, Technology and Research (A*STAR) AME IRG grant (A20E5c0081) and the Singapore National Research Foundation Investigatorship (NRFNRFI2018-03). We thank Prof Atsushi Goto and Dr Jit Sarkar for their help in GPC measurements

Thiolate-assisted route for constructing chalcogen quantum dots with photoinduced fluorescence enhancement

Despite great efforts in the development of diverse nanomaterials, a general route to synthesize metal-free chalcogen quantum dots (QDs) is still lacking. Moreover, the modification of chalcogen QDs is a bottleneck that severely hinders their applications. Herein, we develop a facile method to construct different chalcogen QDs (including S QDs, Se QDs, and Te QDs) with the assistance of thiolates. In addition to stabilizing chalcogen QDs, the thiolates also endow the chalcogen QDs with favorable modifiability. Different from most dyes whose fluorescence is quenched after short-term light irradiation, the prepared chalcogen QDs have significantly enhanced fluorescence emission under continuous light irradiation. Taking advantage of the distinctive photoinduced fluorescence enhancement property, long-time cell imaging with superb performance is realized using the chalcogen QDs. It is envisioned that the chalcogen QDs show promising potential as fluorescent materials in different fields beyond bioimaging.Agency for Science, Technology and Research (A*STAR)National Research Foundation (NRF)This research is supported by the Singapore Agency for Science, Technology and Research (A*STAR) AME IRG grant (A20E5c0081) and the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03). This work was also supported by the National Natural Science Foundation of China (21673037) and the Fundamental Research Funds for the Central Universities

Light-triggered hypoxia-responsive nanoscale metal-organic frameworks for highly efficient antitumor treatment

Photodynamic therapy (PDT), as a noninvasive therapeutic tool, can result in a high level of hypoxia in tumors. Herein, hypoxia-responsive nanoscale metal-organic frameworks (UiO-AZB) are prepared, which contain an azo group in its organic linker. After modifying the surface of UiO-AZB with chlorin e6 (Ce6)-conjugated human serum albumin (HSA), tirapazamine (TPZ) is employed as a hypoxia-activated prodrug to be encapsulated into UiO-AZB. The obtained nanosystem (UiO-AZB/HC-TPZ) can efficiently produce singlet oxygen under 660 nm light irradiation and cause severe hypoxia in tumors. This process in turn triggers the degradation of the frameworks and controllable release of activated TPZ for chemotherapy, finally leading to improved antitumor treatment through combinational PDT and hypoxia-activated chemotherapy. This research demonstrates a distinctive treatment strategy, that is, using a simple stimulus (light irradiation) to trigger a series of activities (PDT, disintegration of UiO-AZB structure, activation of TPZ, and controllable release) for realizing an effective treatment of tumors.Agency for Science, Technology and Research (A*STAR)National Research Foundation (NRF)Submitted/Accepted versionThis research is supported by the Singapore Agency for Science, Technology and Research (A*STAR) AME IRG grant (A20E5c0081) and the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03). The research is also supported by the National Natural Science Foundation of China (52002330), and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)