Research

Postdoctoral and Doctoral Research 

 

Elucidation of the Interactions of Nanomaterials with Biological Entities

 

Nanomaterials, such as the zero-dimensional (0D) nanoparticles (e.g., polymeric nanoparticles, gold nanostars), one-dimensional (1D) nanotubes/nanorods (e.g., carbon nanotubes and gold nanorods), and two-dimensional (2D) nanosheets (e.g., graphene and transition metal chalcogenide nanosheets), have demonstrated tremendous potential for a variety of nanomedicine and theranostic applications, particularly for biomedical imaging, disease diagnostics, and drug delivery. However, the clinical translation of these nanomaterials has been impeded by their poor targeting and theranostic efficacies, which largely stem from a lack of fundamental understanding of the biological responses to nanomaterials once they are introduced into the body. Depending on their properties, nanomaterials may trigger the occurrence of certain biological phenomena in the circulatory system (i.e., circulatory barriers), including non-specific biomolecule adsorption and phagocytic clearance. Additionally, nanomaterials may elicit different biophysical effects on multicellular systems than on individual cells. A better appreciation of this aspect is important as most studies have focused on nanomaterial effects on individual cells, but neglected collective cellular behaviors, which are central to the regulation of numerous physiological processes. To improve the nanomaterial transport and theranostic performance, it is necessary to understand the interactions of nanomaterials with circulatory barriers and multicellular systems.

Motivated by this, throughout my doctoral and postdoctoral research training, I interrogated the interactions between nanomaterials and biological entities responsible for circulatory barriers, including plasma proteins, blood cells, and macrophages, as well as those betweeen nanomaterials and multicellular systems. Furthermore, I systematically investigated the interdependent effects of numerous physicochemical properties of nanomaterials, such as size, shape, surface charge, and lipophilicity, in influencing their biological fate, from molecular to organism levels. These studies have collectively yielded rational frameworks for precise design and engineering of more targeted and safer nanomaterials capable of overcoming different circulatory barriers to combat cancer and vascular diseases.

Representative Publications 

  1. Kenry, Linhao Sun, Trifanny Yeo, Eshu Middha, Yuji Gao, Chwee Teck Lim, Shinji Watanabe, Bin Liu, "In situ visualization of dynamic cellular effects of phospholipid nanoparticles via high-speed scanning ion conductance microscopy." Small 2022, 18, 2203285.
  2. Kenry, Benjamin K. Eschle, Bohdan Andreiuk, Prafulla C. Gokhale, Samir Mitragotri, “Differential macrophage responses to gold nanostars and their implication for cancer immunotherapy.” Advanced Therapeutics 2022, 5, 2100198.
  3. Kenry, Trifanny Yeo, David T. She, Mui Hoon Nai, Von Luigi Marcelo Valerio, Yutong Pan, Eshu Middha, Chwee Teck Lim, Bin Liu, “Differential collective cell migratory behaviors modulated by phospholipid nanocarriers.”ACS Nano 2021, 15, 17412-17425.
  4. Kenry, Trifanny Yeo, Purnima Naresh Manghnani, Eshu Middha, Yutong Pan, Huan Chen, Chwee Teck Lim, Bin Liu, “Mechanistic understanding of the biological responses to polymeric nanoparticles.” ACS Nano 2020, 14, 4509-4522.
  5. Kenry, Parthiv Kant Chaudhuri, Kian Ping Loh, Chwee Teck Lim, “Selective accelerated proliferation of malignant breast cancer cells on planar graphene oxide films.” ACS Nano 2016, 10, 3424-3434.

 

Design and Engineering of Organic Theranostic Nanoprobes for Bioimaging and Disease Therapy

 

Detection and visualization of biological processes in diseased microenvironments at cellular and molecular levels are important for effective disease diagnosis and treatments. One of the most established optical imaging modalities for biological process monitoring is fluorescence imaging. While this imaging modality serves as a feasible tool to interrogate certain biological processes, conventional fluorogens used for fluorescence imaging typically suffer from aggregation-caused fluorescence quenching. As such, the suppression of aggregate formation to minimize fluorescence quenching has been the holy grail of fluorogen design. This endeavor, however, proves to be a non-trivial challenge as aggregation tends to occur naturally when fluorogens exist in a concentration sufficiently high to generate detectable signal.

To overcome this longstanding challenge, during my first postdoctoral research training, I collaborated with my colleagues to rationally formulate numerous organic fluorogens with aggregation-induced emission characteristic (AIEgens) and explore their theranostic applications. As opposed to conventional fluorogens, AIEgens are weakly emissive when they exist as isolated molecular species, but are strongly emissive when they are aggregated. This unique property render them highly attractive for bioimaging and pre-clinical diagnosis and therapy. By precisely refining the molecular design of AIEgens, these fluorogens could be endowed with features, such as high imaging contrast, deep penetration depth, and enhanced production of reactive oxygen species. Through smart molecular engineering, a series of multifunctional AIE nanoprobes capable of simultaneous bioimaging (fluorescence and/or photoacoustic imaging) and therapies (photodynamic therapy and/or immunotherapy) could be constructed and utilized for in vivo theranostics of cancer, bacterial infections, and vascular diseases.

Representative Publications

  1. Kenry, Trifanny Yeo, Purnima Naresh Manghnani, Eshu Middha, Yutong Pan, Huan Chen, Chwee Teck Lim, Bin Liu, “Mechanistic understanding of the biological responses to polymeric nanoparticles.” ACS Nano 2020, 14, 4509-4522.
  2. Yandong Dou, Kenry, Jiang Liu, Fangfang Zhang, Chunhui Cai, Qing Zhu, “2-Styrylquinoline-based two-photon AIEgens for dual monitoring of pH and viscosity in living cells.” Journal of Materials Chemistry B 2019, 7, 7771-7775.
  3. Kenry, Kok Chan Chong, Bin Liu, “Reactivity-based organic theranostic bioprobes.” Accounts of Chemical Research 2019, 52, 3051-3063.
  4. Kenry, Chengjian Chen, Bin Liu, “Enhancing the performance of pure organic room-temperature phosphorescent luminophores.” Nature Communications 2019, 10, 2111.
  5. Kenry, Yukun Duan, Bin Liu, “Recent advances of optical imaging in the second near-infrared window.” Advanced Materials 2018, 30, 1802394.

 

Development of Low-Cost Point-of-Care Biosensors for Early Detection of Infectious Diseases

 

Access to rapid and accurate diagnosis of infectious diseases, particularly malaria, is an important aspect of global health efforts. Early and accurate malaria diagnosis is essential not only to identify patients requiring medical care, but also to discriminate between malaria and other diseases manifesting similar symptoms. Existing techniques for malaria detection, particularly Giemsa staining followed by optical microscopy to identify parasite-infected red blood cells, lack sufficient sensitivity and selectivity. In fact, the poor sensitivity of this approach at low parasitemia levels often increases the false negative risk. On the other hand, artifacts, such as bacteria, fungi, and general debris, can be indistinguishable from parasites and cause false positive diagnosis. While rapid diagnostic tests provide simple and fast readout and have increasingly become alternative methods of malaria diagnosis, they suffer from subpar performance in tropical conditions found in many malaria-endemic regions. This is because most the rapid diagnostic tests rely on the use of monoclonal antibodies, which are typically sensitive to heat and humidity, to detect biomarkers in blood. Additionally, many low-resource areas lack the equipment, infrastructure, or expertise necessary to diagnose malaria using standard methods.

To address these issues, during my doctoral research training, I collaborated with my colleagues to develop aptamer-based fluorescent biosensors for highly specific and sensitive detection of a highly expressed malarial biomarker Plasmodium lactate dehydrogenase (pLDH) protein. pLDH is an attractive target for malaria detection as it is produced by all Plasmodium species and its concentrations have been shown to correlate with parasitemia level. The developed biosensors were highly specific to pLDH protein and displayed a limit of detection of hundreds of picomolar, which has exceeded the sensitivity required for clinical applications (typically in the order of hundreds of nanomolar). We then integrated these fluorescent aptasensors with papers to realize a low-cost point-of-care malaria diagnostic tool, which may be readily used in low-resource settings.

Representative Publications

  1. Alisha Geldert, Kenry, Chwee Teck Lim, “Paper-based MoS2 nanosheet-mediated FRET aptasensor for rapid malaria diagnosis.” Scientific Reports 2017, 7, 17510.
  2. Alisha Geldert, Kenry, Xiao Zhang, Hua Zhang, Chwee Teck Lim, “Enhancing the sensing specificity of a MoS2 nanosheet-based FRET aptasensor using a surface blocking strategy.” Analyst 2017, 142, 2570-2577.
  3. Kenry, Alisha Geldert, Zhuangchai Lai, Ying Huang, Peng Yu, Chaoliang Tan, Zheng Liu, Hua Zhang, Chwee Teck Lim, “Single-layer ternary chalcogenide nanosheets as a fluorescence-based “capture-release” biomolecular nanosensor.” Small 2017, 13, 1601925.
  4. Kenry, Alisha Geldert, Xiao Zhang, Hua Zhang, Chwee Teck Lim, “Highly sensitive and selective aptamer-based fluorescence detection of a malaria biomarker using single-layer MoS2 nanosheets.” ACS Sensors 2016, 1, 1315-1321.