The research objective in Peggy Lo group is to develop multifunctional platforms for understanding, detection and treatment of non-communicable diseases. Toward this goal, we take an interdisciplinary approach that brings together synthetic organic chemistry, DNA chemistry, nanotechnology and molecular biology to 1) synthesize new (macro)molecules; and 2) to build nanometre-scale structures, polish their photophysical, photochemical and biochemical properties, and shape them into smart and biocompatible materials for biomedical and technological applications. There are four major interests of our research.
Using our knowledge as chemists, we seek to create new systems for target drug delivery, diagnostics and data storage using the biocompatibility and programmability of deoxyribonucleic acid. We are currently working on research projects to investigate how self-assembled DNA nanostructures behave and function in vitro and in vivo. The target delivery of therapeutic agents is of great importance to the biomedical community. Using our expertise in DNA assembly, we design and assemble different sizes and shapes of stimuli-responsive 2D networks (Nanoscale 2020) and 3D nanostructures (Small 2015 and Nanoscale Adv. 2019) as nanocarriers for drug delivery in brain (ACS Appl. Mater. Interfaces 2020) and in different intracellular organelles (Small 2016 and Small 2014). We are actively working in the development of a new generation of BBB-permeable carrier systems which deliver anti-inflammatory drugs to the brain for the treatment of ischemic stroke. As DNA base sequences encoding substantial structural and functional information, modification of self-assembled DNA nanostructures with specific functional elements becomes a simple strategy to generate biocompatible tools for detection. We recently reported that self-assembled DNA nanotubes and nanocages modified with aptamer (Nanoscale 2016), G-quadruplex structures (ChemNanoMat 2017) and gold nanoparticles (Nanoscale 2018) recognize multiple targets/disease biomarkers simultaneously and further converts the recognitions into detectable and measurable signals. We are currently working in this area for clinical diagnosis, including detection of cancer or disease biomarkers, and in vivo molecular imaging. We have also interested in applying self-assembly strategy to construct a series of photo-responsive DNA devices as optical tools which imitate function of signal communication in response to different wavelengths of lights (Angew. Chem. Int Ed. 2016). We are actively working in the development of two-photon photo-responsive DNA-based logic gate systems for detecting and monitoring of pathological processes in disease microenvironment at the molecular level for prognosis, diagnosis and therapeutic outcome assessment.
Overcoming the limitations of the physical and chemical properties of DNA/RNA, we synthesize unique α- L-threose nucleic acids (TNAs) as stable antisense materials for uses in cancer therapy. Compared with microRNAs (miRNAs) or small interference RNAs (siRNAs), this TNA-based antisense strategy allows us to effectively deliver antisense oligodeoxynucleotides to target sites of interest in the absence of any carriers, resulting in sequence-specific gene silencing. Using our skills as synthetic chemists, we reported a cost-efficient approach to synthesize the TNA phosphoramidite monomers and sequence-designed TNA polymers via solid phase synthesis in high synthetic yield and purity (ACS Appl. Mater. Interfaces 2018). The production cost of 1g TNA monomers is 10 times less than that of DNA monomers. Compared to natural DNAs/RNAs, TNAs exhibit substantial cellular uptake and tissue penetration without using transfecting agents, strong specificity and affinity towards their complementary targets, very low cytotoxicity in addition to remarkable stability in fetal bovine serum (FBS), human blood serum, pH extremes and even under storage in buffer solutions at room temperature for half a year (Materials Today Bio 2022). We also showed the ability of TNA as an alternative to traditional antisense materials for target gene suppression in vitro and tumor growth inhibition in vivo with no adverse toxicity (ACS Appl. Mater. Interfaces 2019). To improve the therapeutic efficacy, we are currently working in the clinical applications of this high-throughput and low-cost TNA system for triple-negative breast cancer therapy and liver cancer therapy. Additionally, we recently reported the first time the feasibility of using TNA as a building compoment to construct a biocompatible probe for rapid and dynamic miRNA detection in living systems, offering alternative reliable molecular reagents for miRNA-related diagnostics and therapeutics (Mol. Ther.-Nucl. Acids 2022).
Using our knowledge in nanotechnology, we aim at creating nanoparticle-based systems for tracking, imaging and target drug delivery, using the functionalization versatility and non-photobleaching property of nanodiamonds (NDs). We are currently working on research projects to investigate how multi-functionalized NDs behave and function in vitro and in vivo. Using our expertise in surface chemistry, we modified the ND with a variety of functional ligands including polymers, proteins, or peptides and utilize it as a delivery vehicle. We demonstrated the target delivery of anti-cancer drugs to mitochondria for circumventing drug resistance (ACS Appl. Mater. Interfaces 2017) and the nuclear-delivery of antisense oligonucleotides for enhanced gene therapy (ACS Sustain. Chem. Eng. 2018) by these functionalized ND systems. Recently, we reported that biopolymer-coated NDs exhibited enhanced penetration across the blood-brain barrier with no immune response and no inflammatory indications after systemic injection in animal models for brain tumor imaging (Nanoscale 2021). Additionally, we present a ligand-induced self-assembly strategy for constructing ND-gold nanoparticle dimers via stable and strong non-covalent biotin-streptavidin linkage (Nano Lett 2019). This is a robust and scalable strategy, allowing the synthesis of stable dual-functional nanoparticle hybrids which are capable of both heating and sensitive thermometry, offering an important step towards real-time controlled photothermal therapy with high therapeutic accuracy. This programmed dimer fabrication of designed sizes and compositions is also potentially useful in materials science and engineering. The on-going project is to take NDs as a photostable delivery system for spatial- and temporal-controlled release of therapeutic agents in the treatment of triple-negative breast cancer.
Light particularly in the near infrared region is an attractive exogenous, non-invasive stimulus for biological application because it allows for deeper tissue penetration, less photodamage to the living tissues and 3-dimensional control with femtoliter resolution. Using our knowledge in photochemistry, we aim at designing and synthesizing two-photon photocleavable molecules and combining them into the biocompatible systems for turning “off” their biological activity before reaching the sites of interest and then for turning them back “on” in response to light irradiation. We are currently working on research projects in three aspects: 1) Design, synthesis and characterization of different series of multi-functional two-photon caging molecules; 2) Conjugation of the two-photon caging molecules with a large variety of biomolecules including antisense oligonucleotide, RGD peptides, glutamate, gamma aminobutyric acid, doxorubicin, adenosine triphosphate etc. to mask their bioactivity; 3) Using these two-photon caging platforms to regulate the activity of biomolecules in living systems, particularly for cell-signalling, kinetics and mechanistic studies of the central nervous system.
P.K. Peggy LO @ 2022 City University of Hong Kong Department of Chemistry College of Science