Our group are mainly interested in two areas: (1) developing new materials and strategies for drug and nucleic acid delivery; (2) developing molecular imaging agents for biological and biomedical applications. The group is very dynamic and highly interdisciplinary, including synthetic and polymer chemists, material scientists, and cancer biologists. We develop platform technologies and actively collaborate with other groups at BCM to take advantage of their cutting-edge biological discoveries.
Researchers use an extremely wide range of fabrication techniques in order to produce nanostructures. Two main nanofabrication techniques are the “bottom-up” strategy, in which nanostructures are constructed from molecules or atoms, and the “top-down” strategy, in which material is added or removed from a surface. Liposomes, micelles, polymersomes and inorganic nanoparticles are the iconic examples developed using “bottom-up” fabrication. However, because of the self-assembled nature of these nanostructures, they usually have spherical shapes and a wide distribution in size.
As a top-down strategy, the PRINT® (Particle Replication In Non-wetting Templates) technology developed in the DeSimone group enables independent control over particle size, shape, modulus, surface chemistry, and composition. PRINT also provides a convenient approach for systematically tailoring the chemical composition of nanoparticles without changing the size, shape, and dynamics of the particle, a problem that often plagues other particle technologies, especially those derived from self-assembly approaches when one adjusts the chemical composition. A wide range of materials can be used for PRINT particle fabrication, including biocompatible/biodegradable polymers, inorganic materials, and even pure biologics. We will take advantage of the PRINT technology to develop the next-generation nanomedicines with well-defined size, shape and surface chemistry.
RNA interference (RNAi), discovered by Drs. Andrew Fire and Craig C. Mello, is a system within living cells that controls the activities of genes. Even though numerous breakthroughs have been made in indentifying genes related to cancer and other diseases, currently there is no RNAi therapeutics available in clinic. RNA delivery, most typically microRNA (miRNA) and small interfering RNA (siRNA), is the major roadblock for the development of RNAi therapeutics. There are many biological barriers to overcome for successful RNA delivery. We will take an interdisciplinary approach and integrate organic and polymer chemistry, cell biology and biomedical engineering to develop novel nanocarriers for targeted delivery of RNAi.
We are able to fabricate monodisperse ultrasmall (10-30 nm) nucleic acid nanoparticles with tunable sizes. We also took advantage of various cutting edge physical techniques, including single molecule fluorescence imaging measurements with total internal resonance fluorescence (TIRF) microscopy, fluorescence correlation spectroscopy (FCS), isothermal calorimetry (ITC), to quantify the number of nucleic acids in each nanoparticle.
Non-Viral Gene Therapy
Development of non-viral gene delivery carriers has attracted tremendous attentions in recent years. Compared with viral gene delivery, non-viral delivery provides many advantages, including low immunogenicity and cost-effective scalability. Polyethylenimine (PEI) is considered as the gold standard in polymer based gene delivery carriers and has been widely used as a transfection agent in cell cultures and animal models for almost 20 years. However, the non-degradability and toxicity impede the clinical applications of PEI. Ideal gene carriers should be biodegradable and elicit minimal toxicity and immune responses.
We have developed a series of biodegradable polymers with different structures and architectures. These polymers have more than one order of magnitude less toxicity compared with PEI. Enhanced green fluorescent proteins and luciferase encoded plasmid DNAs have been successfully transfected into many different types of cells in vitro. We also demonstrated that the biodistribution and efficacy of in vivo gene expression depends on the molecular weight and architecture. We are currently exploring applications of these novel biomaterials in various disease models.
Novel Thiol Responsive Chemistry
Novel Thiol Responsive Chemistry
Novel bioresponsive materials are crucial for the development of controlled drug delivery. For intracellular delivery, three kinds of biological triggers have been extensively used, including the intracellular enzymatic activities, the acidic environment of the endo-lysosomes and the reductive environment in the cytoplasm. Despite the fact that many enzymatic and acidic triggers have been developed, disulfide remains as the only reduction responsive chemistry used in drug delivery applications. Therefore, there is an urgent need to expand the chemical toolbox for reduction responsive reactions.
We took advantage of the nucleophilicity of glutathione, the chemical responsible for intracellular reducing environment, and introduced thioester as a novel glutathione responsive functionality for drug delivery (J. Am. Chem. Soc., 2013, 135, 10938–10941). Compared with disulfides, thioesters are more convenient to synthesize and have up to an order of magnitude broader tunability in kinetics. Based on the thioester chemistry, we also developed a thioester based traceless PEGylation strategy to modulate the protein activity, which could potentially enhance its in vivo performance. Upon dePEGylation under a reducing environment, the model protein can completely restore its activity. We expect thioesters will play an important role in future studies on thiol responsive controlled drug delivery.
Chemical sensors and Molecular Imaging Agents
Chemical probes play an important roles to monitor the analyte concentration in cell culture, which help to elucidate many biological processes. These chemical probes can also be used as a diagnostic agent for disease, known as molecular imaging. We take advantage of the state-of-the-art instrument development and strive to develop novel chemical sensors and molecular imaging agents. We have some very exciting development going on. Stay tuned....
Release of the drug from nanocarriers can be triggered internally, taking advantage of characteristic biological properties such as intracellular acidic and reducing environments, specific enzymatic activities, etc. The release of the payload can also be triggered externally by electromagnetic or ultrasonic radiation. Internally triggered drug delivery systems can be easily administrated. However, the enzymatic activities and the intracellular environments which are used to trigger drug release can vary depending on patients and disease states, which complicate the pharmacokinetics and therapeutic indices of these drug delivery systems. Externally triggered drug delivery systems are advantageous compared to the internally triggered counterparts in regards to minimizing variances in patients and disease states and achieving site-specific treatment to minimize systemic toxicity. In this project, we will apply our strong photochemistry background to develop novel photonanomedicines to reduce the systemic toxicity of chemotherapeutics.