Research Synopsis and Overarching Goals
Metastasis is one of the most challenging problems in cancer treatment as it accounts for more than 90% of cancer-related deaths. In comparison to primary tumors, metastatic tumors typically grow speading in a large area of tissue, and thus they cannot be removed easily by surgery without damaging vital organs. Metastatic cancer cells are also more resistant to radiotherapy and chemotherapy. Currently, no therapeutic option is available for a complete cure of metastasis, and the majority of patients with metastatic cancer receive palliative care to relieve the symptoms.
Many small molecule compounds have been developed as anticancer drugs for targeted therapy to treat metastasis more effectively by targeting cancer cell signals for growth, division, tissue invasion or even programmed cell death. Despite promising results in the laboratory, most of these drugs have solubility and off-target toxicity issues, which preclude their clinical applications frequently. Therefore, there is an urgent need to develop a tool that can deliver drugs effectively and safety to metastatic tumors. In the absence of such drug delivery tools, the treatment of metastasis and clinical translation of promising drugs will remain problematic.
Nanoparticles hold promise to overcome these limitations. Nanoparticles, typically 20 to 200 nanometers (nm) in diameter, can be used as drug carriers that are small enough to pass through leaky tumor blood vessels yet too large to be removed through filtration in the kidney. As illustrated below, nanoparticles accumulate more efficiently and stay longer in tumors than small molecule drugs. Nanoparticles entrapping anticancer drugs have been shown to increase drug concentrations in tumors, and to improve antitumor activity with reduced off-target toxicity. Many nanoparticle drug carriers have been developed and some of them are in the market or clinical development (e.g. liposomes, albumin nanoparticles, dendrimers, and polymer micelles).
However, currently available nanoparticle drug carriers have achieved limited success in delivering drugs to metastatic tumors. One major reason for this is that metastatic tumors spread by growing into the surrounding blood vessels or lymphatic channels as opposed to primary tumors, which generally grow as large clusters. At present, little is known about how to control nanoparticles to deliver drugs to the metastatic tumor cells selectively without damaging the surrounding normal tissue cells. Answering this question has been challenging because nanoparticles tend to change pharmacokinetic profiles, such as blood retention time, tissue distribution, tumor accumulation, and clearance, depending on their particle properties (biocompatibility, particle size, shape, and surface charge). Varying particle properties also result in different drug release patterns from nanoparticles, altering antitumor activity and toxicity from one formulation to another. The lack of a systematic approach in controlling parameters has left the pharmaceutical development of nanoparticle drug carriers on a trial and error basis.
Bae Lab focuses on addressing these issues by developing multifunctional block copolymer nanoassemblies as nanoparticle drug carriers that can modulate particle properties one at a time (e.g. particle size, shape, surface property, stability, and drug release rates). These nanoassemblies provide tools for not only elucidating mechanisms by which nanoparticle drug carriers distribute in the body, but also delivering various anticancer drugs to metastatic tumors efficiently and safely. Our published and preliminary results suggest that our nanoassemblies have great potential to facilitate the clinical translation of newly emerging drugs for targeted cancer therapy through tumor-targeted delivery and controlled release of the drugs. The Current Research link on the left summarizes our major research achievements at University of Kentucky (UK), current topics, and future directions.
(See also Current Research)