Project Five:
"Smart" MRI Detection of Therapeutics Targeted to Metastatic Breast Tumors
Project References
Marty Pagel, Ph.D.
Jinming Gao, Ph.D.
Case Western Reserve University
The nanoparticles discussed in the above projects each interact with their payloads through non-bonding interactions. Although this strategy provides flexibility of design to meet diverse research goals, non-bonding interactions are more difficult to control and may produce particles with less stability and shorter shelf life. An alternative approach uses bonding interactions to couple payloads to biocompatible nanoparticles, which provides exquisite molecular control and greater stability (1,2). This emerging strategy has been applied to deliver drugs to diseased tissues, but the general utility of this approach is hampered by the need to independently track accumulation of the nanoparticles within the tissue, and bond-breaking release of the drugs from the nanoparticles (3-5).
To overcome this limitation, we are developing innovative molecular imaging agents that can be incorporated within bonded drug-nanoparticle systems to independently track nanoparticle accumulation in diseased tissues and release of drugs from the nanparticles within the same imaging session. These new molecular imaging agents are independently detected using a novel MRI detection mechanism that exploits the unique signals from each agent (6-8). One imaging agent will be coupled to the nanoparticle to track it’s accumulation in diseased tissues. Another imaging agent will be placed in the link that bonds the drug and nanoparticle, and this imaging agent will only be detected by MRI when the bonds between the drug and nanoparticle are severed. These fundamentally new functionalities of independent detection and bond-breaking detection provide “smart” sensing of the unique physical and chemical environments of diseased tissues that are targeted by these drug-naoparticle delivery systems.
To demonstrate the proof-of-concept of this new imaging method, we are conjugating imaging agents to biocompatible polymer nanoparticles consisting of hydroxypropylmethacrylamide (HPMA) (9). Previous results have shown that HPMA nanoparticles preferentially target tumor tissues through passive accumulation (10,11). We are also bonding doxorubicin, a potent cytotoxic drug, to the HPMA nanoparticle with a peptide linker that includes a second imaging agent (12). The peptide linker is efficiently cleaved by Matrix Metalloproteinases (MMPs), prevalent biomarkers in early stage metastatic breast tumors (13-17). This strategy further refines the targeting of doxorubicin to early-stage metastatic breast tumor tissues, which is critical for releasing the potent drug only within diseased tissues (12). Drug release causes bonding changes that provide the imaging agent with new functionality for detection using MRI. We will apply our drug-nanoparticle-imaging agent system within in vivo MCF-7 and MDA-MB-231 breast tumor tissues, and we will validate our results using standard histopathological techniques (18-22).
Case provides an excellent environment for this new approach. We have developed techniques to synthesize and conjugate doxorubicin and molecular imaging agents to polymers, and we have developed MRI techniques to track polymers conjugated to imaging agents within in vivo mouse models with xenograft breast tumors (23-26). All collaborators in our research team are members of the
These “smart” MRI agents constitute a technology platform that may be easily modified to independently track multiple nanoparticle systems and/or bond-breaking biochemical reactions. Other biomedical applications are anticipated, including A) detection of bond-breaking enzymes that phosphorylate nucleolin, which putatively promotes transport of DNA nanoparticles to the nucleus (project 2); B) the detection of caspase enzymes that break peptide bonds during tumor cell apoptosis (Project 4); C) the independent tracking of nanoporous particle accumulation and bond-breaking biodegradation of the nanoparticle’s coating (project 5); and D) the detection of multiple imaging agents to monitor the effect of therapies that inhibit tumor angiogenesis (Project 6). Therefore, the imaging agents and methodologies of this technology platform have excellent potential to become a commercial product, and to promote the commercial development of other projects sponsored by our proposed consortium.