Magnetic drug delivery refers to linking therapeutic or imaging agents with magnetically responsive objects, iron nano-particles for example, and using magnetic fields to focus the agents to a specific site within the body. For cancer, this approach may be therapeutically useful by creating a locally high concentration of drug at a tumor location. At present, the state-of-the-art in magnetic drug delivery utilizes stationary magnets placed outside the skin to attract particles. However, this method is effective to only a limited tissue depth, thus drug targeting is restricted to tumors that are near the skin surface. Alternatively, magnets or objects that concentrate the magnetic field (e.g. stents that contain steel or iron) can sometimes be implanted deep inside the body and enable focusing of drug near deep tumors;however, surgically implanting such objects in a patient is undesirable and not always possible in the clinical setting. To overcome the problems with current magnetic drug delivery methods, we are developing a dynamic feedback control system that uses magnetic fields to focus drugs to deep targets by using a set of externally-applied magnetic fields and controlling them one against another. Although this is a promising approach, there are several technical challenges involved that may be difficult to overcome, such as the need to radiologically image and then target each tumor focus, a difficult task that requires real-time sensing of particle location. A simpler approach for magnetic drug delivery is based on relevant observations of gross and molecular tumor pathology. The observations and implications for tumor therapy are: 1) That clinically significant tumor burden is often localized only to specific anatomic zones of the body, even though the tumor may be widely metastatic. Thus, delivery of drug to specific and defined anatomic regions may provide optimal clinical benefit with minimal toxicity. The target zones will be based on the natural history of each cancer type, the deleterious effect of tumor cells on anatomic structures within the zone, and the efficacy-toxicity ratio of delivering high levels of drug to a particular region of the body. 2) That the blood supply to a subset of metastases in a patient is particularly compromised. This is evidenced by the firm, white, nodular gross appearance of these lesions at autopsy, and the incomplete vasculature as seen at the light microscope level. These lesions are often distinctly different from the primary tumors from which they arose, as well as from other metastases in different parts of the body. This vascular compromise likely results in poor delivery of therapeutic agents to this subset of metastatic lesions, rendering them non-responsive to systemically applied chemotherapeutics, and clinically problematic. Thus, effective drug delivery strategies for these tumor foci likely will require exceptionally high local concentrations of drug, and/or, the ability to magnetically drive the therapeutic into them using the drug reservoir that is present in adjacent normal, well-vascularized tissue, and/or in sub-regions of well-vascularized tumor tissue. Both of the observations and related implications above can be overcome using a modified and simpler version of a magnetic drug delivery system. Moreover, since the technical challenges involved in focusing and holding drug in anatomic zones of the body are less involved than a one-by-one tumor targeting approach, the new system will be easier to develop. In summary, the goal of the project is to subject anatomic regions of the body that harbor a clinically significant tumor burden to high concentrations of a therapeutic agent while sparing the rest of the body from these high drug levels and associated toxicity.
|Nacev, Alek; Kim, Skye H; Rodriguez-Canales, Jaime et al. (2011) A dynamic magnetic shift method to increase nanoparticle concentration in cancer metastases: a feasibility study using simulations on autopsy specimens. Int J Nanomedicine 6:2907-23|