Donghoon Lee - US grants

DESCRIPTION (provided by applicant): Magnetic resonance spectroscopy (MRS) has evolved from a strictly in vitro research tool for chemists to a powerful, non-invasive, diagnostic technique. However, the full potential of MRS-its ability to quantitatively assess metabolite content in vivo-is rarely achieved in practice. Assessment of metabolite content, commonly referred to as absolute quantification, requires accurate determination of the proportionality factor between the local magnetic field (B1m) generated by excited nuclei within the measurement volume and the integrated area of the corresponding spectral peak in the processed data. An impractical level of diligence is required to quantify or control all of the parameters that affect this proportionality factor. As a result, nearly all MRS results are presented in terms of arbitrary units or as ratios, which are difficult to interpret and of limited clinical value. We have developed a new technique, SPIRIT (Synthetic Peak Injection using a Radiation Immune Tickler coil), that could allow more practical and accurate quantification of MRS. We use a small, inductively coupled RF coil to inject an artificial signal, the pseudo-signal, in the main RF coil used to acquire the in vivo signal. The amplitude, frequency and line-width of the pseudo-signal are easily varied and are first set in proportion to a real peak corresponding to a known in vitro metabolite concentration. The same pseudo-signal is then injected during the data acquisition period of an in vivo measurement and used as a calibration factor to convert the real signals into units of metabolite concentration. The salient feature of the SPIRIT method is the use of inductive coupling to inject the pseudo-signal. Since inductive coupling is also the mechanism by which B1m couples to the main RF coil, any subsequent manipulations of the data that affect the proportionality factor- including coil loading conditions, gain of the receiver amplifiers, and data processing algorithms-have an equal effect on the real and pseudo-signals. This makes the proportionality factor immune to these data manipulations and substantially decreases the burden of the metabolite quantification process. We have built a prototype SPIRIT probe that uses a surface coil to excite and receive the in vivo signals. This simple coil was useful for demonstrating feasibility but, like all surface coils, it creates a nonuniform B1 field, which complicates the quantification process. In this project we will build two additional SPIRIT probes that create uniform B1 fields to excite and receive the metabolite signals, validate the method by comparison against biochemical assays of metabolite content in rat hind limb, and demonstrate the ability to accurately quantify changes in metabolite content in human skeletal muscle during physiological perturbations. Our project focuses on measurements in skeletal muscle but the methods could easily be transferred to other organs. Our goal is to validate a powerful new tool for noninvasive quantification of metabolite content that will allow researchers and clinicians access to the full potential of MRS. PUBLIC HEALTH RELEVANCE: We have developed a new method of converting magnetic resonance spectroscopy (MRS) data into units of metabolite concentration. We propose to validate the method in animal studies and demonstrate its value in humans. Successful completion of the project could have widespread impact on a variety of diseases by providing researchers and clinicians with a more practical noninvasive tool for measuring metabolite concentration.

? DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. Surgical resection offers the only chance of cure with an about 20% 5-year survival but more than 80% of patients present with advanced unresectable disease. The overall 5-year survival rate for all types of pancreatic cancer is less than 5%. Pancreatic tumor therapy has been ineffective partly because pancreatic tumors have a dense stroma inhibiting penetration of chemotherapeutic drugs into the tumor. High intensity focused ultrasound (HIFU) can be used to induce targeted hyperthermia leading to increased perfusion potentially enhancing targeted drug delivery (TDD) to pancreatic tumors with deficient vasculature. In addition, pulsed HIFU has potential to mechanically disrupt stroma resulting in increased permeability of the dense stroma in pancreatic tumors. One major challenge with the HIFU-enhanced TDD is the absence of noninvasively assessing treatment efficacy following the HIFU application. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) have been widely used as key noninvasive methodologies for clinical tumor diagnosis and treatment follow-up due to their good spatial resolution compared to other imaging modalities. However, with respect to pancreatic tumors, conventional MRI has been used for qualitative detection of pathologic regions for diagnosis and treatment follow-up with limited resolution and inability of quantification for preclinical studies using mouse models. Therefore, more effective magnetic resonance (MR) biomarkers with high resolution are needed to monitor treatment responses of tumors treated with HIFU in tumor bearing mice. We hypothesize 1) HIFU induced hyperthermia will enhance TDD and pancreatic tumor cell death in a targeted region and quantitative MR will enable assessment of the treatment 2) pulsed HIFU will disrupt stromal layers in pancreatic tumor and MRI/MRS will assess the process of stromal layer disruption. The overall goal of this study is 1) to generate effective HIFU induced hyperthermia for targeted chemotherapeutic drug delivery for a pancreatic tumor mouse model (KPC) that closely resembles human pancreatic cancer and 2) to accurately monitor both mild hyperthermia and responses to pancreatic tumor treatments based on the HIFU-enhanced TDD using noninvasive and quantitative MRI and MRS methods at high resolution. To accomplish the study goal we propose three specific aims: 1) to assess pancreatic tumor progression for the KPC mouse model with advanced MR methods, 2) to evaluate perfusion and degree of stromal layer disruption after HIFU and 3) to assess responses to chemotherapeutic treatments mediated by HIFU. The development of noninvasive MR biomarkers, pulsed HIFU method and effective KPC mouse model will be essential to advance the understanding of this deadly disease and has the potential to be used to assess promising therapies in pre- clinical and clinical trials.

Nanohelix is considered a new and attractive building block element for designing a set of new synthetic nano-actuators and -sensors and combination of them, namely nanorobotics which has broader applications; biomedicine, nanomedicine, key catalyst for synthesis of pharmaceutical medicine, key electrodes for energy devices (battery, solar cells, etc), and proximity tactile sensor of soft-matter robotic hands. If the nanohelix is mechanically flexible and made of magnetically active material, which is controlled under applied magnetic field, such magnetically active nanohelix can be designed into a new robotics system for diagnosis and treatment of difficult-to-treat cancers. The proposed nanorobotics can have multi-functions; (i) swimming under magnetic guidance, thanks to the shape of "helical spring", (ii) mechanical vibrations of the nanorobotics with flexible nanohelix under applied magnetic field and gradient, thus, killing cancer cells due to mechanical stress loading, and (iii) magnetically active material for nanorobotics plays also as a magnetic resonance imaging enhancer, thus, accurate locations of the nanorobots if they are attached to cancer cell sites, can be identified by the magnetic resonance imaging.

We recently synthesized iron-palladium alloy nanohelices by using chemistry processing route; alumina-silica template and electroplating to make solid-state iron-palladium alloy nanohelices. This iron-palladium alloy nanohelix is down-sizing from our previous design of macro-iron-palladium alloy spring which exhibited the fast vibrations under applied magnetic gradient. The key scientific mechanism associated with the macro-iron-palladium alloy spring, which we discovered is a new actuation mechanism (hybrid mechanism), a set of chain-reactions; applied magnetic gradient, magnetic force, stress induced martensite phase from austensite phase, resulting in fast-actuation within a very short time. We recently made molecular dynamics modelling to simulate another actuator mechanism of iron-palladium alloy nanohelices under applied "constant" magnetic field. We also synthesized another nanorobot which is composed of iron-palladium alloy cylindrical head (head) and nanohelix where we can replace the iron-palladium alloy head by an iron head, thus, the nanorobot based on the combination of iron head and iron-palladium alloy helix may serve more effective nanorobot concept.
The goals of the proposed NSF project are multi-fold: (1) to prove the hypothesis driven mechanical stress-induced apoptosis of cancer cells by using the nanorobots under magnetic field, (2) to establish the optimum navigation control of the magnetic nanorobots and (3) to demonstrate the effectiveness of the nanorobots for cancer diagnosis and treatment using in vitro experiment. To achieve the above goals, we propose the following five tasks over a three-year period:

Task-A: High-yield processing of magnetic nanohelices and their nanorobots (Taya)
Task-B: Characterization of the nanostructure and properties of iron-palladium alloy nanohelices (Taya)
Task-C: Modeling work (Kuga/Taya)
Task-D: Production of nanorobots containing solution for apoptosis study (Takao/Taya)
Task-E: In vitro experiment for magnetic nanorobots under applied magnetic field/gradient (Lee/Kuga)

The broader impact of this proposal is that the proposed nanorobots based on magnetic nanohelices, leading to opening up new applications discussed above. We plan to incorporate the results into education,i.e., into the existing graduate course on active and sensing materials and their integrated systems and educational summer program at University of Washington.
The intellectual significances of this NSF project are: (i) to establish high-yield processing route for key building block element of nanorobots, i.e. iron-palladium nanohelices, and combined magnetic head and iron-palladium alloy nanohelix , (ii) to study if the hybrid mechanism of actuation in magnetic nanohelix is realized, (iii) to construct a cohesive model for an accurate control of nanorobots navigation, (iv) to test the hypothesis of mechanical stress loading-induced cell death and (v) to design Helmholtz coil system tailored for accurate navigation of nanorobots.