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Nov. 15-16, 2018 | Harnessing Physical Forces for Medical Applications Symposium

Convergence of Physics, Nanomaterials, Cell Biology and Cancer Research
Kyoto-UCLA-Symposium NavBar

Manish J. Butte, MD, PhD

“Mechano-metabolic regulation of the immune response”

The duration and degree of the T cell response to infections must be tightly constrained: too little and the pathogen wins, too much and collateral damage wreaks havoc. In this talk, I will discuss the mechanisms by which T cells are regulated by mechanical forces at the molecular, cellular, and tissue scales.

Daishi Fujita, PhD

“Synthetic Molecular Wireframes Reinforce Protein Stability
through Molecular Chaperone-like Structural Refolding Effects”

Spatial isolation of molecules is often a powerful strategy for regulating their molecular behavior. Biological systems well-employ such mechanisms, however, scientists have yet to rival nature, particularly for macromolecular substrates. Our team has recently demonstrated that only a “wireframe” molecular scaffold is sufficient to improve the structural and enzymatic properties of a protein encapsulated within (Figure 1). The three-dimensionally confined enzyme (cutinase-like enzyme (CLE): a protein for plastic degradation) did not show any structural melting by DSC experiments up to 130 °C (the Tm of native CLE is around 50 °C). Remarkable stability in a 10:90 aqueous–acetonitrile solution for tens of days was observed, even at room temperature. A kinetic assay of the enzymatic reaction revealed that the key to this stability is the isolated space, which aids protein refolding in a manner reminiscent of molecular chaperones (Figure 2). Although the encapsulated enzyme did partially denature in solutions containing high proportions of organic solvent, it refolded back to the original tertial structure when half-aqueous solvent conditions were restored. Isotope-labeled NMR studies also supported such refolding behavior. The key to protein encapsulation is the self-assembly of giant wireframe hollow metal complexes,1-3 some of which are the largest known artificially self-assembled objects that still possess a precise atomic composition. This protein reinforcing methodology has potential applications for the industrial use of enzymes or as a research tool for enzymology.

Shuhei Furukawa, PhD

“Metal-organic frameworks for gas biology and therapeutic applications”

Gaseous molecules such as nitric oxide (NO) and carbon monoxide (CO) are recently known to be signalling molecules (gasotransmitters) working both for intercellular communications and intracellular regulations. In particular, NO is one of the most investigated gasotransmitters, having important roles in numerous signaling events as well as therapeutic potentials. However, the design of functional scaffolds or devices that can release NO with precisely controlled timing, dosage and location remains challenging, due to handling issues that arise from their high reactivity and physical state. Here we show a synthetic strategy for developing spatiotemporally controllable NO-releasing platforms based on photoactive metal-organic frameworks (MOFs), in which organic molecules are regularly arranged and connected by metal ions through the formation of coordination bonds. By organizing molecules with poor reactivity into framework structures of MOFs, we observe increased photoreactivity and adjustable release using light irradiation. We further embed photoactive MOF crystals in a biocompatible matrix, leading to a functional cell culture substrate, and demonstrate precisely controlled NO delivery at the cellular level via localized two photon laser activation. The biological relevance of the exogenous NO produced by this strategy is evidenced by an intracellular change in calcium concentration, mediated by NO-responsive plasma membrane channel proteins. We further shape photoactive MOF crystals at the mesoscale by coordination modulation and confirm its delivery inside cell and NO stimulation at the subcellular resolution.

William M. Gelbart, PhD

“In vitro reconstituted virus-like particles for RNA gene and RNA vaccine delivery”

In my talk I discuss the advantages of using in vitro reconstituted virus-like particles (VLPs) for delivery of genes and vaccines in the form of self-replicating RNA. The key point is to take advantage of two remarkable facts about positive-sense RNA viruses: (1) they can be prepared in a test tube from purified protein and RNA components; and (2) they provide us with the only known source of RNA replicase enzymes (i.e., RNA-dependent RNA polymerases). In particular I describe the synthesis and functionalization of VLPs whose protective shell is made up of capsid protein from a plant virus (cowpea chlorotic mottle virus [CCMV]) and whose packaged RNA gene has been inserted into the inactivated form of an insect virus (Nodamura) genome. This hybrid, non-infectious, plant/insect virus – self-assembled from purified protein and in vitro transcribed RNA – is shown to make its genetic cargo accessible to the ribosomal machinery of host mammalian cells, where the messenger RNA of interest is amplified one-million-fold, giving rise to strong expression of target protein (therapeutic, diagnostic, or antigenic). Results are presented for: reporter gene quantification; microRNA knockdown; MRI contrast enhancement; in vitro activation of dendritic cells; and mouse vaccination studies for which T-cell responses are measured.

Marcus A. Horwitz, MD

“Functionalized Nanotherapeutics Targeting Intracellular Pathogens and Biowarfare Agents”

Intracellular pathogens are promising targets for nanotherapeutics since their host cells, mononuclear phagocytes, avidly ingest nanoparticles even in the absence of specific targeting molecules. We have studied the efficacy of mesoporous silica nanoparticles (MSNs) engineered for controlled drug release in treating the intracellular bacterial pathogen Francisella tularensis, the causative agent of tularemia and a Tier 1 Select Agent. More effective treatments are needed for tularemia because it can be fatal even with appropriate therapy. We have evaluated MSNs with control mechanisms for releasing drug cargo within macrophages including pH- or redox potential-sensitive nanovalves. pH- and redox-activated MSNs that release the antibiotic Moxifloxacin (MXF) are more efficacious than an equivalent amount of free drug in killing F. tularensis both in vitro in macrophages and in vivo in a mouse model of lethal tularemia. We have also developed pathogen-specific MSNs that release cargo in response to F. tularensis and not other bacteria including closely related species; such MSNs could serve as both diagnostics and therapeutics. We compared the efficacy of redox-activated MXF-loaded MSNs in treating tularemia in mice when administered by different routes; surprisingly, we found that intramuscular (IM) and subcutaneous (SQ) administration is more efficacious than intravenous (IV) administration. To understand the basis for this finding, we assessed the distribution of MSNs to sites of infection and the pharmacokinetics of drug release after IM vs. IV administration. MSNs administered IV but not IM distribute to lung, liver, and spleen of F. tularensis-infected mice, as assessed by tissue silica analysis, and co-localize with lung cells by flow cytometry analysis, indicating that enhanced trafficking to sites of infection does not underlie the increased efficacy of IM-delivered MSNs. In contrast, IM administration of MSNs results in improved pharmacokinetics; the time the blood MXF level is above the Minimum Inhibitory Concentration most closely correlates with efficacy.

Ken-Ichiro Kamei, PhD

“Recapitulation of the cellular microenvironments: Towards re-creation of living systems into a chip”

Pluripotent stem cells (PSCs) are promising tools for elucidating the fundamentals of the developmental processes of living organisms, as well as for drug screening and regenerative medicine. However, regulation of their phenotypes and functionality remains a challenging task.

Cells are the basic unit of living organisms. In complex multicellular organisms, cells are well-organized into different structures and locations and serve specific functions within tissues and organs. To control cell functions, it is necessary to understand their in vivo regulation in physiological conditions. Therefore, we focused on cellular microenvironments, which play critical roles in determining cell fates and functions. However, since conventional macro-scale techniques provide only limited control of such environments, there is a lack of tools that allow accurate and effective manipulation of the cellular microenvironment.

To meet this urgent need, we have recently developed a micro/nanofabrication technology, such as microfluidics and nanofiber ECMs to create artificial regulatory cellular microenvironments for studying how environmental cues alter cell fates and functions. The integration of this approach with stem cell technologies allows us to recapitulate physiological and pathological conditions on a chip, i.e., to establish “Body on a Chip.”

Mineko Kengaku, PhD

“High-resolution Imaging of Neuronal Migration in the Developing Brain”

Fine structures of the mammalian brain are formed by neuronal migration during development. Newborn neurons migrate long distances from the germinal zone to individual sites of function by squeezing their largest cargo, the nucleus, within crowded neural tissue. Nuclear migration is thought to be orchestrated by microtubules, actin and their associated motors, dynein and myosin. However, where and how the cytoskeletal forces are converted to actual nuclear behaviors remain unclear. Using high resolution confocal imaging and traction force microscopy, we visualize the microtubule- and actin-dependent force in live migrating neurons. Microtubules dynamically bind to small points on the nuclear envelope via the plus- and minus-oriented motors, kinesin and dynein, and induce sharpening, rotation and translocation of the nucleus. In contrast to the steering forces of microtubule motors, the strong contractile force of actomyosin instead act on a broad area of the cell and/or nucleus, resulting in massive nuclear deformation and translocation.

Susumu Kitagawa, PhD

“New Dimensions of Porous Coordination Polymers/Metal Organic Frameworks”

We have found unique porous properties of porous coordination polymers (PCPs) or metal-organic frameworks (MOFs), which respond to specific guests, dissimilar to the conventional porous materials.1 The third generation MOFs2 possess flexible or dynamic porous frameworks, which reversibly respond to external stimuli, not only chemical but also physical, unlike the previous generations. They were developed in an effort to realize dynamic porous and collective functionality not found in conventional materials. Their compositions of metal ions and organic molecules have achieved diversity in the electronic states. That is, the spatial and electronic structures can be altered, realizing magnetic and dielectric properties as well as oxidation?reduction functions. Besides normal storage, dynamic MOFs have vast potential for separation with an extremely high selectivity, high-efficiency storage, and catalysis, as well as sensing and actuator functions. For these reasons, many studies investigate these materials. Here, I discuss porous materials with capabilities that exceed current ones (i.e., the fourth generation MOFs) and the future research direction.3-5 It would be fabulous if novel porous materials possessed more features than just the third generation’s excellent characteristics (flexibility, collectivity, and diversity). These additional features include 1) Hierarchy and Hybrid (double-H), which means to combine different functions and pursue the dynamic development of combined functions, (2) Anisotropy and Asymmetry (double-A), which means to learn from living organisms and then go beyond such organisms’ capabilities, and (3) Disorder and Defect (double-D), which may lead to excellent catalytic reactivities and electronic functions. Hereinafter these three characteristics are referred to collectively as “ HAD”  characteristics.

Natsuko Kondo, MD, PhD

“Boron Neutron Capture Therapy in Kyoto University – from reactor based to accelerator based”

Boron Neutron Capture Therapy (BNCT) is a form of tumor-selective particle radiation therapy consisting of two components. First, a boron-10 (10B)-containing drug is administered to the patient in order to obtain a sufficient concentration of 10B in the tumor to sustain a lethal 10B(n, ?)7Li capture reaction. Second, this is followed by irradiation with epithermal neutrons to produce high linear-energy-transfer (LET) alpha particles and recoiling 7Li nuclei. The short path length of the alpha particles (5–9 µm) results in selective killing of tumor cells with a concomitant sparing of adjacent normal tissues. We have applied BNCT in Kyoto University Research Reactor (KUR) for malignant brain tumors, melanomas, and head and neck cancers and etc, since 1985. The total numbers of patients are 553 and type of tumors are summarized in table below. The results obtained had evidence of some clinical efficacy especially for brain tumors, head and neck cancers. Since 2010, we have also conducted a phase I clinical trials on BNCT for malignant pleural mesothelioma (diffusely-spreading tumors along the pleura).

Accelerator – based BNCT clinical trials started for recurrent malignant glioma and for head and neck cancers since 2010 and since 2013, respectively. Both phase II clinical trials completed in 2018 and results will be reported sometime in 2020.

Heather Maynard, PhD

“Biomimetic Stabilizing Polymers for Protein Therapeutics”

Therapeutic proteins are challenging to transport and store, and thus the majority must be refrigerated or frozen. Proteins exposed to these conditions and others such as mechanical agitation often lose activity. This can be harmful or even fatal for patients that take the medications and can also increase costs because of the requirement of the cold chain. Thus, polymeric materials that are capable of stabilizing biomolecules at room temperature and to agitation are of significant interest. This talk will focus on new polymeric materials to address this important problem. Well-defined polymers were synthesized by controlled radical polymerization and ring opening polymerizations. These were tested in their ability to stabilize proteins to room temperature, elevated temperatures, mechanical agitation, and pH changes when added as excipients. Side chains derived from Nature and others from known excipient classes were compared and contrasted, and the mechanisms of stabilization were investigated. Grafting to and grafting from synthetic strategies were utilized to prepare protein conjugates of these polymers, and in vivo testing showed that the polymers significantly increased blood circulation times (i.e. pharmacokinetics) in addition to retaining protein activity after exposure to high temperatures. Synthesis, stabilization properties, and application of the polymers to treat diabetes and wound healing will be presented.

Jeff F. Miller, PhD

“Engineered Contractile Nanotubes as Precision Antibiotics”

Broad-spectrum antibiotics may be expedient from a clinical perspective, but consequences of their use include selection for transmissible drug resistance and microbiome dysbiosis. In contrast, precision antimicrobials would avoid harming beneficial microbes or broadly selecting for transmissible resistance. Contractile nanotubes (CoNTs) are used by myovirus bacteriophages to penetrate bacterial surfaces, often with exquisite efficiency and specificity, and they provide a platform for creating precision antimicrobials. An adaptation of the same contractile mechanism is used by R-type bacteriocins, which function as bactericidal particles by inserting ion-conducting channels across the envelopes of target bacteria. Using cryo-EM we constructed atomic models of pre- and postcontracted states of an R-type bacteriocin to determine the mechanism of penetration and killing. The pre-contracted particle is assembled into a high energy, metastable state in which sheath and tube proteins interact through charge complementarity. Contraction initiates when tail fibers bind to cognate receptors on a bacterial cell surface, triggering a cascade of events that results in coordinated translational movement of sheath subunits intertwined by ?-sheet augmentation. Released energy powers the injection process, which must occur in the absence of ATP. Our structural data showing how energy is stored in the extended state, how it is released during contraction, and how the bacteriocin tube is optimized for dissipating proton motive force provides a roadmap for developing precision antibiotics based on CoNTs engineered to recognize specific ligands on bacterial cell surfaces. Rapid evolution of desired ligand-binding specificities is greatly facilitated by Diversity-generating retroelements (DGRs), which introduce vast amounts of targeted diversity into ligand-binding proteins. DGRs function through a template-dependent, reverse transcriptase-mediated mechanism that introduces nucleotide substitutions at defined locations in specific genes, creating vast repertoires of receptors for ligand-binding interactions.

Andre Nel, MD, PhD

“Use of Nanocarriers for Chemo-Immunotherapy for Pancreatic Cancer”

Pancreatic ductal adenocarcinoma (PDAC) is essentially a death sentence and is currently treated by two major drug regimens, namely gemcitabine, and a 4-drug combination known as FOLFIRINOX (oxaliplatin, 5-fluorouracil, irinotecan, and leucovorin). In addition to the contributions of late diagnosis and early metastatic spread to mortality, a major treatment obstacle is the abundant dysplastic stroma, which provides a barrier to vascular access of chemotherapeutic agents at the tumor site as well as participating in drug resistance. While FOLFIRINOX leads to better survival outcome, the high toxicity levels of irinotecan and oxaliplatin often prevent its use as a first-line treatment regimen. We have recently developed a mesoporous silica nanoparticle (MSNP) carrier, coated by a lipid bilayer, which can effectively deliver (i) a synergistic combination of paclitaxel and gemcitabine, or (ii) irinotecan as a single drug. These “silicasome” carriers outperform commercial nanocarriers (Abraxane and Onivyde) in a rigorous orthotopic PDAC model from an efficacy as well as a survival perspective, including the ability to suppress metastases. Moreover, the irinotecan carrier could also significantly reduce bone marrow and gastrointestinal toxicity compared to a liposomal equivalent. The efficacy of the irinotecan-silicasome is enhanced by involving a novel transcytosis pathway that can be triggered by iRGD co-administration. In addition to improving survival through delivery of cytotoxic anti-cancer drugs, we have also developed a series of nanocarriers and nanoparticles that can be used to generate immunogenic cell death based on the delivery of chemotherapeutic agents or use of nanoparticle physicochemical stimuli towards and immunotherapy for PDAC and other solid cancers. Immunogenic cell death generates tumor-infiltrating CD8+ cytotoxic T cells against the primary tumor as well as its metastases. The combination of immunogenic stimulus with a local metabolic checkpoint inhibitor or checkpoint blocking antibodies synergistically enhances de novo generation of an immune response at the tumor site. It is therefore possible to provide an immune “hot” start at the cancer site that allows an improved response rate for therapies that interfere in immunosuppressive pathways, with the potential to increase the number of patients that will respond to immunotherapy.

Michael E. Phelps, PhD

“Theranostics: Integration of molecular Imaging with PET and radio-isotope ablation on cancer cells”

Theranostics as a combination of molecular targeted imaging diagnostics & radio-ablation of cancer cells, using the same small peptide will be presented. After IV administration, the peptide searches throughout the tissues of the body with high affinity and specificity for binding to a target protein on cancer cells. Theranostics in patients will be illustrated with 68Ga or 18F labeled peptides for PET imaging to select patients for radio-ablation therapy with the same peptide labeled with either 177Lu or 225Ac. 177Lu is beta particle emitter with 90% irradiation within a sphere of ~500 microns diameter. 225Ac is an alpha particle emitter with 90% irradiation within a sphere of ~20 microns diameter. Cancer cells are ~17 to 25 microns. Two examples of Theranostics will be provided. Neuroendocrine Tumors, in which the peptide is Dotatate labelled with either 68Ga for imaging or 177Lu for treatment. The 68Ga- Dotatate is used to answer the question, Does the patient have the protein target? Patients with the protein target are then treated with 177Lu- Dotatate, and the 68Ga- Dotatate PET imaging repeated to answer the question, Are the cancer cells ablated? From the remarkable therapeutic responses with only mild side effects, 68Ga- Dotatate and 177Lu- Dotatate were FDA approve and reimbursed in 2016 and 2017, respectively. Examples will be shown to illustrate this imaging guided cancer cell therapy. Prostate Cancer in which the Theranostics combination is 68Ga-PSMA-11 and 177Lu-PSMA-617, where PSMA-11 and PSMA-617 are the same peptide. Again, the PET imaging is used to answer the same 2 questions asked with the Neuroendocrine Tumors and shown to provide the same remarkable therapeutic responses with only mild side effects. The 68Ga-PSMA-11 is likely to be FDA approved the end of 2018, and 177Lu-PSMA-617 is in a phase III FDA trial. Examples will be shown to illustrate this imaging guided molecular targeted cancer cell therapy. A signal (responders) to noise (non-responders) analysis for therapy trials will be used under reasonable approximates to demonstrate the reduction in patients, cost and time from changing the percent of responders from 20% (common % responders) to 40% and to 80% through the use of molecular diagnostics.

Seth J. Putterman, PhD

“Attempts to Harness the Forces of Cavitation and Sonoluminescence for the Enhanced Treatment of Antibiotic Resistant Soft Tissue Infections”

This talk discusses our attempt to use the extraordinary forces of acoustic cavitation to enhance medical attempts to treat antibiotic resistant infections such as MRSA. A strong ultrasonic sound field creates imploding bubbles that concentrate energy density down to the nanoscale where strong pressure pulses and a flash of ultraviolet light is emitted. Skin and soft tissue wounds are a major global health issue. $50B is spentannually on wound care in the U.S. alone. Chronic non-healing wounds in the US constitute 2% of the general population; 90% of limb amputations in diabetic patients are instigated by an uncontrollable infection. A procedure developed by Barry Silberg cures these wounds by achieving a local concentration of medicine that is so high that common antibiotics such as Cephazolin can be successfully deployed against the MRSA pathogen. Such high concentrations cannot safely be achieved via intravenous medication. The Silberg procedure combines two innovations:1) injection of sufficient antibiotic+saline into the region of infection so as to cause tumescence [swelling]; and 2) application of external ultrasound to assist in the dispersion of the injected fluid into the unhealthy tissue. In an FDA phase 2 clinical trial over 80% of patients have been cured with one treatment. The importance of tumescence, innovation-1) , was measured in live healthy pigs with diffusion-weighted magnetic resonance imaging, computed tomography, and 3D-scanning. Results show that subcutaneous tissue has the remarkable ability to expand several times in thickness upon injections of high volumes of fluid. Pores are opened up, dispersing the fluid and dramatically increasing tissue permeability. Measurements of the MIC [minimum inhibitory concentration] for cefazolin against 1239 strains of MRSA by D. Nicolau support the view that directed tissue dispersion can work where IV administration would be toxic. Attempts to enhance drug delivery with ultrasound have uncovered a surprising resistance of tumescent tissue to cavitate.

Leonard H. Rome, PhD

“Vault Nanoparticles for Immuno-Oncology Therapeutics”

Vault Nanoparticles for Immuno-Oncology Therapeutics. We have developed a therapeutic delivery system that can effectively attack tumors by activating the immune system. This system is based on the naturally-occurring vault nanoparticle. We have worked out the production of recombinant vaults and the packaging of a wide variety of proteins, protein antigens and active peptides inside the nanoparticles. Once packaged, the particles are stable and they protect their protein contents. Using this strategy we engineered a vault particle containing an immune-stimulant called CCL21. Animal studies were carried out utilizing the Lewis lung carcinoma (3LL) cell line for the assessment of antitumor responses in vivo. Intra-tumoral injection of control and CCL21-vaults were compared and the CCL21-vault treatment group was found to have high levels of T cell infiltrates compared to the controls and the tumor size was significantly decreased. We are also engineering vaults to contain tumor antigens with the hope of inducing the body’s own immune system to fight the tumor.

Ke Sheng, PhD

“Presentation Title Radiotherapy in the Era of Precision Medicine”

Radiotherapy is an art of geometrical targeting. In the past decades, with the progress of medical imaging, the precision of radiotherapy has made significant strides. The dose calving ability has been provided by intensity modulated radiation therapy. 4? radiotherapy was invented to further reduce normal organ dose. Heavy ions, due to their unique physical properties of releasing energy at the Bragg peak, is intensively researched and clinically adopted. In addition to the superior dose distribution, their unique radiobiological properties may be exploited to treat cancers that only palliative care was available. Although 3D tumor targeting is made possible by CT based image guided radiation therapy, to answer the need for better soft tissue contrast and tumor discrimination, MRI guided radiotherapy was invented. This new modality also shows the promise of measuring the early tumor response for adaptive treatment. Radiotherapy is not an isolated field. When combining radiotherapy with nanotechnology, both targeting accuracy and treatment efficacy can be improved. A small animal radiation research platform is provided to test the ideas that may lead to more precise, personalized and effective treatment.

Jun Suzuki, PhD

“Phospholipid Scrambling on the Plasma Membranes”

My purpose on whole research is to decipher the biological phenomenon of my own interests at molecular levels. To achieve this, I am trying to identify the important genes that can simply explain the phenomenon. I prefer to perform unbiased screening to discover the genes that are involved in the biological systems of my own interests.

Currently, my lab is interested in the biological phenomenon called phospholipid scrambling. The lipid bilayers on biological membranes are asymmetrically distributed, but by the action of scramblases, the asymmetry is broken. For example, phosphatidylserine (PS) is always restricted to the inner layer of plasma membranes, but is exposed on the cell surface by the scramblase when cells undergo apoptosis (cell death). In this case, exposed PS functions as an “Eat-me” signal for dead cells to be engulfed by phagocytes. When PS is exposed on the cell surface on activated platelets, it functions as a scaffold of coagulation factors, which is activated to stop bleeding. Although the existence of scramblases was suggested about decades ago, their molecular was unknown. We started our research to identify scramblases and previously identified several scramblases (TMEM16 family and Xkr family) that regulate this process.

Toshiki Tajima, PhD

“Laser-Driven Medicine: A Prelude”

Ultrafast ultraintense lasers are capable of inducing a new class of compact pulsed beams of various radio-particles (X-rays, gammas, electrons, ions, radioisotopes, etc.) useful for medical applications [1], [2]. For example, laser wakefield acceleration compactly generates electron pulses so that an intra-operative radiation therapy may become possible [3]. The techniques to deliver laser-driven ion beams have recently made an important stride so that compact ion beam sources may be attainable, such as protons, deuterons, carbons, or even radioactive heavy ions [4]. Using, for example, the laser-driven deuterons, we are also able to generate compact safe neutron sources, which are in turn useful for various radiotherapies, including BNCT. Laser-driven mono-energetic gamma photons can be also useful for the Auger therapy with high-Z elements delivered by vector medicine [2]. Such targeted medicine with the above various radiations can work as a targeted theranostics, as the vector molecules sitting at the site of tumor emit signal and simultaneously radiatively kill the tissues around it. The recent high-rep rated high efficiency fiber laser technology, CAN laser, may facilitate compact practical medical applications.

Fuyuhiko Tamanoi, PhD

“Boron Neutron Capture Therapy and Nanotechnology”

Boron neutron capture therapy (BNCT) can be considered as an ultimate cancer therapy, as cell killing can be restricted to a single cancer cell. The therapy is based on the premise that neutron exposure to boron-10 causes splitting of boron-10 to lithium and helium. The helium nucleus is ?-particle that has strong cell killing activity but travels only the distance of a cell. Thus, if one could deliver boron-10 selectively to cancer cells, it is possible to achieve preferential killing of cancer cells. The source of neutron has been nuclear reactor.

We believe nanotechnology can make significant contribution to BNCT therapy. By using tumor targeting nanoparticles, it is possible to deliver boron-10 to tumor. While current BNCT therapy uses low molecular weight compounds such as BPA and BSH, the preference for the uptake of BPA into cancer cells is still not high and there is a room for improvement and a new generation of boron-10 compounds with much higher tumor accumulation can dramatically improve the BNCT therapy. Our reagent of choice is nanoparticle that contains boron-10. These nanoparticles have the ability to accumulate in the tumor, as they can take advantage of the EPR (enhanced permeability retention) effect. Because of their small size, they can leak out from the blood vessel accumulating in the tumor.

I will discuss the work we have been carrying out in the past ten years to achieve tumor accumulation of nanoparticles. In addition, I will describe experimental approaches we are developing at the Kyoto University Research Reactor Institute (Institute for Integrated Radiation and Nuclear Science) to evaluate the potential of nanoparticles to improve BNCT. Convergence of BNCT and Nanotechnology may in the future dramatically change the outcome of the BNCT cancer therapy.

Koichiro Tanaka, PhD

“Extreme nonlinear optics in solids “

Observation of higher-order harmonic generation (HHG) in solids [1–5] has opened a new platform for investigating the ultrafast electron dynamics because it clearly reflects the electron motion driven by the intense sub-cycle laser field where extremely nonlinear optical phenomena appear. The mechanism of HHG is fundamentally different from that in atomic gases because of the higher density of the atoms and their periodic structure. In particular, recent reports have revealed that HHG is sensitive to the orientation of the electric field relative to the crystal axis [1–4]. They demonstrated that HHG is a good tool for exploring the nature of the electron systems in crystals in terms of the symmetry of the electronic band structure [2], interatomic bonding [3], and the material’s Berry curvature [4]. While this interesting property of HHG clearly reflects the diversity of solids, it may obscure the universal nature of HHG in solids. Among these materials, a monolayer material such as graphene is one of the simplest crystalline materials to explore the origin of HHG. In this talk, we will summarize recent developments of extreme nonlinear optics in solids and discuss the physical mechanism.

Michael Teitell, MD, PhD

“Cell Response Profiling and mitoBLAST “

This presentation will focus on approaches for cell engineering and response profiling.

Hsian-Rong Tseng, PhD

“NanoVelcro Rare-Cell Assays for Detection and Characterization of Circulating Tumor Cells”

Circulating tumor cells (CTCs) are cancer cells shredded from either a primary tumor or a metastatic site and circulate in the blood as the potential cellular origin of metastasis. By detecting and analyzing CTCs, we will be able to noninvasively monitor disease progression in individual cancer patients and obtain insightful information for assessing disease status, thus realizing the concept of “tumor liquid biopsy”. Over the past decade, our research team at UCLA pioneered a unique concept of “NanoVelcro” cell-affinity substrates, in which CTC capture agent-coated nanostructured substrates were utilized to immobilize CTCs with remarkable efficiency. Five generations of NanoVelcro CTC assays have been developed over the past decade for a variety of clinical utilities, including CTC enumeration for prognosis and staging, single-CTC mutational analysis for tracking tumor origin, and CTC-based molecular analysis for treatment monitoring. In this presentation, I will summarize the development of the new generations of NanoVelcro CTC assays and the clinical applications of these new diagnostic devices.

Shimon Weiss, PhD

“Nanomaterials for neuronal action potential”

We have been developing targetable voltage sensing inorganic nanoparticles (vsNPs) that are designed to self-insert into the cell membrane and non-invasively optically record, via the quantum confined Stark effect, action potential on the single-particle level, at multi-sites and in a large field-of-view. We synthesized a library of vsNPs with different compositions and developed a high-throughput screen for optimization of their performance. We have explored several strategies for imparting these vsNPs with membrane-protein-like properties, including functionalization with libraries of peptides, lipids, and nanodiscs. We have developed screening assays for improving the efficiency of vsNPs’ membrane insertion and for their voltage sensitivity once embedded in the membrane. We have demonstrated membrane voltage sensing by membrane-inserted vsNPs in WT HEK cells using valinomycin and modulated concentration of potassium ions in a microfluidic chamber, and by patch-clamped in primary cultured cortical neurons. These novel voltage nansensors hold great promise for electrophysiological investigations of the nervous system.

Jeff Zink, PhD

“Multifunctional Mesoporous Silica Nanoparticles Controlled by Nanomachines for Biomedical Targeting, Imaging and Drug Delivery”

The subjects of this talk are multifunctional nanoparticles controlled by nanomachines for targeting, imaging and drug delivery in cells and in vivo. The nanoparticles are designed to 1) trap therapeutic molecules inside of nanocarriers, 2) carry therapeutics to the site of the disease with no leakage, 3) release a high local concentration of drugs, 4) release only on command – either autonomous or external, and 5) kill the cancer or infectious organism. The most important functionality is the ability to trap molecules in the pores and release them in response to desired specific stimuli. Two types of external stimuli will be discussed: light and oscillating magnetic fields. Activation by internal biological stimuli such as pH changes, redox potential changes and enzymes will also be presented. Molecular machines based on molecules that undergo large amplitude motion when attached to mesoporous silica – impellers, snap-tops and valves – will be described. Derivatized azobenzene molecules, attached to the interior pore walls function as impellers that can move other molecules through the pores. Nanoparticles containing anticancer drugs in the mesopores are taken up by cancer cells, and optical stimulation of the impellers drives out the toxic molecules and kills the cells. Snap-tops with cleavable stoppers release cargo molecules when the stopper is removed from the pore entrance. Nanovalves consisting of rotaxanes and pseudorotaxanes placed at pore entrances can trap and release molecules from the pores in response to stimuli. Activation of these nanodevices by the five types of stimuli in solution, in living cells, and in animal models will be discussed. Applications to treatments of cancers (including pancreatic and breast) and of intracellular infectious diseases (including tuberculosis and tularemia) will be presented.