application of bio-nanotechnology in chinese medicines
TRANSCRIPT
Application of bio-nanotechnology in Chinese medicines
September 10-11, 2015
Seminar on Research and Development of Chinese MedicineHong Kong Convention and exhibition Center
Hong Kong
Ratnesh Lal, Ph.D.Professor of Bioengineering, Materials Science, Mechanical Engineering Co-Director, Center for Excellence in Nanomedicine and Engineering, IEM
University of California, San Diego Visiting Professor, Chinese academy of Sciences
Nano-Bio Lab
Nano-machines and sensors based on:•Cantilevers•Nano chips•Smart materials to sense forces, fields and energies
On-demand, targeted delivery
Nano biotechnology•Nanoimaging•Nanomanipulation•Nanopatterning•Nanoarray designand synthesis
Imaging-based Diagnostics
• Amyloid diseases• Heart diseases• cancer
Today Talk: Can Nanotechnology help Chinese Medicine get Global acceptance
Beginning of Nanotechnology and Nanomedicine•Discovery of Nanotube
• Nanoscale materials with magical properties for interactions with its environment
•Discovery of Scanning Tunneling and Atomic Force Microscopes (STM and AFM)•Allow study of structures, motion and all physical forces at atomic scale in fluid•Allow manipulating and creating structures at atomic scale
Nanoscience and technology is about• Understanding principles of physical world • Designing Technology to unravel world
at the scale of molecules and structures that make and run the world we live in
Accelerating Nanotechnology Applications to Human Health- Nanomedicine
Global Investment: >$1010
• Current Global market: ~$1010
• Global market by 2017: $1012
• Global Nanobio companies: ~103
• Global Population: >109
• Human size: 100
• Human cells: 10-6
• Biological macromolecules: 10-9
• Biological processes: 10-11-101
• Which means billions of us are controlled by structures and mechanicsbillionth times smaller (Nano) than us
Disease Diagnosis: 101
• Disease Treatment: 101
• Disease Prevention: 101
Can TCM gain a larger share of the market?
Scope of Nano-biotech & Nanomedicine
Nano-Diagnostics Nano-Therapeutics
Nano-Devices
Define causeand
Diagnose Pathology
Define TargetsReceptors, Channels
Monitor DiseaseAnd
Therapy states
Design TherapeuticsDrugs, interventions
Optimize EfficacyMinimize Side Effects
Targeted Delivery•Controlled delivery,
•guided delivery•On-demand release
Devices to MaintainTissue Activity
In-vivo Sensors• Diagnosis• Remotely controlled• Multi-functional
Devices for Tissue regeneration•Stem cell therapy•Wound healing•Bone growth
Diagnosis: high resolution and sensitivity
Therapy• Reduce the Dose• Treat localized cells/tissues• Minimize side effects
• Biocompatible/non-toxic• in Vivo Stability• biodegradable
Topics No. of Publications
Nanotechnology in Medical Applications 295,000
Chinese Medicine 2010Homeopathy 652
Ayurveda 644Acupuncture 849Acupressure 49
Japanese Medicine 5Korean Medicine 10
Data collected from Google Scholar
Nanotechnology in Eastern Medicine (<1%)
I will give examples of nanoimaging, nanomaterials and nanomechanics technologythat relates to three essential components of all living systems (structure, motion and interaction withenvironment) can be used in Chinese medicineHolistic ApproachMedicine works by the synergistic action of many active constituents
Nanoimaging for Nanomedicine
• Imaging functional ion channels• Imaging amyloid (misfolded) channels• Imaging single molecule proteolysis
Relevance to Heart and lung diseases, Alzheimer’s and other brain diseases, muscular diseases, cancer
Cell-Cell and Cell-Surround Communication Channels
Immunolabeling of hemichannel
Hemichannel
Gap
Cell 1
Cell 2
Ramachandran et al Plos One, 2006;Thimm et al, J Biol Chem, 2004; Hoh et al, Science, 1991
A key Structure for the Evolution and Sustenance of Multicellular Organisms
openclosed
1
1
2
3
2
34
4
55
6
6
11
22
3 34 4
55
66
3D topography
Surface energetics map
Apoptosis6
Extracellular
Cytoplasm Smoking extract/ ROS Intake
Smoking induced lung diseases: • Emphysema• Cancer
12
345
6
John et al, J Struct Biol, 1997
Good and Bad of Amyloids
• Amyloids as Foe
• Amyloids as friendInfection Amyloid Proteins
(Anti‐microbial Proteins)Death of infecting
agents
• Nervous system• Immunity• Metabolic• Transport
Protein Misfolding
Amyloid Proteins
Accumulation as PLAQUES
Cell Death, Disease and System Failure
Is plaque, fiber or oligomer the mediator?
D 100 µM
500 nm 500 nmUntreated
A CBUntreated 20 µM
40 µM
E
1 mMUntreated 40 μM 100 μM
F
Before adding p3
*
Amyloid peptides Induce dose-dependent synaptic degeneration
Jang et al, PNAS, 2010
Defining New Paradigm of Disease Process And Defining Target (Channel/Receptor) Structure
Amyloid Diseases are a class of “Channelopathies” with Defined Ion Channels
SOD1 mutant
ALS
Quist et al, PNAS, 2005
B CA
Real-time collagen-collagenase Association-dissociationDefining Therapeutics’ Efficacy and Dosage
50 nm
A key Extracellular matrix protein, provides support for tissue sustenance and growth
Single triple helical collagen I molecule: AFM image
Lin et al, Biochem, 1999
Nano-mechanics for Nanomedicine
•Sensing intermolecular interaction•Sensing intracellular mechanics•Sensing whole cell mechanics•Sensing tissue mechanics•Sensing composite materials mechanics•In-vitro sensors for Biomarkers•In-vivo Sensors for Biomarkers and therapy
Diagnostics, Designing therapeutics and Therapy monitoring
Single molecule spectroscopy on living cells
25 min
25
20
15
10
5
025 µm20151050
13
2 4
45 min
100
200 kPa
150
50
0
25
20
15
10
5
025 µm20151050
10 min
Almqvist et al Biophys J, 2004
Online antibody addition
2 µm
10 min0 min 45 min
1 3
24
AntibodyAFM Tip
Cell membrane Antibody
0.03
0.02
0.01
0.00
Pro
babi
lity
300250200150100500Unbinding force (pN)
68 ± 35 pN0.03
0.02
0.01
0.00
Pro
babi
lity
300250200150100500Unbinding force (pN)
78 ± 25 pN163 ± 42 pN
0.03
0.02
0.01
0.00
Pro
babi
lity
300250200150100500Unbinding force (pN)
110 ± 57 pN
Locating Therapeutic Targets: VEGF Receptors
Nanomechanics of a Pulsating Muscle Cell
20 nm Shroff et al, Am J Physiol 1995
•Relevant to Muscular Disease Diagnostics and monitoring
Correlative Nano-Indentation and Tissue Elasticity with an AFM
1 m
Re
Exo
CoEndo
Parbhu et al, Biochemistry, 1999
Tissue stiffness-based diagnosis (cancer, MS, ALS, osteoporosis)Understanding How Acupuncture works
Sherman, Quist, Hansma, J Nano Res, 2009
Stickiness and Surface Roughness Of Composite MaterialsDiagnostics for Infectious bacterial biofilm, sepsis, cell-substrate adhesion
Tota
l Ind
enta
tion
Dis
tanc
e (
m)
Age (years)
Patients with fractures: Indentation diagnosis
A Perez, R Güerri, X Nogues, E Cáceres, MJ Peña, L Mellibovsky, C Randall, D Bridges, JC. Weaver,, D Brimer, KJ. Koester, RO. Ritchie, PK. Hansma, JBMR, 25, 1877-85 (2010)
nanomechanics of human menisci
Kwok et al. Nanomedicine: Nanotechnology, biology, Medicine,
in press, 2014
Diagnosing/Treating human diseases
Remote Sensor System for Various Organs/Tissues
RF, magnetic or thermal input signal and power
Remote RF output signal from implanted edema sensor
Controller module for signal transmitter and signal receiver
Computer analysis and control
Lung edema sensor
Arm edemasensor
Leg edema sensor
Brain edema sensor
Kidneyedema sensor
}
Implanted edema sensor(s)
Stent with attached sensor
Lal, Raman, Jolly, Jin, US patent 2012
Modified from Raman et al, 2009
Remotely Guided in-vivo Theranostics
Lung
Arm
Leg
Brain
Kidney
Remote electromagnet array1 2 3 4 5
1 2 3 4 5
Swallowedcamera
MagnetizablestripesMotion in
gradient fieldIntestine wall
Drug delivery capsule (MEMS or magnetically actuated)
Tumor or ulcer
GI TractBody cavity
Nanodelivery for Diagnosis and Therapy
Nano-carriers• Nanotubes• Nanoclusters• Nanoshells• Dendrimers• Nanoliposomes Magnetically-vectored Nano-capsules Nano bowls, nano-golf balls
Therapeutic Carriers
Diagnostic Augments
Controlled and Targeted Theranostic NanoCapsules
TAG
TAG
TAG
Biocompatible PolymerGate
Targeting Molecule
On‐off Gate
Under patent embargo
Magnetic Gold/Silica Nano Bowls and Capsules
Silica Olive bowl Iron Oxide particles
Remove PS coreGold Seed Gold Plate
Amine Functionalize
‐1
‐0.8
‐0.6
‐0.4
‐0.2
0
0.2
0.4
0.6
0.8
‐15 ‐5 5 15
Magne
tization (emu/g)
Applied Field (kOe)
Moment (emu/g)
For Targeting and controlled delivery
Under patent embargo
Controlled Release using stimuli‐sensitive Caps/coating
Close (remove heat)
Open w/ heat
heating
A
B
C
A: DNA closingB: DNA motors opening and closingC: encapsulation in hydrogel.
DNA based conjugation and actuation
Strand Displacement Devices
DNA thermal melting
Under patent embargo
Tight Junction
BloodEndothelial cell array
Basement membrane
Brain
Switchable drug release from magnetic capsules
BBBH (Step 1. BBB
Crossing)
SS S
NN NPermanent or electromagnet
Drug capsule
(Step 2. Switched-on drug release)
Kong et al, J controlled Release, 2013
BBB crossing by gradient magnetic field
For Brain Diagnosis and Therapy
magnet
Nano-Bio Lab
Funding:NIHNSFRC Nano CorpAlzheimer’s AssocCal Dept of Health
Interdisciplinary TeamNanobiophysicists NanotechnologstsMaterial
Scientists/EngineersBiochemists Cell and system BiologistsMedical Doctors
Dan Cohen, Ph.D., Electrical Engineer, UCSBArjan Quist, Ph.D., RC Nano CorpJai Raman, M.D., Ph.D., Cardiothoracic Surgeon, U ChicagoNeeraj Jolly, M.D., Cardiologist, U Chicago
CollaboratorsSungho Jin, Ph.D.,Materials ScientistShankar Subramaniam, Ph.D.BioinformaticsShyni Vargese, PhDTissue engineering/biomaterialsGina Sosinski, Ph.D.Structural BiophysicistVeronica Shubayev, MDNeurosurgery
Michael Karin, PhDBiochemistry and Molecular BiologyFarooq Azam, Ph.D.Scripps Oceanography InstituteAshok Deniz, PhDScripps InstituteBrian Eliceri, PhDCell BiologistAmi Chand, Ph.D., Materials Scientist, Appl Nannostruct
Group Members:Research Scientists:Srini Ramachandran M.D./ Ph.D. Preston Landon Ph.D.Fernando Arce Ph.D.Graduate StudentsAlan GillmanLaura Connolly Alex MoBrian MeckesJeanie Kwok Michael HwangJoon LeeNirav PatelMukunth Vaidyanathan
UndergraduateLu YangKarl HujsakNader BagherzadehSinduja Karl MarxAlan GomezSuri ShermanCeline LiongMax YangPavan KanekalSanam Mozaffari