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Biomedicine Applications of Nanotechnology towards Sustainable
Public Health
André Nel M.B.,Ch.B; Ph.D
Professor of Medicine and Chief of the Division of NanoMedicine at UCLA
Director of the NSF‐ and EPA‐funded Center for the Environmental Implications ofDirector of the NSF‐ and EPA‐funded Center for the Environmental Implications of Nanotechnology (UC CEIN)
Director of the NIEHS‐funded Center for NanoBiology and Predictive Toxicology
Associate Editor ACS Nano
This materials is based on work supported by the National Science Foundation and Environmental Protection Agency under Cooperative Agreement # NSF‐EF0830117. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation or the Environmental Protection Agency.
Copyright 2010 – The Regents of the University of California. All Rights Reserved. Contact [email protected] to obtain permission to use copyrighted material.
Much of Biology is carried out at the Nanoscale dimension
1. Proteins, lipids, nucleic acids and carbohydrates exhibit nanoscale size,shape, surface recognition features and functions
2. Many biological processes such as ATP production take place in nanoscale assemblies,e.g. energy producing mitochondria
3. Engineered nanostructures can readily interact with bio-molecules, e.g. the protein corona of nanoparticleon its way to the cell surface
Particle
e-
h+
Electronicstates
crystalline
Sizecurvature
Large number of novel physicochemical properties
r Endosome
Lysosome
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+++++
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+ ++
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The Cellular Nano/bio Interface
composition
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+ ++ +
Charge &Surface
functions
Hydro-phobic/philic
curvatureangle
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H2O
H2O
Meng et al. ACS Nano. 2009Nel et al. Nature Materials. 2009Nel et al. Accounts Chem Res, 2012
000
nano
met
ers
Dynamic Sensing of a Silica Nanorod vs a Nanosphere by a Human Cancer Cell Line
M
M
Nano-rods
10,
M
Spheres
Meng, et al., ACS NANO, 2011
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Top Ten Nanotechnology Applications most likely to benefit Developing Countries
1.
2.
3.
Salamanca-Buentello et al PLoS Medicine. 2005. 2, 97
4.
5.
Top Ten Nanotechnology Applications most likely to benefit Developing Countries
6.
7.
Salamanca-Buentello et al PLoS Medicine. 2005. 2, 97
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Top Ten Nanotechnology Applications most likely to benefit Developing Countries
9.
10.
Salamanca-Buentello et al PLoS Medicine. 2005. 2, 97
Billions of People and Oil production
Bill
ion
s o
f p
eo
ple
lion
s o
f b
arr
els
/yr
The Quest for Energy and the introduction of theAnthropocene
B
Bil
Introduction of the Anthropocenein a thin atmospheric sliver
Seven Billionpeople livingin the equivalentof an apple skin
Google Images
3
Climate Change and Human Health
http://ete.cet.edu/gcc/?/healtheffects_teacherpage/http://www.climatecommunication.org/affects/human-health/
The dimensional scale of the physical phenomena that are required for saving, capture, conversion, storage, transmission, and dissipation of energy is inherently NANO
Exciton (electron hole pair) dimension - Photovoltaics
Bandgap engineering by quantum confinement – energy absorption,
Why is Nano key to Energy and Global warming?
Bandgap engineering by quantum confinement energy absorption, multi-exciton
Photocatalytic reaction center – photosynthesis, water splitting
Specific Surface Area – energy storage, catalytic activity
↓Friction/ ↑Lubrication/ ↑Adhesion
Diffusion and Convection – thermal, electrical, chemical transport
Saving of energy
Pillars of NanoMedicine
Diagnostic and
Imaging Tools
Targeted Therapy
and Drug Delivery
Systems
Nanomaterials and Devices
Regenerative
Medicine and
Tissue
i i
Theranostics
Point of Medical Care:
Improved
diagnosis, imaging,
treatment
Safety and Compatibility Issues
engineering
What is Nanomedicine?
The design and synthesis of biologically interactivenanoscale systems that enable medicinal technologyadvances in:
• Prevention, diagnostics, treatment of diseases,including personalized, point of care modalities
• Preservation and improvement of human health
• Chronic and acute pain relief by leveraging significantadvantages nanosystems hold over traditional methodsfor sensing, imaging, reconstruction, delivery andinteractivity of biological systems.
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Examples of Nanocarriers for Drug Delivery
Stage of the Development of Nano Delivery System • Drug encapsulation:
circulation half‐life, protection• ↓ Drug toxicity• Synergistic drug combinations• Systemic siRNA delivery and
co‐delivery with drugs• Theranostics and multifunctional design• Off‐patent drugs
Inorganic
Liposome
Micelle
Polymer
Preclinical Clinical Trail Approved
Mesoporous Silica
Liposome
Carbon nanotubeVault Nanocapsule
DendrimerPolymer
Quantum Dots
drug
Spherical nucleic acid
Albumin nanospheres‐Abraxane
Nanoparticle Drug Delivery in Cancer
• Encapsulation, increased circulation time, retention at the tumor site (passive targeting)
• Active targeting
• Reduced drug toxicity (including hydrophobic drugs)
14
g y ( g y p g )
• Systemic siRNA delivery, which can be combined with drugs
• Combination therapy to overcome tumor drug resistance
• Nanoparticles designed as multi-functional systems with tumor targeting ability, therapeutic and theranostic capabilities
• Waves of therapy as an engineered approach to treatment
The Mesoporous Silica Nanoparticle as amulti-functional platform for controlled delivery
CTABN
Me
Me
Me
Br -
Self assembly of surfactantDrug Thread
Si
OR
RO
OR
SiO
OR
OR
ORSi
RO OH
RO OR
Si
HO OR
RO OR
+TEOS
Liong, Lu, Tamanoi, Zink, et al. ACS Nano , 2, 889‐896 (2008)
Condensation of Si source
Removal of surfactant
Targetingepitope
ImagingProbe
Paramagnetic FeO
MotorizedBifunctional
valve
Stopper
4. Metal/Metal oxide core
1. Hydrophobic and hydrophilic drugs
Meng, et al., ACS NANO, 2010
3. Magnetically activated
Thomas, et al., JACS, 2010
5. Nanovalve
Fe3O4
AgGd2O3
Liong, et al., ACS NANO, 2008
Meng, et al., JACS, 2010
2. Surface functionalization
Xia, et al., ACS NANO, 2009Meng, et al., ACS NANO, 2011
(PEI/PEG)
5
Nano Cancer treatment
Liposomes
tumor
liver kidney
Systemic Drug Delivery Challenges and the need to adapt the Nano carrier design for therapeutic efficacy
of
do
se
50%
100%
First generation MSNP
Aglommeration
Liver/spleen/lung/kidney
4 hr
72 hr
10 days
Protein corona Opsonization
Pe
rce
nt
o
0
50%
RES Solid tumor
Rodent <1% retention
Material Design
Iterative ProcessFine Tuning
Using iterative control of the Nano/bio Interface to Develop new Cancer treatment
12% retention
Cellular Testing Animal testing
Fine TuningComputational modeling
Huan Meng et al ACS Nano 2011
<1% retention
Surface functionalization with PEG
Improved Biodistribution and enhancing tumor retentionthrough Size Tuning and Surface Functionalization
NP1
130 nmNaked surface
NP2
50 nmPEG-coated
NP3
50 nmPEG/PEI co-polymer
+
++
++
+
+
Meng et al, ACS Nano, 2011
6
Tumor
Liver
Heart
Lung
Spleen
Kidney
Brain
Serum
0
5
10
15
20
25
30
NP1 NP2 NP3
Na
no
pa
rtic
le d
istr
ibu
tio
n (
%)
*
Iterative Design to achieve a 12% EPR effectMeng, et al., ACS NANO, 2012
12%
Liver
Lung
Spleen
Tumor
Liver
Lung
Spleen
Tumor
Liver
Lung
Spleen
Tumor
NP1 NP2 NP3
Liver
Heart
Lung
MuscleSpleen
Kidney
Tumor
Brain
Saline
Additional Obstacles at the Cancer Site
Pericyte coverage in different cancer types
-Pancreatic cancer +++++-Colon cancer +-Ovarian cancer +-Prostate cancer ++-Glioblastomas ++-Breast cancer ++
first wave(TGFβi-
Trapped
Extravasated
Extravasated
Trapped
Pancreatic Cancer Exhibit a prominent Dysplastic Stroma:Introduction of an Engineered Rx Approach
Erkan et al. Nature Reviews
Wave 1: Stromal targeting(to enhance particle access)
Wave 2: Chemotherapy(gemcitabine)
. .
.
.
Huan MengMedicine/CNSI
Jeffrey ZinkChem & Biochem
Timothy DonahueSurgery
Andre NelNanomedicine
Choice of a MSNP to deliver the TGFβ inhibitor
0
20
40
60
80
(%,
w/w
)
500 500 500 500MSNP (μg)
(120 nm, +43 mV)
(121 nm,+40 mV)
(125 nm, +38 mV)
(130 nm, +30 mV)
Loading Capacity
PEG/PEI‐coated
H‐bond
TGFβi-MSNP LY364947
50 100 200 400TGFβi (μg)
Meng, et al., ACS NANO, 2013
7
10 nm
Second Wave NIR-labeled NP
Engineered Vascular Access using twoMSNP Waves
Before OpeningThe door
After OpeningThe door
Meng, et al., ACS NANO, 2013
Liver
Heart
Spleen
BrainKidney
Lung
Tumor
Liver
Heart
Spleen
Brain
Kidney
Lung
Tumor
MSNP alone (single-wave)
0
10
20
30
40
50
MS
NP
dis
trib
utio
n (
%)
Two-wave
60 h
*(>10 times)
Single-wave (red-liposome alone)
Two-wave (TGFi-MSNP + red-Liposome)
0.2 mm0.2 mm
2nd wave Liposome access to tumor tissue after 1st wave Rx
25x 25x
400x 400x
Meng, et al., ACS NANO, 2013
1200
1400
1600
1800
SalineFree LiposomeTGFβi-MSNP alone
(mg
)
1 7 14 21 28 35 Time (Days)
Tumorimplantation #1 #2 #3 #4 #5 #6
i.v. injection Animal sacrifice
Two wave Therapy becomes effective in a Xenograftafter 25 days
0
200
400
600
800
1000
1200
0 5 10 15 20 25 30 35
Free GEM
GEM-Lip
Two-wave (TGFβi-MSNP + GEM-Lip)
Tum
or
we
igh
t
Time (days)
* * *
Meng, et al., ACS NANO, 2013
Barcode AssayNew fMol and aMol Diagnostics
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• Image structure and function
• Whole body imaging
• Improved spatial and temporal resolution
• Capability to probe tumor microenvironment –information on tumor mass and its biochemical signatures
Th ti t t ll f t iti d
Imaging and Nanotechnology
• Theranostic constructs allow for tumor recognition and subsequent treatment – image-guided therapy
• Intra-operative techniques to monitor margins of surgically removed issue in real-time
SpectroPen
Spherical Nucleic Acids (SNAs)
Fluorescein
37 atoms
1 nm
13 nm Au NP~67,500 atoms
40-mer Oligo-Nucleotide 1400 atoms
Mirkin et al, Nature 1996 (382) 607-609
Red: ELISABlue: SNA Assay
DNA Sequencing Technology beyond the Sanger Chain termination being carried out by Capillary Electrophoresis
SiO2
The Gated Nanopore
Si
Si3N4
Requirements: Nanopore Nanogap electrode DNA transport physics Base pair discrimination
..to the $1000personal genome
Current Status of Nanopore DNA Sequencer
Status: Nanopore ☺ Nanogap electrode ☺ DNA transport physics ☺ Single base pair discrimination
☺
electrode
electrode
9
Pipeline for New Antibiotics Running empty: Antimicrobial Mechanisms of Nanomaterials
1) Semiconductor/photocatalytic production of ROS that damage cellular and viral components,
2) Compromising the bacterial cell wall/membrane, 3) Interruption of energy transduction4) inhibition of enzyme activity and DNA synthesis
Antimicrobial NP
Kang et al. Langmuir. 2008
SWNTs exhibit the strongest antimicrobial activityvia combination of membrane and oxidative stress,in three-steps:
Initial SWNT bacteria contactMembrane perturbationMembrane oxidation in an electronic structure (i.e., metallic vs. semiconducting)
dependent manner.
Biofilm formation and subsequent biofouling ofsurfaces may be sufficiently prevented bySWNTs
Targeted Intracellular Delivery of Anti‐Tuberculosis Drugs to Mycobacterium tuberculosis‐Infected Macrophages via Functionalized Mesoporous Silica Nanoparticles
RIF
NP‐RIF
Clemens. Antimicrob. Agents Chemother. 2012, 56(5):2535.
TEM images of A)MSNP, B) PEI‐coated MSNP and C) MSNP equipped with pH operated nanovalves.
Anti‐tuberculosis drug loaded MSNP are internalized efficiently by human macrophages infected with M. tuberculosis (A‐D)
PEI‐NP‐RIF
PEI coating on MSNP enhances the delivery of RIF to M. tuberculosis‐infected human macrophages.
10
CCL‐21
Use of Nanotechnology to boost Immune Responses and to make Vaccines
Immune modulation
NLRP3
Caspase‐1
Pro‐IL‐1βIL‐1β
AlOOHAlOOH NPNPShapesShapes
Alum CNTs
vaults
Lysososome
3D porousscaffold
NP antigen delivery to APC
modulation
Adjuvant effects
Cathepsin B
100 nm
Rod 1 Rod 2 Rod 5
Plate Polyhedron Alum
50 nm 50 nm 50 nm
100 nm 100 nm100 nm
AlOOHAlOOH NPShapesNPShapes
γ-AlOOHNanocrystals
Al(OH)3
Nuclei
OOO
Developing a new AlumAdjuvant by Shape & Crystallinity Engineering
Bingbing Sun, Ivy Ji, Tian Xia
IgG1
IgE
IFNγ
TH2 cell
TH1 cell
ILIL--11ββProPro--ILIL--11ββ
T cell
LysosomeLysosome
ROSROS
ShapeShape--dependant Adjuvant dependant Adjuvant effects and stimulationeffects and stimulationof adaptive immune of adaptive immune responseresponse
NLRP3NLRP3InflammasomeInflammasome
CathepsinCathepsin BB
O OH H H H HH
γ-AlOOHNanorods γ-AlOOH
Nanoplates
BasicAcidic
H bonds destroyed
H bonds retained
γ-AlOOHNanopolyhedra
A Nano-Immunotherapy Strategy for Cancer: 3D Porous Scaffolds
EXAMPLE: PLG loaded with GM‐CSF, and decorated with condensed CpG. Melanoma tumor lysate was utilized as the cancer antigen.
GMCSF recruited DCs to the scaffold, DCs were activated by CpG, they processed the tumor antigen. Activated DCs homed to the draining lymph nodes (dLNs) and primed naive T cells.
This vaccine induced 90% prophylactic tumor protection and generated complete regression of established melanoma in a fraction of the animals.
Current Opinion in Immunology: from Ali et al. Nat. Mater 2009, 8:151-158.
DC
Regenerative Medicine: Cell Sheet Engineering for Patch-repair and reconstruction of damaged organs
Poly(N-isopropylacrylamide)
20°C 37°C
Masuda et al. Adv Drug Deliv Reviews 60 (2008) 277–285
Teruo Okano, Ph.D.Director and ProfessorInst. Adv. Biomed. Eng. & Sci.Tokyo Women’s Medical University
11
A Cell Sheet of Primary Cardiac Myocytes…the beat goes on
Courtesy Teruo Okano, Ph.D.
Stacking Cardiomyocyte Sheets creates a Contractile Tissue
Courtesy Teruo Okano, Ph.D.
Stacking Cardiomyocyte Sheets creates a Contractile Tissue
Courtesy Teruo Okano, Ph.D.
Patching a dyskinetic myocardial wall
Courtesy Teruo Okano, Ph.D.
12
Promises of Nanomedicine
Cu
rre
nt
ScreeningDiagnosis& Staging
Treatment& Monitoring
• Relative low sensitivity
• Macroscale imagingof organs and regions
• Established disease
• Macroscale imaging
• Invasive approaches, e.g., surgery/biopsy
• Batch testing
• Individual biomarkers
• Surgery
• Radiation
• Debilitating chemo
• Total body effects
Na
no
Imp
ac
t
• Targeted drug delivery
• On-demand drug delivery
• Imaged drug delivery
• Image structure & function
• Whole body/Non-invasive
• Multiple biomarkerslab-on- a-chip
• Million fold ↑ in sensitivity
• Whole body imaging
• Disease inception
Nanotechnology Long-term Impacts and Research Directions: 2000 – 2020
Business
Technology
Engineering
Bio-medicinePhysicsChemistry
NanoMedicine
Technology
Business
Acknowledgements
Nel Laboratory:Andre NelSaji GeorgeHuan MengXiang WangNing LiHaiyun Zhang
Collaborators:Tian XiaLutz MaedlerSuman PohkrelJeff ZinkIvy Ji
Haiyun ZhangSijie LinRuibin LiMeiying WangYu-Pei Liao
Grant support: NIEHS-funded U19 and RO-1NSF- and EPA-funded CEIN
Hilary GodwinRobert DamoiseauxYoram CohenRon LuiRober Rallo
CEIN MEMBERS
