nanoparticles for nanomedicine neil s. forbes nanotechnology institute university of massachusetts,...
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![Page 1: Nanoparticles for Nanomedicine Neil S. Forbes Nanotechnology Institute University of Massachusetts, Amherst July 24, 2009 University of Massachusetts Chemical](https://reader035.vdocuments.net/reader035/viewer/2022062618/551487e9550346b0158b5b77/html5/thumbnails/1.jpg)
Nanoparticles for Nanomedicine
Neil S. Forbes
Nanotechnology Institute
University of Massachusetts, Amherst
July 24, 2009
University of MassachusettsChemical Engineering
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Targeted Delivery to Tumors
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Many Different Length Scales
10cm
1cm
100m
1m
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Relative Size of Nanoparticles
Nanoparticle with a 2 nm core and an octanethiol functionalized monolayer
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Making Gold Nanoparticles
HAuCl4NaBH4
HS
S
S
S
SS
SSSSSS
SS SS
S
HS
HS
S
S
S
SS
SSSSSS
SS SS
S
HSS
S
S
SS
SSSSSS
SS SS
S
HSHS
• AuCl4- salts are reduced using NaBH4 in the presence of thiol capping ligands
• The core size of the particles formed can be varied from <1 nm to ~ 8 nm
• The surface functionality can be controlled through the choice of thiols
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Fluorophores and Drugs Selectively Dissociate Inside Cells
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Control of Surface Charge
Au SFITC
S
COO-
S
NMe3+
3
3
3O
~1 nm
2~5 nm
OC9
C9
C9
O
DrugorAu S
FITC
S
COO-
S
NMe3+
3
3
3O
~1 nm
2~5 nm
OC9
C9
C9
O
Drugor
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Investigating Delivery Using Cylindroids
100 mPlug
WellPlate
MicroscopeObjective
Cylindroid
Viable
Dead
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Nanoparticles in Cylindroids
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Nanoparticle Diffusion
0
10
20
30
40
50
FITC Positive Negative
D x
10^
7 (c
m2/
sec)
4hrs
24hrs
dc
a
x
y
b
D×
107 cm
2 /se
c
0
0.2
0.4
0.6
0.8
1
0 2000 4000 6000
µm
Nor
mal
ized
Int
ensi
ty
6hrs12hrs18hrs24hrs
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Modeling Particle Diffusion
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Predicting Behavior in Tumors
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Delivery of Doxorubicin
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How Does Particle Charge Affect Tissue Penetration?
Transcellular
Paracellular
Cells
A
B
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Engineering Approach: Targeted Intratumoral Therapy
• Quantify tumor microenvironments
• Develop vectors to target tumor quiescence
NecroticQuiescentProliferating
Therapeutic
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Microenvironments in CylindroidsV
iabi
lity
A
crid
ine
Ora
nge
Scale bar is 100 µm Kasinskas, Forbes. 2006. Biotech Bioeng, 94:710
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Bacteria Accumulate in Mouse Tumors
0
1
10
100
1,000
10,000
100,000
1,000,000
Tumor Liver Spleen Lungs Heart SkinAcc
umul
atio
n (C
FU
/mg)
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Bacteria are Tiny Robot Factories
• Target specific molecular signals
• Can controllably produce therapeutics
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Bacterial Accumulation in Cylindroids
100 m
P Q N
Plug
WellPlate
MicroscopeObjective
Cylindroid
96-well plate
Culture Media
Polycarbonate Lid
Cylindroids mimic tumor microenvironments
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Control of Cytotoxicity
1. Inject modified bacteria
2. Induce peptide with radiation
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Tumor Growth and Mouse SurvivalPBS
Control Bacteria
Cytotoxic Bacteria
PBS + 2Gy
Control Bacteria + 2Gy
Cytotoxic Bacteria + 2Gy
Cytotoxic Bacteria
Control Bacteria
PBS
Bacteria + RadiationControl + 2Gy
PBS + 2Gy
Median survival doubles from 14.0 to 26.0 days
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Effect of Double Dose
• Delayed growth 30.3 days
• 30-day survival increased from 0% to 100%
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Acknowledgements
Graduate StudentsAdam St. JeanCharley SwoffordBhushan ToleyRaja VenkatasubramanianMiaomin Zhang
Undergraduate StudentsBrett BabinJason LeeMarissa McGarry
AlumniDr. Sabha Ganai, MD PhD
Surgical Oncology, Baystate Medical Center
Dr. Rachel Kasinskas, PhDDr. Byoung-jin Kim, PhDColin Walsh
Collaborators Michael A Henson, PhDRichard B Arenas, MDVincent M Rotello, PhD
FundingNIH, NSFSusan G. Komen For the CureUMass Center for Biomedical ResearchRays of Hope, Springfield, MA
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Cells
A
B C