Transcript Targeting Tumors: Metabolic Flux Analysis and

Nanoparticles for Nanomedicine
Neil S. Forbes
Nanotechnology Institute
University of Massachusetts, Amherst
July 26, 2007
University of Massachusetts
Chemical Engineering
Targeted Delivery to Tumors
Many Different Length Scales
10cm
100mm
1cm
1mm
Relative Size of Nanoparticles
Nanoparticle with a 2 nm
core and an octanethiol
functionalized monolayer
Making Gold Nanoparticles
HAuCl4
HS
Na BH4
S S SS
S
S
S
S
S
S
S
S
SS
S S
HS
S S SS
S
S
S
S
S
S
S
S
SS
SS
HS
S S SS
S
S
S
S
S
S
S
S
SS
SS
HS
HS
HS
• 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
Fluorophores and Drugs Selectively
Dissociate Inside Cells
Control of Surface Charge
Investigating Delivery Using
Cylindroids
Plug
100 mm
Cylindroid
Well
Plate
Microscope
Objective
Viable
Dead
Nanoparticles in Cylindroids
How Does Particle Charge Affect Tissue
Penetration?
A
Paracellular
Transcellular
B
Cells
Engineering Approach:
Targeted Intratumoral Therapy
Necrotic
Quiescent
Proliferating
Therapeutic
•
Quantify tumor
microenvironments
•
Develop vectors to
target tumor
quiescence
Bacterial Penetration into
Cylindroids
100 mm
Acridine
Orange
Viability
Microenvironments in Cylindroids
Scale bar is 100 µm
Kasinskas, Forbes. 2006. Biotech Bioeng, 94:710
Accumulation (CFU/mg)
Bacteria Accumulate in Mouse
Tumors
1,000,000
100,000
10,000
1,000
100
10
1
0
Tumo r
Liver
Spleen
Lungs
Heart
Skin
Control of Cytotoxicity
1. Inject modified
bacteria
2. Induce peptide
with radiation
Tumor Growth and Mouse Survival
PBS
PBS + 2Gy
Control
Bacteria
Control
Bacteria + 2Gy
Cytotoxic
Bacteria
Cytotoxic
Bacteria + 2Gy
Cytotoxic
Bacteria
Control
Bacteria
PBS
Median
survival
doubles from
14.0 to 26.0
days
Bacteria +
Radiation
Control + 2Gy
PBS + 2Gy
A
B
C
Cells