Nanoparticles for Nanomedicine

Neil S. Forbes

Nanotechnology Institute

University of Massachusetts, Amherst

July 24, 2009

University of MassachusettsChemical Engineering

Targeted Delivery to Tumors

Many Different Length Scales

10cm

1cm

100m

1m

Relative Size of Nanoparticles

Nanoparticle with a 2 nm core and an octanethiol functionalized monolayer

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

Fluorophores and Drugs Selectively Dissociate Inside Cells

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

Investigating Delivery Using Cylindroids

100 mPlug

WellPlate

MicroscopeObjective

Cylindroid

Viable

Dead

Nanoparticles in Cylindroids

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

Modeling Particle Diffusion

Predicting Behavior in Tumors

Delivery of Doxorubicin

How Does Particle Charge Affect Tissue Penetration?

Transcellular

Paracellular

Cells

A

B

Engineering Approach: Targeted Intratumoral Therapy

• Quantify tumor microenvironments

• Develop vectors to target tumor quiescence

NecroticQuiescentProliferating

Therapeutic

Microenvironments in CylindroidsV

iabi

lity

A

crid

ine

Ora

nge

Scale bar is 100 µm Kasinskas, Forbes. 2006. Biotech Bioeng, 94:710

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)

Bacteria are Tiny Robot Factories

• Target specific molecular signals

• Can controllably produce therapeutics

Bacterial Accumulation in Cylindroids

100 m

P Q N

Plug

WellPlate

MicroscopeObjective

Cylindroid

96-well plate

Culture Media

Polycarbonate Lid

Cylindroids mimic tumor microenvironments

Control of Cytotoxicity

1. Inject modified bacteria

2. Induce peptide with radiation

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

Effect of Double Dose

• Delayed growth 30.3 days

• 30-day survival increased from 0% to 100%

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

Cells

A

B C