Microfluidic Synthesis of Polymeric Microfluidic Synthesis of Polymeric NanoparticlesNanoparticles

Rohit KarnikDepartment of Mechanical Engineering

Massachusetts Institute of Technology

October 25, 2007

AcknowledgementsAcknowledgements

• Frank Gu, Pamela Basto, Chris Cannizzaro, Suman Bose, Eliza Vasile

• Omid Farokhzad• Robert Langer

• MTL staff• NIH

Targeted polymeric nanoparticlesTargeted polymeric nanoparticles

• Versatile carriers

• Targeting capability

• FDA approved

polymers

• Controlled release

• Tunable properties

PLGA PEG+

NH2

Add to water

+

EDC/NHS

Drug Nanoprecipitation

Aptamer

Nanoparticle

Targetednanoparticle

Nanoparticle

Farokhzad, et al. PNAS (2006)

ChallengesChallenges

• Uptake by organs such as liver and spleen• Optimization required

– Size– Surface characteristics– Charge– Targeting moieties

• Batch-to-batch variation• Polydispersity

Single step nanoparticle synthesisSingle step nanoparticle synthesis

Single step synthesis

Precursor composition nanoparticle properties

PLGA PEG+

NH2PLGA PEG APT

Controlled precipitation

Purification High ThroughputScreening

Combinatorial Synthesis

Precipitate nanoparticlesby dilution in water

Mix in selected ratio

Synthesis of 100 types ofnanoparticles per minute

Dru

g

COOH NH

PE

GP

LG

A

Aptamer

…COOH NH 2

PE

GP

LG

A

Aptamer

…+ + + +

COOH NH 2

PE

GP

LG

A

Aptamer

…PE

GP

LG

A

Aptamer

…PE

GP

LG

A

Aptamer

…+ + + +

Precipitate nanoparticlesby dilution in water

Mix in selected ratio

Synthesis of 100 types ofnanoparticles per minute

Dru

g

COOH NH

PE

GP

LG

A

Aptamer

…COOH NH

PE

GP

LG

A

Aptamer

…PE

GP

LG

A

Aptamer

…PE

GP

LG

A

Aptamer

…+ + + +

Precipitate nanoparticlesby dilution in water

Mix in selected ratio

Synthesis of 100 types ofnanoparticles per minute

Dru

g

COOH NH

PE

GP

LG

A

Aptamer

…COOH NH

PE

GP

LG

A

Aptamer

…PE

GP

LG

A

Aptamer

…PE

GP

LG

A

Aptamer

…+ + + +

Mix

Inlet streams

Mixedstream

Mix

Inlet streams

Mixedstream

Advantages of microfluidic synthesisAdvantages of microfluidic synthesis

w wfPolymericsolution

Water

Water

Formation of nanoparticlesby nanoprecipitation

Nanoparticles out Rapid mixing and homogenization

Controlled nanoprecipitation

Combinatorial synthesis

Screening and optimization

Other advantages

On-chip purification, scale up

Mixing by hydrodynamic flow focusingMixing by hydrodynamic flow focusing

22 48

1)( yw

dx

dPyu

wwf

PLGA-PEG in acetonitrile

Water

Water

Formation of nanoparticlesby nanoprecipitation

Nanoparticles out

Rw

w f

13

2

2

22

1

1

94~

RD

w

D

w fmix

Approximate flow profile

Width of focused stream

Mixing timescale

Typical timescale~ 0.5 to 5 ms

Effect of mixing timeEffect of mixing time

Nucleation Growth by insertion and aggregation

Barrier to insertion

Johnson and Prud’homme PRL 2003

Effect of mixing timeEffect of mixing time

Johnson and Prud’homme PRL 2003agg

mixpDa

Nanoprecipitation by flow focusingNanoprecipitation by flow focusing

Syringe pump to control flow rate

Device

Nanoparticles

Nanoprecipitation by flow focusingNanoprecipitation by flow focusing

TEM Image- Eliza Vasile

Effect of flow ratio on nanoparticle sizeEffect of flow ratio on nanoparticle size

2

22

1

1

94~

RD

w

D

w fmix

(1/R)

mix~0.04 ms mix~0.4 ms

mix~3000 ms

Effect of flow ratio on nanoparticle Effect of flow ratio on nanoparticle polydispersitypolydispersity

0

5

10

15

20

25

0 20 40 60 80 100

Size (nm)

Vo

lum

e %

Flow ratio 0.03

Flow ratio 0.1

Bulk mixingFaster mixing

Sensitivity of polymer composition to Sensitivity of polymer composition to mixing timemixing time

Effect of mixing time and polymer Effect of mixing time and polymer composition on drug loadingcomposition on drug loading

0

5

10

15

20

Chip w/o PLGA Bulk w/o PLGA Chip w/PLGA Bulk w/PLGA

Dru

g lo

adin

g (

Mas

s %

)

Future WorkFuture Work• Characterize effects of mixing time and precursor composition• Design automated system for controlled combinatorial synthesis

and screening

Thank you!Thank you!