microfluidic synthesis of polymeric nanoparticles rohit karnik department of mechanical engineering...
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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
Nanoprecipitation by flow focusingNanoprecipitation by flow focusing
Syringe pump to control flow rate
Device
Nanoparticles
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
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