Smart Dust: Nanostructured microcarriers for drug delivery

Michael J. Sailor, Ph.D. Professor, UCSD Department of Chemistry and Biochemistry msailor@ucsd.edu William R. Freeman, M.D., Ph.D. Professor, UCSD Department of Ophthalmology Lingyun Cheng, M.D. Assistant Project Scientist, UCSD Department of Ophthalmology Erkki Ruoslahti, M.D., Ph.D., The Burnham Institute Sangeeta N. Bhatia, M.D., Ph.D. Associate Professor, MIT Department of Bioengineering

2 technologies for controlled drug delivery to the eye

Unidirectional episcleral plaques use a nanostructured template to prepare a polymeric material that can be sewn onto the back of the eye. The plaque has a designed nanostructure that can be used to control the rate of release of the drug. PLA

porous Si master

composite nanotemplated polymer

nanoporous membrane backing

eye interior

sclera reservoir

Encoded microparticles use a nanoporous Si or SiO2 material. Methods to load, seal, and trigger release of small molecule, peptide, or protein-based drugs have been developed.

Above: Photonic color code changes when particle releases payload. Right: Porous Si microparticles in the rabbit eye.

Smart Dust photonic crystal particles

Michael J. Sailor, UCSD Design a mother ship nanostructure to carry and release a cargo or perform a diagnostic test Build a code Load a drug Target the nanostructure to a desired location Monitor the nanostructure in-vivo

Smart Dust

Ophthalmoscope image of porous Si photonic crystals (green color) in the intravitreal region of the rabbit eye. These particles are the size of the diameter of a human hair. Courtesy William R. Freeman, M.D. and Lingyun Cheng, M.D., Shiley Eye Center, University of California, San Diego

Porous Silicon Synthesis

H 2Si + 6 HF + 2 h+ Si + H2SiF6 + 2H+ + 1/2 H2

Porous Si Surface
Electronmicroscope imageofporousSi. SideviewofporousSi electrochemically etchedintoasingle crystalSiwafer.

20 m

Background: Properties of Porous Silicon; Canham, L., Ed.; EMIS Datareviews, INSPEC: London, 1997; Vol. 18.

Pore size is controlled electrochemically

Depends on: Current density HF concentration Electrolyte composition (usually ethanol, but other organic solvents have been used) Dopant type, and dopant concentration Current Density for samples at right: (A) 1.5 x 1.5 mm, 150 mA/cm2 (B) 5 x 5 mm, 295 mA/cm2 (C) 5 x 5 mm2, 370 mA/cm2 (D) 5 x 5 mm2, 440 mA/cm2 (E) 5 x 5 mm, 515 mA/cm2 (F) 5 x 5 mm2, 600 mA/cm2

Range of Accessible Pore Sizes

P o r o u s S ilic o n P o r B e i S l i oz ge i c a l o
R e d b lo o d c

M
e lls

le c u

1 0 0 0

n m

it o

h o

n d

ria

1 0 0

n m
H u m a n s e ru m a lb u m in

Photonic Crystals-color from a nanostructure

Calloodes grayanus Porous Si multilayer

2 mm

1 m

PARKER, A. R., et.al., J. Exper. Biol. 1998 201, 13071313.

Modulation of pore dimensions using current modulation

H 2Si + 6 HF + 2 h+ Si + H2SiF6 + 2H+ + 1/2 H2

Pt HF/Ethanol

Porous Si Surface

Porosity

Current Silicon Time

8

AC

Background: Lehmann, V. Electrochemistry of Silicon (Wiley-VCH, Weinheim, Germany, 2002).

Encoding strategy

Berger, M. G.,et al., Thin Sol. Films 1997, 297, 237-240 Meade, S. O.;et al. Adv. Mater. 2004, 16, 1811-1814.

Complicated codes can be placed on a particle

Adv. Mater. 2004, 16, 1811-1814. 10

Microdroplet patterning
to produce a composite photonic crystal
e t c h s i l i c o n p o r o u s S i pt ha ol tr o n iy c c s N( a a Oq H) s p r a y p o lr y m e 2 5 0 C 3 0 m i n

Reflected intensity (rel)

5 hr 4 hr 3 hr 2 hr 1 hr bare with polymer 0 hr 400 500

Can encapsulate drugs, attach targeting moieties

Wavelength (nm)

600

700

800

900

1000

Li, Y. Y.; Kollengode, V. S.; Sailor, M. J. Adv. Mater. 2005, in press.

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Opening pores to load a drug

Dexamethasone HF/DMSO 30 min

Langmuir 2004, 20, 11264-11269. 12

Chemistry can change rate of release of dexamethasone from porous Si

120 100

% Drug Released

Fresh 80 60 40 Hydrosilylated 20 0

H-terminated material completely releases dexamethasone after 2 hours, corresponding to complete dissolution of the porous Si layer. After 7 hours only 5060% of the drug is released from the more stable hydrosilylated material. After an initial 2-hour burst, these hydrosilylated samples steadily released drug for a 8 period of 3 days.

Time (hours)
Langmuir 2004, 20, 11264-11269. 13

Polymer imprints from 1-D photonic crystals

In situ polymer.

hydrolysis

Electropolished PSi

Polymer-PSi Composite

Polymer-based Photonic film

Etching conditions : p++ Type Si wafer, HF:EtOH = 3:1 solution 100 mA/1.3 cm2 ~ 250 mA/1.3 cm2 2 sec intervals; 50 repeats Electropolishing conditions: HF:EtOH = 1:14 solution 22 mA/1.3 cm2 2 min
Li, Y. Y. et al. Science 299, 2045-2047 (2003).
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Flexible 1-D photonic crystals

S i R in n g O p e i n g M e t a t h e s i s P o la y m e r i z t i o n S i C o m p o s i t e

P o r o u s S i

T e m p l a t e

Relative Intensity

Composite

Fresh Porous Si

400

500

Porous Si/polynorbornene composite film held between two pairs of tweezers, showing the mechanical stability of the materials

600 700 800 Wavelength (nm)

900

1000

Yoon, et. al. Chem. Commun. 2003, 680-68.

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Monitoring drug delivery with a biocompatible polymeric photonic crystal

1700 0.06

Caffeine absorbance in solution

Relative rugate peak intensity

1600

0.05

1500

0.04

1400

0.03

1300

0.02

1200

0.01

1100 10 100

0 1000

Time, min

Measurement of degradation of polylactide rugate peak as a surrogate for the delivery of caffeine (pH=10, aqueous) Li, et. al. Science, 2003 (299) 2045-2047.

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Chemical Sensing with a Si Photonic Crystal

S i R R S i

+ A
S i R R S i
40 40 50 50 60 60 70 70 80 0 5 0 5 0 5 0 5 0

Wnn a gm v t( ) eh l e

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Targeted Microcarriers

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Self-orienting, self-targeting smart dust particles

hydrophobic

1-dodecene

Etch Silicon

Hydrosilylate Porous Si Mirror Modified Porous Si Etch

hydrophobic

Sonicate
hydrophilic

Release, oxidize Double Mirror

Smart Dust

Freestanding Porous Si

J.R. Link and M.J. Sailor, Proc. Nat. Acad. Sci. 2003, 100, 10607-10610.

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Encoded particles self-assemble on a target

alkylated
Hydrophobic Hydrophilic

oxidized

Proc. Nat. Acad. Sci. 2003, 100, 10607-10610.

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Superparamagnetic Smart Dust

altd lye k a 1de -oce den E th c so ii n lc pui os r S o ptn rs h i c tl o cy o a 1 2C 0 meosi oidru dp S i o f E th c Ifs e ne uF mt ae gi nc ahii mh p lc i p pils ae rc t
3 4

Rs ee la e Sa ot ne i c 2d -ie sd ptn rs h i c tl o cy o a

Dorvee, J. R.; Derfus, A. M.; Bhatia, S. N.; Sailor, M. J. Nature Mater. 2004, 3, 896-899.

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Spectral barcodes: Reflected Intensity (rel)

Smart dust chaperones

for liquid droplets

AgI

(s)

+ Ag (aq) I (aq)
600 700 800 Wavelength, nm 900
Nature Mater. 2004, 3, 896-899. 22

500

Summary
Porous photonic crystals with optical barcodes can be made that allow invivo monitoring Chemistry and electrochemistry allow control of loading, degradation, and release rates Porous materials can be used as templates to produce biomaterials with controlled pore size, porosity, and optical properties Preliminary animal studies show no irritation, toxic effects Targeting can be achieved by incorporation of magnetic domains or homing molecules

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