biomedical applications of nanotechnology || color plates

Color-plate JWBK002-Labhasetwar June 24, 2007 17:39 Char Count=

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nucleus

plasma membrane

coated pit

endosome

endosome

coated pit

nuclear membrane

A

B

C

H+

H+

Figure 2.1. Viral entry into cells, schematic overview. Viruses bind to cell surfaces via

receptor–ligand interactions. Many virus species are taken up into cells by endocytosis, like

adenovirus (A) or membrane-coated viruses such as influenza virus (C). Other membrane-

coated viruses such as retroviruses (B) directly fuse their membranes with the plasma mem-

brane. Endocytosis proceeds via segregation of membrane-surrounded vesicles (endosomes)

from the plasma membrane. A proton pump in the endosomal membrane mediates the acid-

ification of the endosomal lumen. This pH change triggers conformational rearrangements

of viral proteins, which then by interaction with the endosomal membrane can lead to the

disruption of endosomes (like in the case of adenoviruses) or to the fusion of endosomal and

viral membranes (like in the case of influenza virus). These membrane disruption/fusion events

are essential parts of viral entry into cells, which ultimately leads to uptake/transport of viral

genetic information into the cell nucleus.

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application

receptor binding

nuclear transport biocompatibility

endocytosis endosome lysis

DNA compaction

Figure 2.2. Nonviral vectors for nucleic acid delivery (sometimes called artificial viruses) are

prepared by self-assembly of synthetic modules that mimic essential viral functions that allow

them to infect cells. The self-assembly process is mostly based on noncovalent interactions of

the individual modules such as electrostatic and hydrophobic interactions. The most important

interaction is the one between the nucleic acid and a polycation or a cationic lipid, which can

lead to the formation of a charged nanoparticle that is able to transfect cells. The functionali-

ties of receptor binding, membrane destabilization (such as endosome lysis), nuclear targeting,

and biocompatibility can be covalently coupled to a DNA binding/compacting moiety or can be

incorporated into the complex as individual molecules by noncovalent interactions. The center

of the figure shows toroidal nanoparticles that are typically formed upon mixing of plasmid

DNA and polycations.

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Organ

Cell

DNA

Tablet

Microspheres

Dendrimer

Figure 5.1. Progress of drug delivery from “macro” systems that interact at the organ level

to “micro” systems that interact at the cellular level to “nano” systems that interact at the

cellular level. Length scale has a significant influence on drug delivery in terms of reaching the

target site, modifying the biodistribution of the drug, and enhancing the efficacy of the drug.

(a) (b)

(c) (d)

Figure 5.6. Confocal images showing lung epithelial cells. (a) Under phase contrast. (b) Local-

ization of FITC-labeled PAMAM G4 hydroxyl terminated dendrimer in the cytoplasm. (c) Local-

ization of lysosomal marker (lysotracker) in the lysosomes. (d) Co-localization of FITC-labeled

dendrimer and lysostracker in the lysosomes. Images were captured 30 min after treatment.

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00

200 400

FL1-H

(a)

(b)

Cou

nts

600 800 1000

500

400

300

200

100

Figure 5.7. (a) Flow cytometry analysis of lung epithelial cells treated with FITC-labeled

ibuprofen–PAMAM G4 OH dendrimer conjugate at different time points. The shift in intra-

cellular fluorescence intensity indicates the rapid cellular uptake of the conjugate. Key: Red,

0 min; green, 5 min; black, 30 min; blue, 60 min; brown, 240 min (b) Confocal image showing

the localization of FITC-labeled ibuprofen–dendrimer conjugate in the cytoplasm after 2 hr of

treatment.

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Figure 6.5. Poly(ethyleneimine) cross-linked poly(ethylene oxide) nanogel. (Reproduced

with permission from Ref. 71, Figure 6.1. Copyright 2005, Elsevier Ltd.)

Figure 6.9. Y-shaped copolymer self-assembly to give micelle structures. (Reproduced with

permission from Ref. 113, Figure 6.8. Copyright 2006, John Wiley & Sons, Inc.)

Figure 6.10. Internal structural variation in micelle gels. (Reproduced with permission from

Ref. 117, Figure 6.1. Copyright 2001, Elsevier, Ltd.)

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Figure 6.11. Schematic representation of CHP nanogel preparation by physical cross-linking

(self-assembly). (Reproduced with permission from Ref. 128, Figure 6.1. Copyright 2004,

Elsevier, Ltd.)

(a)

(b)

Figure 6.14. Classical emulsion polymerization technique for nanogel preparation.

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High polymer concentration and low

dose

(a)

Low polymer concentration and high

dose

(b)

Figure 6.16. Radiation mechanism for (a) bulk/micro gel and (b) nanogel formation. (Repro-

duced with permission from Ref. 203, Figure 6.2. Copyright 2003, American Chemical Society.)

with nanocageswithout nanocages

320

OC

T s

igna

l (a.

u.)

340Depth (µm)

360 380

0.9

0.8

0.7

0.6

0.5

0.4

0.3

(a) (b)

Figure 7.3. (a) OCT image of a gelatin phantom embedded with TiO2, and the concentration

of TiO2 was controlled at 1 mg/mL to nimic the background scattering of soft tissues. The right

portion of the phantom contained 1 nM of gold nanocages while the left portion did not

contain any gold nanocages. (b) Plots of the OCT signals on a log scale as a function of depth.

Note that the OCT signal recorded from the portion of phantom with gold nanocages decays

faster than the portion without nanocages. (Reprinted with permission from Nano Lett. 5 (3),

473–477, 2005. Copyright c© 2006 American Chemical Society.)

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Figure 7.5. (a) Schematic illustration of tumor targeting and surface attachment of nanopar-

ticles. (b) Gold nanoparticles mediated tumor therapeutic modalities.

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