Biomedical Engineering Reference
In-Depth Information
Fig. 9
Possible mechanisms for the role of ultrasound in enhanced drug delivery (reproduced from
Pitt et al.
2004
with permission). (
a
) therapeutic agent (triangles); (
b
) gas bubble undergoing stable
cavitation; (
c
) microstreaming around cavitating bubble; (
d
) collapse cavitation emitting a shock
wave; (
e
) asymmetrical bubble collapse producing a liquid jet that pierces the endothelial lining;
(
f
) completely pierced and ruptured cell; (
g
) non-ruptured cells with increased membrane perme-
ability due to insonation; (
h
) cell with damaged membrane from microstreaming or shock wave;
(
i
) extravascular tissue; (
j
) thin-walled microbubble decorated with agent on surface; (
k
) thick-
walled microbubble with agent in lipophilic phase; (
l
) micelle with agent in lipophilic phase;
(
m
) Nanocarriers with therapeutic agent; (
n
) vesicle decorated with targeting moieties
Wang and Huang
1984
; Lee et al.
2003b
; Gao et al.
2005c
) (Fig.
10
). The second
strategy involves formation of an acid labile linkage between the therapeutic agent
and the micelle forming copolymer, which leads to the pH dependant cleavage of
drug from micellar nano-conjugates at the pH of tumor extracellular or endosomal
environment (Yoo et al.
2002
; Bae et al.
2003b
; Gillies and Frechet
2003
; Gillies
et al.
2004
; Gao et al.
2005a
; Han et al.
2003
).
Thermoresponsive polymeric micelles
- Local hyperthermia is receiving increasing
attention as a tool to promote selective delivery of drugs to solid tumors (Crile
1962
).
Many normal mammalian cells start to damage at about 42°C. Therefore the aim of
thermoresponsive drug delivery is to achieve therapeutic effect just a few degrees
above physiological temperature (van der Zee
2002
). The architecture of vasculature
in solid tumors is chaotic resulting in regions with hypoxic and low pH which are not
found in normal tissue. These environmental factors make the tumor cells more sensi-
tive to hyperthermia (Huang et al.
1978
; Yatvin et al.
1978
; Takei et al.
1995
; Okano
et al.
1993, 1995
). Local hyperthermia might cause preferential drug uptake by the
tumor cells through: (i) promoting local drug release at higher temperatures,
(ii) increasing the local blood flow; (iii) increasing endothelial permeability pro-
moting enhanced accumulation of colloidal carrier, (iv) increasing the permeability or
susceptibility of target cells to the released drug, and (v) increasing the cellular inter-
action and uptake of the colloidal carrier (Hales et al.
2004
; Takei et al.
1993
).
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