Biomedical Engineering Reference
In-Depth Information
O
O
O
N
N
O
O
O
O
HN
OH
O
O
-T FA+ H
3
N
O
2)
DIEA, THF, reflux
H
2
SO
4
/HNO
3
3/1 (v/v
)
sonication
1) oxalyl chloride, reflux
O
O
NH
O
O
OH
OH
HO
O
HN
N
O
O
OH
OH
OH
OH
O
OH
HO
O
O
O
O
O
O
OH
NH
2
O
O
H
O
O
O
N
H
O
O
N
N
N
OH
1) HCL/dioxane
2) Fmoc-AmB, EDC/HOBt/DIEA
3) piperidine/DMF (1/3)
1) N
2
H
4
,ethanol,reflux
2) FITC, DMF
O
NH
O
NH
O
NH
S
S
O
O
O
O
HN
N
H
O
N
H
O
N
O
O
HN
HO
2
C
HO
2
C
O
OH
O
O
OH
O
Scheme 2.6
AmB-FITC-functionalised carbon nanotubes.
In the study with AmB-functionalised CNTs it was demonstrated that the
free drug at a dose of 10
μ
g/mL, which corresponds to the amount of the
drug covalently bound to 40
μ
g/mL
of MWCNTs, determined more than 40%
of cell death, while all cells remained alive following the treatment with the
AmB-CNT conjugate. Very interestingly, once linked to the nanotubes, AmB
preserved its high antifungal activity. To verify this characteristic, different
types of pathogens comprising
Candida albicans
,
Candida paropsilosis
and
Cryptococcus neoformans
were treated with AmB-CNT conjugates, and the
results were in some cases superior than those obtained using the drug
alone. Although the reason for such improvement in activity are still unclear,
it might be that the increase in the solubility of the drug, together with its
favourable multi-presentation to the fungal membrane by CNTs, determined
the enhancement of its therapeutic effect by decreasing mammalian toxicity
and increasing antifungal activity (Scheme 2.7).
In addition, it was also observed that AmB-CNT conjugates were
rapidly internalised into mammalian (Jurkat) cells in a dose-dependent
manner and with a mechanism that excluded endocytosis. About this
aspect, there are two versions regarding the uptake mechanism. The irst
corresponds to nanopenetration, passive insertion/diffusion experimentally
demonstrated by several groups,
49,50,87,126
-
128
while the second is based on
a phagocytosis/endocytosis internalisation processes proposed by other
researchers.
53,68,79,129,130
The great divergence seems to be attributable to
signiicant differences both in the nanotube materials and in the type of
functionalisation.
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