Biomedical Engineering Reference
In-Depth Information
(macrophages and dendritic cells) (Peek et al.
2008
). This approach can be applied
to both protein antigens (van Broekhoven et al.
2004
) and DNA vaccines
(Greenland and Letvin
2007
).
A number of microorganisms - bacteria, viruses and parasites - are able to live
within macrophages. Colloidal drug carriers loaded with antibiotic drugs can be
used to reach these infections (Pinto-Alphandary et al.
2000
). Poly (isohexylcyano-
acrylate) nanospheres loaded with Ampicillin allowed a large increase in efficacy
compared with free antibiotic in mice infected with
Salmonella typhimurium
and
Listeria monocytogenes
(Fattal et al.
1989
; Youssef et al.
1988
). Studies using elec-
tron microscopy and confocal fluorescence microscopy with labeled
S. typhimurium
and nanospheres revealed the carrier system and the bacteria in the same intracellular
compartment (Pinto-Alphandary et al.
1994
).
A fluoroquinolone antibiotic, ciprofloxacin, was encapsulated within poly
(isobutylcyanoacrylate) (PIBCA) and PIHCA nanospheres in an attempt to kill both
dividing and non-dividing bacteria; however, the formulation was not effective
against persistent Salmonella (Page-Clisson et al.
1998
). More recently, the same
antibiotic was encapsulated in PLGA nanospheres (Jeong et al.
2008
). PLGA nano-
spheres are also able to deliver gentamicin to the liver and spleen of
Brucella
melitensis
-infected mice (Lecaroz et al.
2007
). Nanospheres prepared from poly
(D,L-lactide) containing the antiparasitic drug primaquine were also efficient at
delivering this drug to the liver (Rodrigues et al.
1994
). Co-localization of nano-
spheres and
Leishmania donovani
parasites in Kupffer cells was observed.
Another infectious disease in which the organism responsible is to be found in
macrophages is visceral leishmaniasis. One of the effective drugs against this dis-
ease is Amphotericin B, a polyene antibiotic. This amphiphilic molecule has been
associated with several lipid-based drug delivery systems (Barratt and Bretagne
2007
). Although the main advantage brought by nanoencapsulation is the reduction
of Amphotericin B's dose-limiting toxicity, the use of colloidal carriers also means
that the drug can reach the same intracellular compartment as the parasite.
4
Intracellular Delivery of Nucleic Acids
A second application in which colloidal drug carriers can provide intracellular
delivery is that of the administration of nucleic acids. Progress in molecular biology
has led to the availability of therapeutic genes and shorter nucleic acid sequences,
in particular anti-sense oligonucleotides (AS-ODN) and small interfering RNA
(siRNA). However, these large, negatively charged molecules cannot penetrate cell
membranes and are also susceptible to degradation by nucleases, particularly the
single-stranded AS-ODN. The stability problem for AS-ODN can be overcome by
chemical modification, yielding structures such as phosphorothionate, methylphos-
phonate and boranophosphonate analogues that are resistant to enzymes but retain
the capacity to bind to messenger RNA. However, the barrier of intracellular pen-
etration remains. Furthermore, passage of the cell plasma membrane is not the last
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