Biomedical Engineering Reference
In-Depth Information
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Fig. 7
Biodegradable hydrophobic polymers used for gene delivery: (
a
) poly(lactide -co-
glycolide) (PLGA), and (
b
) poly(ortho esters)
3.8.1
Poly(Lactide-co-Glycolide)
PLGA has been approved by FDA for drug delivery and other biomedical applica-
tions. DNA-loaded microparticles have been extensively investigated for the induc-
tion of immune responses (Fig.
7a
) (Jilek et al.
2005
). The degradation half-life of
PLGA can be, on one hand, modulated by its composition, while on the other regu-
lated by molecular weight. DNA can be encapsulated into microparticles via spray-
drying, w/o/w (water-in-oil-in-water) double emulsion solvent evaporation or
coacervation technique. Alternatively, DNA can be adsorbed on cationic micropar-
ticles, which can be easily fabricated by introducing cationic molecules during
microparticle formulation. Study by Luby et al. showed that immunization of
HLA-A2/Kb transgenic mice with PLGA microparticles containing pDNA encoding
human cytochrome P450 CYP1B1 (CYP1B1) elicited durable HLA-A2-restricted
T cell responses that recognize naturally processed CYP1B1 peptide produced in
cells endogenously expressing CYP1B1 (Luby et al.
2004
). In addition, this formu-
lation was found to be safe and well tolerated even following repeated administra-
tions. However, hydrolysis of PLA or PLGA may lead to a low pH within
microparticles that can result in DNA degradation (Fu et al.
2000
). Incomplete
release of DNA from PLGA microparticles is often observed (Wang et al.
1999
). In
addition, the release rate sometimes may be too slow to prompt a robust immune
response (Kaech and Ahmed
2001
).
3.8.2
Poly(Ortho Esters)
Poly(ortho esters) (POEs) are another types of biodegradable polyesters with well-
controlled degradability and excellent biocompatibility (Fig.
7b
). POEs were
originally developed as biomaterials in the 1970s by Heller and colleagues (Heller
et al.
2002
). They are stable at pH >7, while degrade rapidly at reduced pH. These
characteristics can be utilized to temporally and spatially control the release of
DNA. To overcome the drawbacks of the polyester-based DNA delivery systems,
Heller and Langer et al. have molecularly engineered POE microspheres that are
non-toxic to cells (Wang et al.
2004a
). These particles could protect the payload
DNA from degradation, and release DNA rapidly in response to phagosomal pH
post-uptake by APCc. The optimized formulation could elicit distinct primary and
secondary humoral and cellular immune responses in mice, and suppress the
growth of tumour cells bearing a model antigen.
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