Biomedical Engineering Reference
In-Depth Information
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Figure 4.7
Structure of dendrimers.
characterize their solubility and chemical behavior. As nonviral gene delivery
vectors, dendrimers have a couple of unique advantages. Their nanometer size
enables them to mimic cell organelles, easing the transport of therapeutic genes
from the cytoplasm to the nucleus. The intense proton sponge effect helps the
dendrimer/DNA complex escape from the lysosome, thereby avoiding
enzymatic degradation. Therefore, dendrimers display high transfection
efficiency in vitro. However, in vivo, the sensitivity of the size and dispersal
stability of these types of polyplexes to buffer systems and serum results in high
toxicity, low transfection efficiency, poor pharmacokinetics, and poor
biological distribution. To solve these problems, various surface modifications
to dendrimers have been developed.
4.4.1 Polyamidoamine Dendrimers
Polyamidoamine (PAMAM), based on an ethylenediamine or ammonia core
with four and three branching points, was the first complete dendrimer family
to be synthesized, characterized, and commercialized. PAMAM dendrimers
have been widely studied for gene delivery processes in vitro and in vivo,and
their transfection capability appears to depend on the generation and number
of primary amino groups on the surface. However, high cytotoxicity and
relatively low transfection efficiency in the presence of serum limited their
clinical application. Thus, tremendous research efforts have been made to
develop PAMAM dendrimer-based gene vectors with low generation, low
toxicity, and high transfection efficiency.
Biodegradable PAMAM dendrimers have been developed to reduce the
cytotoxicity and improve the release of DNA inside the cell. Xue et al.
synthesized bioreducible PAMAMs containing repeating disulfide linkages in
the main chains and dendritic PAMAMs in the side chains via repetitive
Michael addition and amidation (Scheme 4.7A).
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These dendrimers showed
low cytotoxicity. In comparison to the original disulfide-containing PAMAM
