Biomedical Engineering Reference
In-Depth Information
accumulation in tumor tissue, and enhanced diff usion within tissue
[5-7]. The uptake to most cells is through fluid phase pinocytosis,
where the size limit is 150 nm. A diff erent way of internalization is
through receptor-mediated endocytosis, in which macromolecules
bind to complementary receptors on the cell surface and enter the
cell as receptor-macromolecule complex in clathrin-coated vesicles.
This process increases the efficiency of internalization of particular
macromolecules more than 1000-fold compared with ordinary
pinocytosis [8]. The macromolecule, which enters the cell through
either process, finds itself in the interior of the endosome, where
the environment is kept acidic (pH 5-6) and many receptors release
their bound cargo. From the endosome the molecules proceed to the
digestive lysosome, in which about 40 types of hydrolytic enzymes
are active at the acidic pH [8]. Many strategies use the acidic pH or
the proteolytic enzymes for the release of the therapeutic agent from
the polymeric nanocarrier. However, care must be taken that the
hostile environment of the lysosome will not hamper the structure
and activity of the therapeutic agent.
In order to design a polymeric nanocarrier, one should pay
a careful attention to each one of the diff erent components; the
polymer backbone, linker, targeting moiety if it exists, and obviously
the therapeutic agent itself should be chosen after taking into
consideration the (i) stability of the polymer-therapeutic attachment
during circulation and transport, (ii) adequate loading capacity in
relation to the potency of the therapeutic agent being carried, and
(iii) ability to target the diseased cell or tissue by an active or a
passive mechanism. In the next sections, we first elaborate on the
diff erent components, and then we will review the diff erent families
of polymer therapeutics with stimulating examples from research
and clinical trials.
4.1.1 PolymericBackbone
The choice of polymeric backbone for the conjugate has great
implications on the pharmacokinetics and pharmacodynamics of
the drug. The polymer characteristics, such as molecular weight,
polydispersity, architecture, charge, and hydrophilicity, impose the
drug solubility, its biodistribution, body excretion, and the interaction
with the immune system. The polymeric backbone of the conjugate
can be synthetic, natural, or semi-natural. Copolymerization enhances
 
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