Chemistry Reference
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1994; Langer 2000). Furthermore, homogeneous gel beads consisting of the naturally
occurring polysaccharides alginate and chitosan have found use as drug-delivery
vehicles and particularly in cell encapsulation. Seminal work by Franklin Lim and
Anthony Son showed that cells could be encapsulated in polysaccharide particles
and continue to function in vivo (Lim and Sun 1980), culminating in an implantable,
artificial pancreas in at least one human subject (Soon-Shiong et al. 1994).
8.4.2. Interfacial Polymerization
As discussed in Section 8.2.2, hollow, liquid-core microcapsules were first used for a
biomedical application by Chang in 1964 (Chang 1964). Chang used a stirred emul-
sion to create a dispersed phase of di- or polyamines in aqueous enzyme solution and
a continuous phase of diacid chloride in an organic solvent. Interfacial polyconden-
sation yielded polyamide microcapsules surrounding enzymes in an aqueous environ-
ment. Although additional encapsulated reagents were required in some cases to
retain activity, in vitro tests showed that the enzymes usually retained significant
activity relative to free enzymes. The microcapsules were also tested for in vivo com-
patibility. In some cases, such as encapsulated urease, enzyme activity was retained
and the microcapsules showed little sign of toxicity when placed in vivo intrave-
nously, subcutaneously, or intraperitoneally. Chang's early work (Chang 1964;
Chang et al. 1966) still stands as a breakthrough in the field of encapsulated thera-
peutics. Chang continued to study these liquid-cored microcapsules for 5 years
after his initial innovation. He showed how enzymes were stabilized (Chang
1971b) against degradation by the cell-like environment within microcapsules. In
addition, microcapsules containing asparaginase (Chang 1971a) could stave off the
onset of tumors in mice injected with lymphosarcoma cells for at least five times
longer than free asparaginase.
Despite these early advances, the use of interfacial polymerization to make micro-
capsules for therapeutic agents slowed during the 1970s. Polyamide microcapsules
were later used to create an implantable delivery system for insulin that responded
rapidly to changes in external glucose levels (Makino et al. 1990), although this
approach never reached clinical trials. In addition, poly(alkyl cyanoacrylate)
(PACA), the major constituent of Super Glue, has been used to prepare water-
cored nanocapsules via interfacial polymerization (Lambert, Fattal et al. 2000).
These capsules have been used to encapsulate anticancer oligonucleotides
(Lambert, Fattal et al. 2000), which had previously been difficult to use in therapeutic
applications because of low stability and inadequate cellular penetration. PACA-
encapsulated oligonucleotides have been shown to inhibit sarcoma-related tumors
in mice when injected directly into tumors (Lambert, Bertrand et al. 2000;
Lambert, Fattal et al. 2000).
8.4.3. Colloidal Templates
Colloidal templating techniques offer the potential of precise tuning for drug-release
applications (see Section 8.2.4). For instance,
the Feldheim group used gold
