Biomedical Engineering Reference
In-Depth Information
efficiency to simplify the manufacturing process and minimize losses of these
very expensive anticancer drugs.
4) High drug-loading content. In current commercial formulations, the
drug-loading content tends to be on the low side.
211-213
High drug-loading
contents are needed to minimize the body's exposure to excipient carrier
matter, even if it is biocompatible and relatively benign. For instance, PEG-
containing liposomal carriers may induce acute immune toxicity, manifested in
hypersensitivity reactions (HSRs).
214,215
d
n
4
y
3
n
g
|
2
3.4 Challenges of Rational Design for Translational
Nanomedicine
With the above analysis in mind, it is clear that the key to translational
nanomedicine
is
to
develop
nanocarriers
with
optimal
2R2S
capability,
excipientability, and scale-up ability.
As for the nanocarrier 2R2S capability, we still do not have ones that can
fully and simultaneously achieve the 2R2S capability, despite a large volume of
the scientific literature on each topic separately, or on various subsets of them,
giving rise to unsatisfied therapeutic efficacy and side effects. As a
consequence, a particular problem of those systems is that a large majority
doses of the drugs are still sequestrated in the liver or spleen, even though the
tumor drug accumulations are indeed enhanced compared to free drugs.
133,216
For instance, the PF-PTX micelles
217
and IT-101 CPT conjugates
218
give drug
accumulation in tumors much better than Taxol
1
and CPT, respectively, but
the total amounts of drugs accumulated in the liver were still about 4.5 and 3.5
times of those in tumors. In many cases, only a few percent of the injected
drugs were in the tumors. Thus, for many nanomedicine systems, liver toxicity
is the killer for further developments. Other necessities are how to achieve
effective cellular uptake of the nanocarriers once in the tumor and robust
intracellular release. Delayed or insufficient intracellular release directly leads
to lower cytotoxicity than the free drugs.
219,220
The material excipientability of nanocarriers and the production scale-up
ability of the nanocarriers and their nanomedicine systems are equally
important. For instance, a large variety of inorganic nanomaterials and
sophisticated polymeric nanostructures have been proposed and investigated
as nanocarriers for cancer drug delivery. These studies provide useful proof-of-
concepts and rich insights into various aspects of cancer drug delivery essential
to the design of nanocarriers towards 2R2S capability, but those aimed at
clinical applications must comprehensively design and characterize their
materials, nanosize effects, and scale-up ability. Of the three, the material is
the basic concern for a translational nanocarrier. If the material used for the
nanocarrier is not proper for in vivo clinical uses (for instance, inherently toxic
or non-clearable from the body), the resulting nanocarrier, even with perfect
nanosize effects and 2R2S capability, would not be able, or take an
impractically long time, to be translated into clinics. Thus, except for proof-
