Biomedical Engineering Reference
In-Depth Information
Taxol
1
is a good example of the need for good carriers. Taxol
1
consists of
paclitaxel solubilized in Cremephor EL
1
, which is a highly toxic mixture of
castor oil and ethanol. This excipient can cause hypersensitivity reactions in
patients undergoing chemotherapy and can be a treatment limiting problem.
13
Furthermore, the active pharmaceutical ingredient, paclitaxel, is known to
cause dose limiting neurotoxicity at high doses.
14
If stability and long
circulation are achieved, it will be able to travel through the body and
eventually reach the site of the tumor. Here, carrier technology can encourage
treatment preferentially to the tumor by using environmental characteristics or
cellular components, such as surface proteins, as targets.
The carrier can target environmental characteristics of the tumor. Some of
the environmental characteristics provide a means for passive accumulation via
the EPR effect. The EPR effect is possible because of two hallmarks of cancer:
unchecked growth and continued angiogenesis.
15
Continuous growth of the
tumor leads to a chaotic tumor environment, with cells in hypoxic regions
producing angiogenic factors which stimulate the production of new blood
vessels. These new blood vessels are poorly formed and have gaps or
fenestrations in the endothelium that allow passage of macromolecules into the
tumor from the blood.
16
Increased mass transport from the blood vessels is
beneficial for a tumor that is starved of nutrients. Therapies can take
advantage of this hyperpermeability that allows nanoparticles to accumulate in
the tumor where this leakiness occurs. Furthermore, retention in the tumor is
aided by the lack of functional lymphatics that would normally drain the
tissue.
17
Once in the tumor environment, molecular targeting is a method used to
provide treatment preferentially to tumors. Some cancer cell types overexpress
certain surface markers. These markers are present in other cells, but can be
much more abundant in some tumors. Overexpression of folate receptor and
human epidermal growth factor receptor 2 (HER2) have been shown to be a
predictor of poor prognosis of breast cancers.
18,19
These and other over-
expressed proteins have become a target implemented into the designs of drug
carrier technologies.
20-22
Alternatively, some carriers use a membrane
penetration mechanism, such as the TAT peptide, to increase cell internaliza-
tion in a nonspecific way.
23
While techniques not relying on protein expression
can increase efficacy, methods must be used to block activity outside the tumor
environment. To achieve this, the carrier's actions can designed to be triggered
by environmental characteristics of the tumor. Some drug carriers use pH-
sensitive groups to provide a triggered action in the acidic environment.
24
The
low pH is a result of metabolism in hypoxic conditions that exist in the core of
most solid tumors.
25
As not all tumors possess a markedly low pH, it has been
shown that a glucose infusion in nondiabetic patients can lower the pH in
tumors.
26
It also might be possible to use the high concentration of matrix
metalloproteinases (MMPs) in the extracellular matrix (ECM) of tumors for
triggering an active form of the carrier.
27
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