Biomedical Engineering Reference
In-Depth Information
Thus, the current paradigm is to have the carrier stably transport the drug
while circulating through the bloodstream so that it can accumulate in the
tumor, where a targeting mechanism will provide selective treatment. This
paradigm has a plethora of opportunities for polymer therapeutics and
nanomedicine. Designs can be custom tailored to fit certain aspects of the
paradigm. What often happens is a therapeutic approach will focus on one
specific aspect of the paradigm to increase efficacy. Unfortunately, this can
result in shortcomings in other areas. Overall, there is still a low rate of clinical
success for targeted drug delivery.
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1.3 Challenges to Current Paradigm
Methods for targeted drug delivery have trouble showing that they are safe,
effective, and better than what is currently used for treatment. Currently,
ligand-receptor targeting drug carriers have challenges getting approved. For
example, Mylotarg
1
is an antibody-drug conjugate that was approved for
clinical use to treat leukemia. However, it has since been withdrawn due to
poor results from a post-approval clinical trial, and continued postmarketing
surveillance reveals lack of improved efficacy and unacceptable side effects.
The antibody has no trouble binding to its target antigen of CD33, but lack of
antigen exclusivity to the cancer and accumulation in the liver doomed this
product.
28,29
To
make
successful
targeted
drug
delivery
products,
the
assumptions underlying these magic bullets will have to be questioned.
For solid tumors, an additional barrier seems to be intratumoral
distribution. Once the carrier reaches the site of the tumor, it might be
tempting to assume it will then invariably reach and enter the cancer cells.
However, there are various factors that prevent the nanoparticle from
penetrating into the tumor core.
30
Figure 1.1 shows how accumulation in
the tumor is possible but also how penetration is limited. Tumors grown in
window chambers show heterogeneous permeation and the accumulation of
nanoparticles adjacent to the blood vessel.
31
Other studies also show that the
permeability varies and that liposomes do not diffuse far from blood vessels.
32
Distribution beyond the vicinity of blood vessels is a challenge even for viruses
and free drug molecules.
33,34
Challenges to successful targeted drug delivery come from carrier dependent
factors and tumor dependent factors. Current targeted drug delivery
formulations are not magic bullets. Biodistribution and the EPR effect depend
on carrier characteristics and these carriers are not always well characterized or
stable or safe. Also, if good results with a drug carrier are seen in a mouse
model, the success does not translate into the clinical model. The tumor resists
treatment from the environmental to the cellular level. Aspects of the paradigm
need to be examined in order to see improvements. There have been critical
examinations of targeted drug delivery for quite some time now,
35
and certain
challenges are beginning to be understood.