“9.61x6.69” b2815 Tissue Engineering and Nanotheranostics
Multifunctional Nanomaterials for Cancer Theranostics 243
hand, solid tumors exist high interstitial fluid pressure, which can
avoid successful uptake and homogenous distribution of drugs in the
tumor. Larger and longcirculating nanocarriers (100 nm) are
retained more in the tumor, whereas smaller molecules easily diffuse.
Another drawback is that not every type of tumor allows for penetrat
ing accumulation via the EPR effect, including gastric and pancreatic
cancers.^230
4.2. Active Targeting
Although passive targeting has achieved some success, the tumor tar
geting efficiency needs to be improved. In active targeting, targeting
groups that bind to appropriate receptors expressed at the target site
are linked at the surface of the nanocarrier. The targeting ligands can
actively recognize and bind to a receptor overexpressed by tumor cells
or tumor vasculature and not expressed by normal cells.72,78,231–235 The
binding affinity of the ligands affect the tumor penetration because of
the “bindingsite barrier”.236,237 According to reported studies, there
are many types of targeting ligands.
Monoclonal Antibodies (mAbs). mAbs as currently clinically avail
able ligands are widely used for active targeting.238–241 Clinically avail
able mAbs targeted nanomaterials are mainly rituximab for
lymphoma,^242 trastuzumab for breast cancer treatment,^243 bevaci
zumab for angiogenesis inhibition,^244 and cetuximab for treatment of
advanced colorectal cancer.^245 However, these large mAbs have seri
ous limitations. Firstly, most mAbs hardly penetrate into tumors
because they are too big to easily leave blood vessels and efficiently
diffuse into tissues, which leads mAbs to be trapped by antigens
located on the perivascular tumor cells to prevent permeation into the
tumor mass. Secondly, slow clearance of mAbs from the body results
in high normal tissue exposure. Most mAbs tend to accumulate in the
excretory organs and do not reach their targets. In addition, even the
humanized mAbs may also induce immune response involving hyper
sensitivity, neutralizing effects, and changeable pharmacokinetic
properties.
