Recent Progress in Polymer Therapeutics as Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 86

since cathepsin B is overexpressed in many tumor cells and tumor
endothelial cells [40]. This spacer is cleaved intracellularly in the
lysosome and therefore is used for drug release to the cytosol. Another
common enzymatically cleavable tetrapeptide is the Gly-Gly-Pro-Nle
spacer, which is cleaved by cathepsin K. Cathepsin K is involved in
bone resorption (osteoporosis, osteoarthritis and bone neoplasms),
and overexpressed in bone metastases. In contrast to cathepsin B,
it is localized and active in the tumor microenvironment. Cathepsin
K-cleavable peptide has been used in polymer-drug conjugates to
deliver drugs to bone tissues for the treatment of calcified diseases.
It should be noted that there are further peptide sequences, which
are known to be cleaved by cathepsin B, K and others, such as Phe-
Lys or Val-Arg by cathepsin B [41] and Phe-Arg by cathepsin B and L
[42].
Other proteases, which are overexpressed in tumors and play a
critical role in tumor progression, tumor angiogenesis and metastasis,
were studied. For example, the lysosomal proteases legumain [43,
44] and the matrix metallopreoeinases (MMPs), i.e., MMP2 and
MMP9 [45], which are active intracellularly and extracellularly,
respectively.
Because the enzymes that are used for pro-drug activation are
also present in normal cells, activation of an enzymatically cleavable
pro-drug can be observed in healthy tissue too. Thus, there is a
growing demand for improving tumor uptake through active or
passive targeting and to study the overexpression of those enzymes
in the individual tumor clinically.
The acid-labile spacers are extensively used in the field of
polymer-drug conjugates. There is a significant drop in the pH value
from the physiological pH 7.2-7.4 in the blood or extracellular space
to pH 4.0-6.5, in the various intracellular compartments [46]. In
addition, the fact that the extracellular pH surrounding tumor tissue
is also slightly lower than that of normal tissue also supports the
rationale for the corporation of these spacers.
Typical examples of acid-sensitive bonds are N -cis-aconityl,
hydrazone and carboxylic-hydrazone bonds, acetal, imine and trityl
bonds. While N -cis-aconityl and hydrazone linkers are the most
studied ones, several pro-drugs with acid-labile acetal bonds have
also been investigated [36, 46]. Careful attention should be given
to the choice of suitable linkers. The chosen chemical bond eff ect