Recent Progress in Polymer Therapeutics as Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 85

reaction. Using the RAFT technique, several HPMA copolymer-drug
conjugates were designed, synthesized, and characterized [32, 33].
HPMA, PGA, and dextran are most commonly used as a backbone
for polymer-drug conjugates.
4.1.4 Linker
One aspect in utilizing polymeric nanocarriers for therapeutics is
the specific release of the original form of the active agent at the
target site. Thus, the choice of linker between the active agent and
the polymer backbone has a significant role in achieving this aim.
Furthermore, the linker should be stable in the bloodstream and
the extracellular interstitium in physiological pH. For some medical
applications, the drug is essentially biologically inert when attached
by a linker to the polymer. So a drug that would otherwise cause side
eff ects can exist in the bloodstream as a conjugate and will not harm
the patient.
In the case of cancer, the unique pathophysiology of tumors, such
as the acidic, neoplastic supporting microenvironment is being used.
It has been found to overexpress specific proteases that are active in
the acidic conditions of the tumor. The drug is selectively released to
its target by linking it with a spacer cleavable by hydrolysis at low pH
or by lysosomal or tumor-associated overexpressed enzymes. Thus,
the linkers in the polymer therapeutics field are either enzymatically
cleavable [34, 35] or pH-sensitive [36-38]. The release of the free
drug can occur extra- or intra-cellularly.
Disulfide linkers that are cleaved by reduction have also been
proposed as alternative, but it has not been progressed beyond an
experimental stage [39] . Many diff erent classes of enzymes, including
nucleases, proteases, phosphatases, lipases, etc., are present in the
lysosomes. Since water-soluble polymer-drug conjugates enter the
cell via endocytosis and then continue to the lysosomes, the presence
of an enzymatically cleavable linker between the backbone and the
drug enables selective targeting.
A common example is the oligopeptide spacers, terminated
with a drug and susceptible to enzymatically catalyzed hydrolysis
in the lysosomes, specifically by cathepsin B and K. The cathepsin
B-cleavable tetrapeptide Gly-Phe-Leu-Gly was extensively used
in HPMA copolymer for delivery of several anti-cancer drugs,