Recent Progress in Polymer Therapeutics as Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 87

the pH-dependent stability of the pro-drug, as well as the molecular
weight of the carrier and the site attachment on the carrier.
Another interesting sub-group of acid-labile linkers are pH-
sensitive bonds that incorporate in the backbone of the polymeric
carrier. Recently, a number of reports on linear polymers were
published in which the monomer units were linked by ketal, acetal,
and cis -aconityl bonds [46]. By doing so, the polymer backbone
undergoes a breakdown under the acidic conditions after cellular
uptake and thus has the benefit of being biodegradable. This strategy
still suff ers from several disadvantages, such as low Mw and absence
of functional groups for attaching drugs, and thus requires further
optimization.
Recently, a novel class of polymer backbone in which the drug and
the polymer backbone are connected via a non-covalent, biologically
inspired binding motif was proposed [47]. This linker consists of a
pair of complementary peptides that are wound around each other
in a super-helical fashion to form a tertiary structural motif that is
referred to as coiled coil. In order to form the non-covalent polymer
therapeutics, the polymeric carrier functionalized with one peptide
is mixed in an aqueous solution with the drug of interest, which is
functionalized with the complementary sequence to the peptide.
The drug will be intracellularly released when the conjugate will be
exposed to the relatively low pH of the endosomal compartments.
This innovative coiled coil-based peptide linkers may be useful to
form diff erent compound libraries, depending on the pool of carriers
and drugs that we create.
4.1.5 TargetingMoiety
As mentioned above, passive targeting of polymeric nanocarriers
is obtained by utilizing the EPR eff ect. However, there are
several limitations to this approach, including variable vascular
hyperpermeability among diff erent tumor types and diff erent areas
of the heterogenic tumor tissue. In addition, low cellular uptake of
nanocarriers after extravasation can be another limitation, reducing
the actual drug concentration within the tumor cells due to the
stagnation around the tumor tissue. Thus, a targeting moiety can
be used in order to direct the molecule of interest to the target in a
more specifically way, and basically overcome those limitations.