Biomedical Engineering Reference
In-Depth Information
achieve targeted drug delivery. Another key challenge with polymeric and dendritic
prodrug forms has been to achieve the complete elimination of these macromol-
ecules from the body. More precisely, SIDs are reported to be excreted easily from
the body due to their complete biodegradability [29]. Furthermore, the advantage
of cleavage effect in SIDs with tumor-associated enzyme or a targeted one could
be amplifi ed and therefore may increase the number of active drug molecules in
targeted tumor tissues.
The conventional method has been to attach covalently bioactive molecules to
dendritic scaffolds by controlling the loading and release of active species. Chemi-
cal conjugation to a dendritic scaffold allows covalent attachment of different kinds
of active molecules (imaging agents, drugs, targeting moieties, or biocompatible
molecules) in a controlled ratio [14, 21, 23]. The loading as well as the release can
be tuned by incorporating cleavable bonds that can be degraded under specifi c
conditions present at the site of action (endogeneous stimuli, e.g., acidic pH,
overexpression of specifi c enzymes, or reductive conditions as well as exogeneous
stimuli, e.g., light, salt concentration, or electrochemical potential). In a recent
report, Calderon
et al.
reported the use of the thiolated PG scaffold for conjugation
to maleimide- bearing prodrugs of doxorubicin ( DOX ) or methotrexate ( MTX )
which incorporate either a self - immolative para - aminobenzyloxycarbonyl spacer
coupled to dipeptide Phe-Lys or the tripeptide d - Ala - Phe - Lys as the protease
substrate [30]. Both prodrugs were cleaved by cathepsin B, an enzyme overex-
pressed by several solid tumors, to release DOX or an MTX lysine derivate. An
effective cleavage of PG - Phe - Lys - DOX and PG - D - Ala - Phe - Lys - Lys - MTX and
release of DOX and MTX-lysine in the presence of the enzyme was observed.
Another challenge in dendritic or polymeric platforms is to tune the pharma-
cokinteics and extend the ability of a macromolecule to carry multiple copies of
bioactive compounds [31]. This can be achieved by designing PEGylated dendrim-
ers, which can circumvent the synthetic and biological limitations [27]. The poly-
meric architecture can be designed to avoid the destructive side reactions during
dendrimer preparation while maintaining the biodegradability. Here, in this
chapter, we highlight dendrimers with biodegradable characteristic in the pres-
ence of a suitable environment (e.g., pH). Chemical synthetic approaches have
been discussed in detail, limited for their biodegradation and their biological
implications.
10.2.1
Is Biodegradation a Critical Measure of Biocompatibility?
In the past, many polymers have been proven clinically safe. For example, PEG
and PLGA polymers are being routinely used in delivering anticancer bioactives
[23]. However, newer polymeric forms, which are currently being used in the
biomedical fi eld, are inherently heterogeneous in their structures, wherein the
individual molecules have different chain lengths, due to their intrinsic polydis-
persed nature [8]. Therefore, their biodegradation profi le is a crucial measure since
the heterogeneous traits can substantially increase undesired effects on the
