Biomedical Engineering Reference
In-Depth Information
Enzymatic degradation systems have been prepared by Yui and coworkers by
end-capping pPRXs with several different bulky peptides as stoppers. In the early
stages of research, PEG/CD-based PRXs were end-capped with
L
-Phe to give PRX
exhibiting enzymatic degradability by papain [
269
]. Later, two kinds of enzy-
matically degradable tripeptides were employed as end-capping groups to enhance
specific degradability of the PRXs. The PRXs end-capped with Tyr-Gly-Gly or
Phe-Gly-Gly tripeptide with controlled threading percentages of
a
-CD were
prepared by varying the reaction conditions. In some cases, the PRXs were
converted to be water-soluble by modification of the threaded CDs with
hydroxypropyl groups [
270
,
271
]. These tripeptide end-capped PRXs showed
significantly improved enzymatic degradation by aminopeptidase M compared
with linear polymers having the same tripeptides. These results suggested that a
more straight and rigid supramolecular structure improved the accessibility of
enzyme to the terminal peptides.
Hydrolyzable PRXs were firstly reported by Yui and coworkers by introduction
of ester linkages between the end groups of pPRX and stoppers. In this system, the
relationship of hydrolysis rate of the end-capping groups and degree of acetylation
of CDs was investigated. The degradation period could be prolonged from 80
to 1,000 h, when the degree of acetylation of CDs was ~30% [
272
,
273
]. The
polyrotaxane was used for regeneration of bone and cartilage by molding in porous
hydrogel forms [
267
,
274
]. Thompson and coworkers also synthesized PRXs
end-capped with esters and examined the degradation kinetics [
275
]. There were
two types of PRXs designed for acid-triggered cleavages. Water-soluble PRXs
end-capped with hydrazone bond were synthesized by introduction of carboxyl
groups of the CDs using succinic anhydride, and exhibited degradation in acidic
solution [
276
]. Vinyl ethers are well-known acid-cleavable linkages that have been
applied to DDS. PRXs end-capped with vinyl ether linkages were found to be stable
under neutral pH, but degraded within about 45 min under acidic pH (4.0) [
275
].
Usually there are many kinds of thiol (-SH) compounds in cells, and intracellu-
lar (cytosol) conditions are reductive. PRXs that are cleavable under the reductive
conditions of the cytosol were also prepared by introduction of disulfide bonds
to the end-capping groups. Yui et al. reported the application of PRXs cleavable
under reductive conditions for gene delivery systems [
277
]. Dimethylaminoethyl
(DMAE)-modified PRX having disulfide end-capping groups formed a polyplex
of 178-189 nm diameter with DNA. The polyplexes were completely dissociated
upon the addition of polyanionic dextran sulfate in the presence of 10 mM
dithiothreitol (DTT). Transfection experiments using PRX/rhodamine-labeled
DNA polyplex were carried out. Effective escape of the DNA from the endo-
some/lysosme compartments and significant expression was confirmed.
Research on the second strategy has been reported for several types of PRX
materials. Most studies concern pPRXs formation between
a
-CD and polyesters
(Table
1
)[
278
-
290
]. A pPRX of
a
-CD/PLLA was firstly demonstrated by Tonelli
and coworkers [
282
]. Subsequently, we reported the pPRX formation of
a
-CDs and
PLLA-
b
-PEG-
b
-PLLA triblock copolymer [
288
]. In this report, the formation of an
inclusion complex and the stoichiometry of the amphiphilic biodegradable triblock
