Biomedical Engineering Reference
In-Depth Information
with the membrane and disrupt it. These polymers have
been used in intracellular drug delivery to disrupt endo-
somal membranes as pH drops in the endosome, en-
hancing the cytosolic delivery of drugs, and avoiding
exposure to lysosomal enzymes.
Effect of copolymerization
on LCST of poly (NIPAAm)
AAm
Smart polymer-protein
bioconjugates in solution
Copolymer
LCST
( ° C)
N-tBAAm
Smart polymers may be conjugated randomly to proteins
by binding the reactive end of the polymer or reactive
pendant groups along the polymer backbone to reactive
sites on the protein ( Fig. 3.2.6-4 ). One may utilize chain
transfer free radical polymerization to synthesize oligo-
mers with one functional end group, which can then be
derivatized to form a reactive group that can be conjugated
to the protein. NIPAAm has also been copolymerized
with reactive comonomers (e.g., N -hydroxysuccinimide
acrylate, or NHS acrylate) to yield a random copolymer
with reactive pendant groups, which have then been
conjugated to the protein. Vinyl monomer groups have
been conjugated to proteins to provide sites for co-
polymerization with free monomers such as NIPAAm.
These synthesis methods are described in several publi-
cations ( Cole et al. , 1987; Monji and Hoffman, 1987;
Shoemaker et al. , 1987; Chen et al. , 1990; Chen and
Hoffman, 1990, 1994 ; Ya n g et al., 1990 ; Ta k e i et al.,
1993a ; Monji et al., 1994; Ding et al. ,1996 )(seealso
Section 3.2.16 on biologically functional materials).
Normally the lysine amino groups are the most re-
active protein sites for random polymer conjugation to
% AAm or N-tBAAm in monomer mixture
Fig. 3.2.6-3 Copolymerization of a thermally sensitive polymer,
PNIPAAm, with a more hydrophilic comonomer, AAm, raises the
LCST of the copolymer, whereas copolymerization with a more
hydrophobic comonomer, N-tBAAm, lowers the LCST. (Hoffman
et al., Journal of Biomedical Materials Research 2000).
monomer is copolymerized with more hydrophilic
monomers such as acrylamide, the LCST increases and
may even disappear. If NIPAAm monomer is copoly-
merized with more hydrophobic monomers, such as n-
butylacrylamide, the LCST decreases ( Fig. 3.2.6-3 )
( Priest et al. , 1987 ). NIPAAm may also be copoly-
merized with pH-sensitive monomers, leading to random
copolymers with temperature- and pH-responsive com-
ponents ( Dong and Hoffman, 1987; Zareie et al. , 2000 ).
NIPAAm has been copolymerized with pH-responsive
macromonomers, leading to graft copolymers that in-
dependently exhibit two separate stimulus-responsive
behaviors ( Chen and Hoffman, 1995 ).
A family of thermally gelling, biodegradable triblock
copolymers has been developed for injectable drug de-
livery formulations ( Vernon et al. , 2000; Lee et al. , 2001;
Jeong et al. , 2002 ). They form a medium viscosity,
injectable solution at room temperature and a solid
hydrogel at 37 C. These polymers are based on compo-
sitions of hydrophobic, degradable polyesters combined
with PEO. The copolymers are triblocks with varying
MW segments of PLGA and PEO. Typical compositions
are PEO-PLGA-PEO and PLGA-PEO-PLGA.
Tirrell (1987) and more recently, Stayton, Hoffman,
and co-workers have studied the behavior of pH-sensitive
alpha-alkylacrylic acid polymers in solution ( Lackey et al. ,
1999; Murthy et al. , 1999; Stayton et al. , 2000 ). As pH is
lowered, these polymers become increasingly protonated
and hydrophobic, and eventually phase separate; this
transition can be sharp, resembling the phase transition at
the LCST. If a polymer such as poly(ethylacrylic acid) or
poly(propylacrylic acid) is in the vicinity of a lipid bilayer
membrane as pH is lowered, the polymer will interact
Random, end-linked
Random, pendant-linked
active site
close to active site
far away from active site
Site-specific, end-linked
Site-specific, pendant-linked
Fig. 3.2.6-4 Various types of random and site-specific smart
polymer-protein conjugates. In the latter case, conjugation near
the active site of the protein is intended to provide stimulus control
of the recognition process of the protein for its ligand, whereas
conjugation far away from the active site should avoid any
interference of the polymer with the protein's natural activity
(Hoffman et al., Journal of Biomedical Materials Research
2000).
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