α-helical hydrophobic domain connected to a charged hydrophilic domain. Since
this original work, many laboratories have prepared different variants of block
copolypeptide vesicles based on this scheme. In 2007, Hadjichristidis reported
lysine-PBLG-lysine (i.e., K x PBLG y K x ) triblock copolypeptides, where the helical
PBLG core favors vesicle formation [97]. Jing and coworkers prepared vesicleforming lysine-phenylalanine (K x F y ) copolypeptides containing α-helical
phenylalanine segments [98]. These vesicles were also found to be useful in
encapsulating hemoglobin and acting as oxygen carriers. Deming’s laboratory
also reported the formation of vesicles from dual hydrophilic triblock
copolypeptides composed of arginine–glutamate–leucine (R x E y L z ) or PEGylated
lysine–arginine–leucine (K
P
x R y L z ) sequences [99]. The use of triblock architectures
was intended to retain some homoarginine residues for cell uptake, but have the
majority of the hydrophilic segments anionic or uncharged to minimize cytotoxicity, all without disrupting vesicle formation. A number of different compositions
were prepared and it was found that, although vesicles exhibiting low cytotoxicity
could be formed with a R 5 E 80 L 20 copolypeptide, the R segments were unable to
promote intracellular uptake. With the K
P
x R y L z samples, the presence of the
“PEGylated” outer blocks was able to diminish cytotoxicity while still allowing
the center R segments to promote cellular uptake [99].
Using a different approach to vesicle formation, Jan and coworkers prepared
lysine–glycine (i.e., K x G y ) copolypeptides, where the polyglycine segment does not
adopt an α-helical conformation and has inherent higher flexibility compared to
helical segments [100]. Due to the lack of a rigid hydrophobic segment, and due to
the hydrophilicity of glycine compared to leucine or phenylalanine, much longer
“hydrophobic” segments were needed to drive self-assembly in water and vesicle
formation. A K 200 G 50 block copolypeptide was found to form vesicles in water
using MeOH/H 2 O processing, and was also mineralized with silica for entrapment
of molecules [101].
Other recent variants of block copolypeptide vesicles have incorporated
functionality within one of the segments. In 2010, Deming’s laboratory reported
the preparation of lysine–dihydroxyphenylalanine (i.e., K 60 DOPA 20 )-based
vesicles, where the hydrophobic DOPA segments have the added feature of being
sensitive to oxidation [102]. DOPA residues are found naturally in mussel byssus
and are important components in the ability of byssal threads to adhere underwater
and to crosslink into rigid networks [103]. In a biomimetic process, K 60 DOPA 20
vesicles were oxidized in aqueous media resulting in crosslinking of the vesicle
membranes Eq. (18). The resulting membranes were very robust and stable to
organic solvents, freeze drying, and osmotic shock. Similar materials, in the form
of glutamate–lysine/DOPA [i.e., E x (K m /DOPA n ) y ] copolymers were reported in
2012 by Qiao and coworkers [104], where the hydrophobic domains were statistical
copolymers of different ratios (m:n) of lysine and DOPA that could be assembled
and oxidized to crosslinked vesicles at high pH.
Synthesis and Self-Assembly of Well-Defined Block Copolypeptides via. . .
25
this original work, many laboratories have prepared different variants of block
copolypeptide vesicles based on this scheme. In 2007, Hadjichristidis reported
lysine-PBLG-lysine (i.e., K x PBLG y K x ) triblock copolypeptides, where the helical
PBLG core favors vesicle formation [97]. Jing and coworkers prepared vesicleforming lysine-phenylalanine (K x F y ) copolypeptides containing α-helical
phenylalanine segments [98]. These vesicles were also found to be useful in
encapsulating hemoglobin and acting as oxygen carriers. Deming’s laboratory
also reported the formation of vesicles from dual hydrophilic triblock
copolypeptides composed of arginine–glutamate–leucine (R x E y L z ) or PEGylated
lysine–arginine–leucine (K
P
x R y L z ) sequences [99]. The use of triblock architectures
was intended to retain some homoarginine residues for cell uptake, but have the
majority of the hydrophilic segments anionic or uncharged to minimize cytotoxicity, all without disrupting vesicle formation. A number of different compositions
were prepared and it was found that, although vesicles exhibiting low cytotoxicity
could be formed with a R 5 E 80 L 20 copolypeptide, the R segments were unable to
promote intracellular uptake. With the K
P
x R y L z samples, the presence of the
“PEGylated” outer blocks was able to diminish cytotoxicity while still allowing
the center R segments to promote cellular uptake [99].
Using a different approach to vesicle formation, Jan and coworkers prepared
lysine–glycine (i.e., K x G y ) copolypeptides, where the polyglycine segment does not
adopt an α-helical conformation and has inherent higher flexibility compared to
helical segments [100]. Due to the lack of a rigid hydrophobic segment, and due to
the hydrophilicity of glycine compared to leucine or phenylalanine, much longer
“hydrophobic” segments were needed to drive self-assembly in water and vesicle
formation. A K 200 G 50 block copolypeptide was found to form vesicles in water
using MeOH/H 2 O processing, and was also mineralized with silica for entrapment
of molecules [101].
Other recent variants of block copolypeptide vesicles have incorporated
functionality within one of the segments. In 2010, Deming’s laboratory reported
the preparation of lysine–dihydroxyphenylalanine (i.e., K 60 DOPA 20 )-based
vesicles, where the hydrophobic DOPA segments have the added feature of being
sensitive to oxidation [102]. DOPA residues are found naturally in mussel byssus
and are important components in the ability of byssal threads to adhere underwater
and to crosslink into rigid networks [103]. In a biomimetic process, K 60 DOPA 20
vesicles were oxidized in aqueous media resulting in crosslinking of the vesicle
membranes Eq. (18). The resulting membranes were very robust and stable to
organic solvents, freeze drying, and osmotic shock. Similar materials, in the form
of glutamate–lysine/DOPA [i.e., E x (K m /DOPA n ) y ] copolymers were reported in
2012 by Qiao and coworkers [104], where the hydrophobic domains were statistical
copolymers of different ratios (m:n) of lysine and DOPA that could be assembled
and oxidized to crosslinked vesicles at high pH.
Synthesis and Self-Assembly of Well-Defined Block Copolypeptides via. . .
25