The
synthesis of new amino acid-containing, cell-specific, therapeutically
active polymers is presented. Amino acids served as starting material
for the preparation of tailored polymers with different amino acids
in the side chain. The reversible addition–fragmentation chain-transfer
(RAFT) polymerization of acrylate monomers yielded polymers of narrow
size distribution (Đ ≤ 1.3). In particular,
glutamate (Glu)-functionalized, zwitterionic polymers revealed a high
degree of cytocompatibility and cellular specificity, i.e., showing association to different cancer cell lines, but not with
nontumor fibroblasts. Energy-dependent uptake mechanisms were confirmed
by means of temperature-dependent cellular uptake experiments as well
as localization of the polymers in cellular lysosomes determined by
confocal laser scanning microscopy (CLSM). The amino acid receptor
antagonist O-benzyl-l-serine (BzlSer) was
chosen as an active ingredient for the design of therapeutic copolymers.
RAFT copolymerization of Glu acrylate and BzlSer acrylate resulted
in tailored macromolecules with distinct monomer ratios. The targeted,
cytotoxic activity of copolymers was demonstrated by means of multiday in vitro cell viability assays. To this end, polymers with
25 mol % BzlSer content showed cytotoxicity against cancer cells,
while leaving fibroblasts unaffected over a period of 3 days. Our
results emphasize the importance of biologically derived materials
to be included in synthetic polymers and the potential of zwitterionic,
amino acid-derived materials for cellular targeting. Furthermore,
it highlights that the fine balance between cellular specificity and
unspecific cytotoxicity can be tailored by monomer ratios within a
copolymer.
Synthetic peptides with cyclic arginine-glycine-aspartate motif (cRGD) play an important role in cell recognition and cell adhesion. cRGD-decorated soluble polymers and polymeric nanoparticles have been increasingly used for cell-specific delivery of antitumor drugs. While the significance of cRGD modification for tumor cell-specific targeting of polymeric carriers is well-accepted, straightforward procedures ensuring the fidelity of cRGD modification of polymeric systems are still lacking. Herein, we have reported an in-situ polymerization approach for synthesis of cRGD-end-functionalized well-defined polymers as potential building blocks of targeted drug delivery systems. A new cRGD peptide functionalized RAFT agent was synthesized as confirmed by MALDI-TOF and 1 H NMR spectroscopy. The ability of this RAFT agent to control polymerizations was then tested using two different monomers oligoethyleneglycol acrylate and t-butyl methacrylate. The RAFT-controlled character of polymerizations and the living characteristic of the synthesized polymers were investigated through a series of kinetic experiments. The cytotoxicity and targeting capability of cRGD-functionalized OEGA polymers were investigated using cell lines expressing α v β 3 integrins at varying extents.
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