Amphiphilic Brush-Like Copolymers Involving Hydrophobic Amino Acid- and Oligopeptide-Side Chains for Optical Tumor Imaging In Vivo

Abstract

Amphiphilic brush-like copolymers having simple amino acids or oligopeptides and poly(ethylene glycol) as side chains were synthesized via ring-opening metathesis polymerization and further transformations. All of the synthesized copolymers formed spherical self-assemblies in water and their hydrodynamic diameters were 100–250 nm, as measured by dynamic light scattering. Amphiphilic polymers bearing leucine and valine can form stable spherical self-assemblies in water because of the synergistic effects of intermolecular hydrogen bonding and hydrophobic interaction. The oligomerization of leucine moieties and capping with the proper length of fatty acyl groups at an N-terminus could significantly affect both the stability and fluorescence intensity of near-infrared fluorescent (NIRF) dye-containing polymeric self-assemblies. All of the self-assemblies consisting of leucine- and oligoleucine-grafted copolymers with a NIRF indocyanine green dye and hydrophilic targeting agents showed low cytotoxicity in cell viability tests. Furthermore, self-assemblies consisting of N-acetylleucine-grafted copolymers with strong fluorescence could visualize a tumor site with high-contrast in vivo, while low contrast images were obtained by utilizing oligoleucine-grafted self-assemblies because of their weak fluorescence. These results indicate that the precise control of both the number of leucine moieties and the length of the fatty acyl groups is important to produce highly functionalized tumor-targeting vehicles delivering a NIRF dye.

Grubbs’ and Schrock’s Catalysts, Ring Opening Metathesis Polymerization and Molecular Brushes—Synthesis, Characterization, Properties and Applications

“…PEO molecular brushes have been incorporated in more complex architectures ( Figure 4 ) due to the living character of Grubbs’ catalysts. Copolymers with polylactides [ 56 , 57 , 58 ], polystyrene and polystyrene derivatives [ 8 , 27 , 47 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ], ε-caprolactone [ 52 , 53 ], (meth)acrylates [ 70 , 71 , 72 , 73 ], peptides [ 35 , 74 , 75 , 76 , 77 ] have been synthesized and studied. The covalent attachment of drug molecules on the PEO side chains or as a separate block on the main chain has also been employed for drug delivery purposes [ 78 , 79 , 80 , 81 , 82 , 83 , 84 ].…”

“…The covalent attachment of drug molecules on the PEO side chains or as a separate block on the main chain has also been employed for drug delivery purposes [ 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. Other small molecules serving a specific function have also been covalently bonded on the PEO side chains or in umbrella-like structures [ 72 , 73 , 74 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 ]. In some cases, more complex structures have been synthesized, depending on the needs of applications, or for academic interest.…”

“…Core–shell structures ( Figure 4 E) have been synthesized with PS- b -PEO, PEO- b -PS [ 27 ] diblock side chains. The living character of Grubbs’ catalysts provided the means to synthesize complex architectures consisting of a block of PEO side chains, a block of poly(2-ethylhexyl methacrylate) side chains and two more blocks of small molecules attached to an NBE main chain [ 72 , 73 , 74 ]. Stars bearing brush PEO arms with covalently bonded anticancer drugs have been synthesized by crosslinking the arms with stimuli-degradable crosslinkers [ 58 , 80 , 81 , 82 ].…”

“…In vivo imaging studies were conducted in cancer infected mice. Their results offered great potential for noninvasive and effective optical imaging, but also for drug delivery applications [ 72 , 73 , 74 , 90 ]. Zhang and his coworkers have exhibited the potential of molecular brushes of oligonucleotides in molecular imaging and targeted therapy through an in vivo study with mice [ 100 ].…”

Sonication‐Induced Formation of Size‐Controlled Self‐Assemblies of Amphiphilic Janus‐Type Polymers as Optical Tumor‐Imaging Agents

“…Recently, we reported the synthesis of dye‐conjugated amphiphilic polysaccharide analogues, which are dual‐type polymers having a polypentose‐mimicked backbone, via ring‐opening metathesis polymerization (ROMP) and dihydroxylation, and their application to high‐contrast optical tumor imaging in vivo ( Figure a) . We successfully prepared various kinds of polymeric solid self‐assemblies (diameter: 150–250 nm) by introducing small alkyl groups, poly(methacrylate)s (PMAs), amino acids, and oligopeptides as hydrophobic side chains.…”