Polymer-based nanostructures for the targeted delivery of bioactive agents from ring-opening metathesis polymerization.

摘要

Novel, general strategies for the rational construction of well-defined polymer-based nanostructures capable of incorporating a diverse array of bioactive agents have been developed. These methods exploit the unique ability of ring-opening metathesis polymerization (ROMP) to tolerate a wide range of organic functional groups during the preparation of well-defined polymers with pre-programmed architectures.; As an initial demonstration, a series of monodisperse amphiphilic diblock copolymers containing pendant groups of the hydrophobic small-molecule therapeutic indomethacin and the hydrophilic hexaethylene glycol moiety were synthesized from ROMP using the olefin metathesis catalyst (PCy3)2Cl 2Ru=CHPh. The directed-assembly of these amphiphilic copolymers into core-shell polymer nanoparticles (PNPs) in aqueous media was investigated as a function of copolymer composition, concentration, and degree of polymerization. In general, PNPs with average diameters in the range of 90--1000 nm were characterized, the smallest values obtained from the shortest copolymers in the most dilute solutions. Similar methodology was employed for the construction of PNPs containing a high density of covalently linked doxorubicin, one of the most potent and extensively used chemotherapeutic agents in modern cancer treatment. Significantly, sustained release of doxorubicin from these nanoparticles was observed upon exposure to acidic media.; The ROMP-based PNP platform was further used to construct heretofore unattainable drug-containing polymer nanoparticles with reactive surface moieties for conjugation with antisense oligonucleotides and tumor-specific antibodies. The biopolymer components of these multifunctional polymer nanoparticles maintained their molecular recognition capabilities as evidenced through hybridization with gold nanoparticle probes functionalized with complementary motifs. Significantly, they were shown to internalize in SKBR3 human breast cancer cells.; Efforts toward interfacing multifunctional polymer architectures with silicon-based devices have also been described. Hybrid organic-inorganic polymer nanostructures were prepared through surface-initiated ROMP from local field-induced oxide (FIO) patterns drawn on hydrogen-passivated Si(111) surfaces using an atomic force microscope (AFM).