Synthesis, characterisation and functionalisation of BAB-type dual-responsive nanocarriers for targeted drug delivery: evolution of nanoparticles based on 2-vinylpyridine and diethyl vinylphosphonate

Abstract

The emerging field of nanomedicine gives new opportunities in the treatment of cancer. Aspects such as dosage, bioavailability or the application to the patient can be drastically improved. Previously our group reported an efficient route towards cross-linked nanospheres based on ABB′ block copolymers made from 2-vinylpyridine (2VP), diethyl vinylphosphonate (DEVP) and diallyl vinylphosphonate (DAlVP). Followed by thiol–ene click chemistry stable nanoparticles were formed. Herein, this promising concept was extended to copolymers with the analogous B′BABB′ architecture. In this context the new yttrium complex 5 was investigated in the rare-earth metal-mediated group transfer polymerisation (REM-GTP) and used for the generation of copolymers with different monomer feeds (2VP: 100–300 equiv.; DEVP: 200–300 equiv.; DAlVP: 6–20 equiv.) to explore the influence of the copolymer compositon on the nanoparticle properties. After successful cross-linking with various cross-linking agents, all nanoparticles were characterised via DLS and TEM. These size measurements revealed defined, almost spherical particles (d_DLS = 17–52 nm; d_TEM = 17–43 nm) and were mainly affected by the 2VP content and the cross-linking density. Zeta potential measurements resulted in values in the range from −6 mV to −22 mV and revealed an influence of the cross-linking agent on the surface charge. Studies on the release behaviour exhibited the fastest release at pH = 4.5. Temperature-wise best results were achieved at 42 °C. Furthermore, we aimed for the conjugation of folic acid as a model compound for a potential application in active drug targeting. The consecutive couplings of cysteamine and dithiol 6 enabled the formation of an amine-modified precursor which was reacted with a folic acid derivative. Zeta potential measurements and analysis by NMR spectroscopy corroborated a successful conjugation while DLS and TEM (d_DLS = 44 nm; d_TEM = 38 nm) indicated defined nanoparticles.