Impact of spacer chain length on self-assembly of paclitaxel-biotin conjugates

Here we describe the synthesis and physicochemical evaluation of a series of paclitaxel-biotin conjugates with systematically varied linker lengths. The structure of the synthesized compounds was confirmed by NMR spectroscopy and HRMS. Elongation of the spacer chain was found to increase hydrophobicity and decrease aqueous solubility. Conjugates with linkers of at least 17 linearly connected atoms retained the ability to self-assemble into spherical nanoparticles with characteristics suitable for passive tumor targeting. Nanoparticle formation via nanoprecipitation proceeded with high encapsulation efficiency. Increasing the spacer chain length resulted in a lower ζ-potential and a modest increase in the hydrodynamic diameter, while the polydispersity index remained consistently below 0.2, indicating a narrow size distribution of the nanostructures. The nanoparticles demonstrated high colloidal stability in aqueous medium. Importantly, the increased hydrophobicity did not lead to significant changes of the key nanostructures' characteristics in diluted plasma, suggesting potential in vivo stability. The conjugates' structure did not affect the hemolytic activity of the nanostructures. The obtained results allow us to consider paclitaxel-biotin nanoparticles as a promising platform for dual targeted drug delivery.