Controlled Fab installation onto polymeric micelle nanoparticles for tuned bioactivity

Science and Technology of Advanced Materials

Kazunori Kataoka¹  Herren Wu²  Abigail Teitgen²  Changshou Gao²  R. James Christie²  Stelios Florinas²  Ze-Qi Xu³  Shaoyi Chen⁴  Horacio Cabral⁴ 

[1] Kawasaki Institute of Industrial Promotion;MedImmune;SynChem, Inc;The University of Tokyo;

关键词: Polymeric micelle;    Fab modification;    conjugation efficiency;    ligand density;    bioactivity;   

DOI  :  10.1080/14686996.2017.1370361

来源: DOAJ

【 摘 要 】

Antibodies and antigen-binding fragments (Fabs) can be used to modify the surface of nanoparticles for enhanced target binding. In our previous work, site-specific conjugation of Fabs to polymeric micelles using conventional methods was limited to approximately 30% efficiency, possibly due to steric hindrance related to macromolecular reactants. Here, we report a new method that enables conjugation of Fabs onto a micelle surface in a controlled manner with up to quantitative conversion of nanoparticle reactive groups. Variation of (i) PEG spacer length in a heterofunctionalized cross-linker and (ii) Fab/polymer feed ratios resulted in production of nanoparticles with a range of Fab densities on the surface up to the theoretical maximum value. The biological impact of variable Fab density was evaluated in vitro with respect to cell uptake and cytotoxicity of a drug-loaded (SN38) targeted polymeric micelle bearing anti-EphA2 Fabs. Fab conjugation increased cell uptake and potency compared with non-targeted micelles, although a Fab density of 60% resulted in decreased uptake and potency of the targeted micelles. Altogether, our findings demonstrate that conjugation strategies can be optimized to allow control of Fab density on the surface of nanoparticles and also that Fab density may need to be optimized for a given cell-surface target to achieve the highest bioactivity.

【 授权许可】

Unknown