Controlling the Biological Fate of Micellar Nanoparticles: Balancing Stealth and Targeting

Integrating nanomaterials with biological entities has led to the development of diagnostic tools and biotechnology-derived therapeutic products. However, to optimize the design of these hybrid bionanomaterials, it is essential to understand how controlling the biological interactions will influence desired outcomes. Ultimately, this knowledge will allow more rapid translation from the bench to the clinic. In this paper, we developed a micellar system that was assembled using modular antibody-polymer amphiphilic materials. The amphiphilic nature was established using either poly(ethylene glycol) (PEG) or a single-chain variable fragment (scFv) from an antibody as the hydrophile and a thermoresponsive polymer (poly(oligoethylene glycol) methyl ether methacrylate) as the hydrophobe. By varying the ratios of these components, a series of nanoparticles with different antibody content was self-assembled, where the surface presentation of targeting ligand was carefully controlled. In vitro and in vivo analysis of these systems identified a mismatch between the optimal targeting ligand density to achieve maximum cell association in vitro compared to tumor accumulation in vivo. For this system, we determined an optimum antibody density for both longer circulation and enhanced targeting to tumors that balanced stealthiness of the particle (to evade immune recognition as determined in both mouse models and in whole human blood) with enhanced accumulation achieved through receptor binding on tumor cells in solid tumors. This approach provides fundamental insights into how different antibody densities affect the interaction of designed nanoparticles with both target cells and immune cells, thereby offering a method to probe the intricate interplay between increased targeting efficiency and the subsequent immune response to nanoparticles.