Harnessing the Protein Corona towards Surface Design for Nanoparticle Tumor Delivery

Abstract

Background Nanoparticles (NPs) decorated with functional ligands (e.g., antibodies) are promising candidates for cancer diagnosis and treatment. However, many studies have shown that chemically coupled targeting moieties on NPs lose their targeting capability in biological milieu because they are shielded or covered by a "protein corona". It is highly desirable to increase the proportion of targeting moieties on the surface of NP-corona complex for purposes of cancer therapy. Results We designed and implemented an alternative engineering strategy for targeted drug delivery by linking a recombinant affibody (RA) scaffold to magnetosomes (BMPs). Pre-adsorption of BMP-RA with anti-HER2 humanized mAb trastuzumab (TZ) resulted in formation of BMP-RA-TZ complex. Linking of TZ to BMP via glutaraldehyde (GA) produced BMP-GA-TZ, which was used as control. Both engineered BMPs contained large amounts of TZ (~ 0.2 mg per mg BMP); however, TZs in BMP-RA-TZ were oriented in a consistent manner with HER2 binding site (Fab) toward the outside, whereas TZs in BMP-GA-TZ were oriented randomly. Degree of HER2 binding to BMP-RA-TZ was > 3x higher than that to BMP-GA-TZ. Incubation of BMP-RA-TZ and BMP-GA-TZ with normal human plasma or IgG-supplemented plasma resulted in alteration of surface proteins because of corona formation. GA-TZ-containing BMPs, in comparison with RA-TZ-containing BMPs, had larger hydrated radii and more surface proteins. The TZ-containing BMPs all could be targeted to and internalized in HER2-overexpressing breast cancer cell line SK-BR-3; however, their targeting efficiencies varied considerably: 50–75% for RA-TZ-containing BMPs, but only 9–19% for GA-TZ-containing BMPs. To simulate human body tumor environment, we incubated BMPs, plasma (100%), and cancer cells together. In this milieu, BMP-RA-TZ uptake efficiency of SK-BR-3 was nearly 80% (slightly lower than for direct interaction with BMP-RA-TZ), whereas BMP-GA-TZ uptake efficiency was < 17%. Conclusion Components of NP protein corona can be modified by linking RA scaffold to NP surface. Application of RA scaffold promoted an oriented arrangement of targeting ligands and reduced the shielding effect of corona proteins. This engineering strategy avoids reduction by corona formation of targeting capability in drug (NP) delivery.