Polymeric Nanoparticles with a Sera-Derived Coating for Efficient Cancer Cell Uptake and Killing

[Image: see text] Nanoparticle-mediated cancer drug delivery remains an inefficient process. The protein corona formed on nanoparticles (NPs) controls their biological identity and, if optimized, could enhance cancer cell uptake. In this study, a hyperbranched polyester polymer (HBPE) was synthesized from diethyl malonate and used to generate NPs that were subsequently coated with normal sera (NS) collected from mice. Cellular uptake of NS-treated HBPE-NPs was compared to PEGylated HBPE-NPs and was assessed using MDA-MB-231 triple-negative breast cancer (TNBC) cells as well as endothelial and monocytic cell lines. NS-treated HBPE-NPs were taken up by TNBC cells more efficiently than PEGylated HBPE-NPs, while evasion of monocyte uptake was comparable. NS coatings facilitated cancer cell uptake of HBPE-NPs, even after prior interaction of the particles with an endothelial layer. NS-treated HBPE-NPs were not inherently toxic, did not induce the migration of endothelial cells that could lead to angiogenesis, and could efficiently deliver cytotoxic doses of paclitaxel (taxol) to TNBC cells. These findings suggest that HBPE-NPs may adsorb select sera proteins that improve uptake by cancer cells, and such NPs could be used to advance the discovery of novel factors that improve the bioavailability and tissue distribution of drug-loaded polymeric NPs.