Protein corona in drug delivery for multimodal cancer therapy in vivo

The protein corona is inevitably formed on nanoparticles (NPs) when they are introduced in vivo and has been associated with a reduction in targeting yield, immune recognition and rapid blood clearance, leading to poor tumor accumulation. We have recently shown that it is possible to exploit the protein corona for drug delivery by exploiting it for loading and triggering the release of a photosensitizer Chlorin e6 (Ce6) for simultaneous photodynamic (PDT) and photothermal therapy (PTT) in vitro. Here, we extended our previous in vitro studies to evaluate its effectiveness in vivo. Specifically, we pre-formed the protein corona from mouse serum (MS) around gold nanorods (NRs) and loaded it with Ce6 to form NR-MS-Ce6. The intravenous delivery of NR-MS-Ce6 at a dose of 10 mg kg^-1 Au loaded with 9.63 μg kg^-1 Ce6 into tumor-bearing NCr nude mice resulted in their tumor accumulation reaching a peak concentration of 560.3 μg Au per kg tissue (0.0752% dose) within 6 h post-injection. Subsequent localized laser irradiation of the xenograft tumor resulted in a significant tumor temperature increase of 16.85 °C within 20 min. Combined with the simultaneous reactive oxygen species (ROS) production by Ce6 for PDT, complete tumor regression was achieved within 19 days with no tumor regrowth up to 31 days. Similar to other NPs, significant gold accumulation was observed in the major reticuloendothelial system (RES) organs, particularly the liver and spleen, although no acute toxicity was observed histologically 31 days post-treatment. Our results demonstrated for the first time an in vivo application of the protein corona around NPs in the loading and delivery of drugs in small animals. The ease of drug loading and the biocompatibility of the endogenous serum-based protein corona could make it useful for drug delivery and therapeutic applications instead of merely being considered as a biological artefact to be eliminated.