Genetically Encoding Albumin Binding into Chemotherapeutic-loaded Polypeptide Nanoparticles Enhances Their Antitumor Efficacy.
We report the development of drug-encapsulating nanoparticles that bind endogenous albumin upon intravenous injection and evaluate their in vivo performance in a murine as well as canine animal model. The gene encoding a protein-G derived albumin binding domain (ABD) was fused to that of a chimeric polypeptide (CP), and the ABD-CP fusion was recombinantly synthesized by bacterial expression of the gene. Doxorubicin (DOX) was conjugated to the C-terminus of the ABD-CP fusion, and conjugation of multiple copies of the drug to one end of the ABD-CP triggered its self-assembly into ∼100 nm diameter spherical micelles. ABD-decorated micelles exhibited submicromolar binding affinity for albumin and also preserved their spherical morphology in the presence of albumin. In a murine model, albumin-binding micelles exhibited dose-independent pharmacokinetics, whereas naked micelles exhibited dose-dependent pharmacokinetics. In addition, in a canine model, albumin binding micelles resulted in a 3-fold increase in plasma half-life and 6-fold increase in plasma exposure as defined by the area under the curve (AUC) of the drug, compared with naked micelles. Furthermore, in a murine colon carcinoma model, albumin-binding nanoparticles demonstrated lower uptake by the reticuloendothelial system (RES) system organs, the liver and spleen, that are the main target organs of toxicity for nanoparticulate delivery systems and higher uptake by the tumor than naked micelles. The increased uptake by s.c. C26 colon carcinoma tumors in mice translated to a wider therapeutic window of doses ranging from 20 to 60 mg equivalent of DOX per kg body weight (mg DOX equiv·kg-1 BW) for albumin-binding ABD-CP-DOX micelles, as compared to naked micelles that were only effective at their maximum tolerated dose of 40 mg DOX equiv·kg-1 BW.
Yousefpour, P; McDaniel, JR; Prasad, V; Ahn, L; Li, X; Subrahmanyan, R; Weitzhandler, I; Suter, S; Chilkoti, A
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