Metal (Au)-Decorated Chitosan-l-Arginine Polymeric Vector for Codelivery of Gefitinib and miR125b for Lung Cancer Therapy AITranslate

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DOI：https://doi.org/10.1021/acsapm.1c01515

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The progression of lung cancer is highly associated with the aberrant activation of epidermal growth factor receptor (EGFR) tyrosine kinase and the positive feedback loop between cancer cells and tumor-associated macrophages (TAMs). Hence, we use chitosan (CS) as a backbone and l-Arginine (l-Arg) as lateral chains to synthesize a biocompatible copolymer [(CS)-co-(l-Arg)]. With the electrostatic coupling between Au particles and [(CS)-co-(l-Arg)], the copolymer was further fabricated into [(CS)-co-(l-Arg)]-(AuNPs) nanoparticles with a nest-type perforated structure (CAAu NPs). Owing to the perforated structure and cationic property, CAAu NPs exhibit a high capacity for coloading of gefitinib (GFT) and miR125b, forming GFT-miR125b@CAAu nanomedicine. GFT-miR125b@CAAu shows a pulmonary-anchoring advantage, which is attributed to the mucoadhesion of the CS backbone. Meanwhile, l-Arg residues play a biomimetic role, which endows GFT-miR125b@CAAu with efficient internalization by cancer cells through Arg transporter-mediated endocytosis. Within the acidic tumor microenvironment, the electrostatic bonding of GFT-miR125b@CAAu cleaves, which facilitates pH-responsive release of GFT and miR125b. By combination of EGFR blocking and miR125b augmenting, GFT-miR125b@CAAu nanomedicine not only inhibits cancer cell survival but also deactivates protumoral TAMs, implementing a combination therapy against lung cancer.