Amplification of endoplasmic reticulum stress (ERS) to realize enhanced cancer therapy has been considered to be unique in current cancer nanomedicine design. Herein, the design of metal-phenolic-network-coated dendrimer-drug conjugates as a novel theranostic nanoplatform based on ERS amplification is reported. In the design, acetylated generation-5 poly(amidoamine) dendrimers are conjugated with an ERS drug, toyocamycin (Toy), through the attached phenylboronic acid moiety, and coated with an iron (Fe)-tannic acid (TF) network. The generated nanocomplexes with a size of 50.2 nm are stable under the physiological environment, and can rapidly release Toy under the tumor microenvironment due to the pH- and reactive-oxygen-species-responsive boronic ester bonds to effectively inhibit the ERS-mediated cancer cell adaptation. Meanwhile, the coated TF network enables the nanocomplexes to generate cytotoxic hydroxyl radicals through a Fenton reaction, amplifying the ERS for improved chemo/chemodynamic therapy of cancer cells in vitro and a xenografted breast tumor model in vivo. Moreover, the coating of TF also renders the complexes with an eminent r1 relaxivity for in vivo T1 -weighted tumor magnetic resonance imaging. The created intelligent nanocomplexes may represent an advanced nanomedicine formulation uniquely integrated with a metal-phenolic network and dendrimer nanotechnology for imaging-guided cancer therapy through ERS amplification.
Keywords: amplification of endoplasmic reticulum stress; chemo/chemodynamic therapy; dendrimers; iron-tannic acid networks; toyocamycin.
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