Tumor-Specific Endogenous Fe^II-Activated, MRI-Guided Self-Targeting Gadolinium-Coordinated Theranostic Nanoplatforms for Amplification of ROS and Enhanced Chemodynamic Chemotherapy

Abstract

Low drug payload and lack of tumor-targeting for chemodynamic therapy (CDT) result in an insufficient reactive oxygen species (ROS) generation, which seriously hinders its further clinical application. Therefore, how to improve the drug payload and tumor targeting for amplification of ROS and combine it with chemotherapy has been a huge challenge in CDT. Herein, methotrexate (MTX), gadolinium (Gd), and artesunate (ASA) were used as theranostic building blocks to be coordinately assembled into tumor-specific endogenous Fe II -activated and magnetic resonance imaging (MRI)-guided self-targeting carrierfree nanoplatforms (NPs) for amplification of ROS and enhanced chemodynamic chemotherapy. The obtained ASA-MTX-Gd III NPs exhibited extremely high drug payload (∼96 wt %), excellent physiological stability, long circulating ability (half-time: ∼12 h), and outstanding tumor accumulation. Moreover, ASA-MTX-Gd III NPs could be specifically uptaken by tumor cells via folate (FA) receptors and subsequently be disassembled via lysosomal acidity-induced coordination breakage, resulting in drug burst release. Most strikingly, the produced ASA could be catalyzed by tumor-specific overexpressed endogenous Fe II ions to generate sufficient ROS for enhancing the main chemodynamic efficacy, which could exert a synergistic effect with the assistant chemotherapy of MTX. Interestingly, ASA-MTX-Gd III NPs caused a lower ROS generation and toxicity on normal cell lines that seldom expressed endogenous Fe II ions. Under MRI guidance with assistance of self-targeting, significantly superior synergistic tumor therapy was performed on FA receptor-overexpressed tumor-bearing mice with a higher ROS generation and an almost complete elimination of tumor. This work highlights ASA-MTX-Gd III NPs as an efficient chemodynamic-chemotherapeutic agent for MRI imaging and tumor theranostics.

Chemodynamic Therapy via Fenton and Fenton‐Like Nanomaterials: Strategies and Recent Advances

“…In addition to DOX and cisplatin, there are also other drugs that are suitable for the synergy of chemotherapy and iron‐based CDT, such as cinnamaldehyde (CA), [ 76,77 ] methotrexate (MTX), [ 78 ] PTX, [ 79 ] and tamoxifen. [ 80 ] Xu and co‐workers prepared a pH/redox dual‐responsive supramolecular nanoreactor (termed HA‐CD/Fc‐CA NPs) for synergistic chemotherapy/CDT.…”

“…used methotrexate (MTX), gadolinium (Gd), and artesunate (ASA) to design ASA‐MTX‐Gd III NPs according to the fact that the endoperoxide of ASA could react with Fe(II) to generate toxic O 2 •− . [ 78 ] The authors employed MTX and Gd III as building blocks to form MTX‐Gd III complex via coordination interaction. Then the complex was self‐assembled with ASA, leading to the formation of ASA‐MTX‐Gd III NPs.…”

Shuttle-Shape Carrier-Free Platinum-Coordinated Nanoreactors with O2 Self-Supply and ROS Augment for Enhanced Phototherapy of Hypoxic Tumor

“…Recently, the combination therapy of various chemodrugs and other therapeutic modalities such as photodynamic therapy (PDT) and photothermal therapy (PTT) has broken through the limitations of a single-modal treatment method owing to the superiorities of both modalities and by dodging the shortcomings of each modality. , A classic example is that chemodrug 10-hydroxycamptothecin (CPT) as an inhibitor of hypoxia-inducible factor-1α (HIF-1α) can trigger excessive ROS generation within mitochondria . In addition, PDT as a noninvasive method can generate ROS within tumor cells under light irradiation, resulting in irreversible damage toward tumor cells. , Nevertheless, the PDT efficiency is substantially impeded by the hypoxia characteristics of solid tumors. − Therefore, improving tumor hypoxia and ROS augment is urgent and essential.…”

Rationally Designed Micellar Nanocarriers for the Delivery of Hydrophilic Methotrexate in Psoriasis Treatment

“…In a recent report, MTX was incorporated into a metal-organic complex nanoparticle with Gd III ions and artesunate with a total drug content of 94% (wt %) for chemodynamic therapy. 24 Although many more NPs and prodrugs have been applied for MTX delivery, 25−29 it remains challenging to develop an efficient nanocarrier for efficient MTX delivery with small size and high loading capacity and stability for immune-modulating therapy and cancer therapy. The chemical structure of MTX is featured with significant negative charges and aromatic and hydrogen-bonding components, which can be rationally targeted in the nanocarrier design.…”

“…The drug content reached 85% in the co-precipitates, however, with relatively large particle sizes of over 180 nm, which led to significant reticuloendothelial system (RES) clearance in the liver and spleen. In a recent report, MTX was incorporated into a metal-organic complex nanoparticle with Gd III ions and artesunate with a total drug content of 94% (wt %) for chemodynamic therapy . Although many more NPs and prodrugs have been applied for MTX delivery, − it remains challenging to develop an efficient nanocarrier for efficient MTX delivery with small size and high loading capacity and stability for immune-modulating therapy and cancer therapy.…”