Tumor Microenvironment Cascade-Responsive Nanodrug with Self-Targeting Activation and ROS Regeneration for Synergistic Oxidation-Chemotherapy

Abstract

Carrier-free nanodrug with exceptionally high drug payload has attracted increasing attentions. Herein, we construct a pH/ROS cascade-responsive nanodrug which could achieve tumor acidity-triggered targeting activation followed by circularly amplified ROS-triggered drug release via positive-feedback loop. The di-selenide-bridged prodrug synthesized from vitamin E succinate and methotrexate (MTX) self-assembles into nanoparticles (VSeM); decorating acidity-cleavable PEG onto VSeM surface temporarily shields the targeting ability of MTX to evade immune clearance and consequently elongate circulation time. Upon reaching tumor sites, acidity-triggered detachment of PEG results in targeting recovery to enhance tumor cell uptake. Afterward, the VSeM could be dissociated in response to intracellular ROS to trigger VES/MTX release; then the released VES could produce extra ROS to accelerate the collapse of VSeM. Finally, the excessive ROS produced from VES could synergize with the released MTX to efficiently suppress tumor growth via orchestrated oxidation-chemotherapy. Our study provides a novel strategy to engineer cascade-responsive nanodrug for synergistic cancer treatment.

Investigating the crucial roles of aliphatic tails in disulfide bond-linked docetaxel prodrug nanoassemblies

“…Certain drugs or prodrugs were found to self-assemble into uniform nanoassemblies without the help of any amphipathic materials, thus significantly simplifying the fabrication process and improving drug loading efficiency [20] . Particularly, prodrug strategy has been proven to improve the physicochemical properties and to mitigate toxicity of chemotherapeutic agents [21] . Several chemotherapeutic prodrugs have been developed and entered clinical trials, such as elaidic acid-cytarabine prodrug, docosahexaenoic acid-paclitaxel prodrug, and elaidic acid-gemcitabine prodrug [22] .…”

Small‐Molecule Prodrug Nanoassemblies: An Emerging Nanoplatform for Anticancer Drug Delivery

“…C 2 ) Confocal laser scanning microscope (CLSM) images of ROS levels in HeLa cells after treatment at pH 6.5 for 6 h. Reproduced with permission. [ 116 ] Copyright 2020, Springer‐Verlag.…”

“…Using the dual‐responsive strategies, a cascade‐responsive nanoplatform was developed (Figure 12 C 1 ). [ 116 ] The vitamin E succinate (VES)–SeSe–methotrexate (MTX) (VSeM) prodrug nanoassemblies were functionalized with an acidity‐cleavable VES‐N CHPEG PEGylation prodrug. Once reaching tumor sites, acidity‐triggered detachment of PEG would result in enhanced tumor accumulation and cellular uptake.…”

A self-amplified ROS-responsive chemodrug–inhibitor conjugate for multi-drug resistance tumor therapy

“…TPGS consists of α-TOS and polyethylene glycol (PEG), which is not only a P-gp inhibitor, but also a ROS amplifier. 24,25 As shown in Scheme 1a, the terminal hydroxyl of TPGS was first modified with 3-amino-1,2-propanediol and then conjugated with TAM via an aryl boronic ester linker to form a ROS-responsive TPGS-TAM conjugate. Due to the amphiphilic feature of the TPGS-TAM conjugate, it could easily self-assemble into NPs.…”