Cascade-Promoted Photo-Chemotherapy against Resistant Cancers by Enzyme-Responsive Polyprodrug Nanoplatforms

Cisplatin has long been the first-line treatment for a variety of solid tumors. However, the poor pharmacokinetics and intrinsic or acquired drug resistance are the main challenges in cancer therapy. Herein, endogenous enzyme-responsive cisplatin polyprodrug nanoplatforms were developed for cascade-promoted photo-chemotherapy against drug-resistant cancers. The polyprodrug nanoplatforms, ICG/Poly(Pt), were fabricated from the indocyanine green (ICG) photosensitizer and cisplatin polyprodrug amphiphiles, PEG-b-P(Pt-co-GFLG)-b-PEG, consisting of repeated enzyme-degradable GFLG peptides and cisplatin prodrug units in the hydrophobic block and hydrophilic PEG chains, exhibiting ∼24.7 wt % cisplatin loading. Upon cellular uptake in lysosomes, cathepsin B could partially degrade the nanoplatforms into cisplatin prodrug, and then 808 nm laser irradiation would excite ICG to afford reactive oxygen species (ROS) and local hyperthermia, thus launching the phototherapy. Furthermore, the concurrent photodynamic and photothermal process could damage lysosomes to accelerate the cytosolic movement of the cisplatin prodrug away from lysosomes, which was followed by GSH reduction into active cisplatin to initiate cascade chemotherapy. In addition, the polyprodrug nanoplatforms provided dual-model photoacoustic and fluorescence imaging to guide the therapeutic treatments. In vitro and in vivo explorations proved that ICG/Poly(Pt) could significantly inhibit the cisplatin-resistant A549/DDP cancers. The well-defined polyprodrug nanoplatforms exhibited great potential for imaging-guided cascade treatments of resistant cancers in intelligent biomedicine.