Precisely Assembled Nanoparticles against Cisplatin Resistance via Cancer-Specific Targeting of Mitochondria and Imaging-Guided Chemo-Photothermal Therapy

Abstract

Cisplatin resistance in tumor cells is known mainly due to the reduced accumulation of platinum ions by efflux, detoxification by intracellular GSH, and nucleotide excision repair machinery-mediated nuclear DNA repair. In this work, theranostic Pt(IV)-NPs, which are precisely self-assembled by biotin-labeled Pt(IV) prodrug derivative and cyclodextrin-functionalized IR780 in a 1:1 molecular ratio, have been developed for addressing all these hurdles via mitochondria-targeted chemotherapy solely or chemophotothermal therapy. In these nanoparticles, IR780 as a small-molecule dye acts as a mitochondria-targeting ligand to make Pt(IV)-NPs relocate finally in the mitochondria and release cisplatin. As demonstrated by in vitro and in vivo experiments, Pt(IV)-NPs can markedly facilitate cancer-specific mitochondrial targeting, inducing mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage, thus greatly increasing the Pt accumulation, reducing the GSH levels, and avoiding DNA repair machinery in cisplatin-resistant cancer cells (A549R), finally resulting in significant inhibition of A549R tumor growth on animal models by chemotherapy solely. Upon nearinfrared irradiation, mitochondria-targeted chemophotothermal synergistic therapy can be realized, further overcoming cisplatin resistance and even eliminating A549R tumors completely. Moreover, such novel Pt(IV)-NPs integrate multimodal targeting (cancer and mitochondria targeting), imaging (near-infrared imaging and photoacoustic imaging), and therapeutic (chemo-and photothermal therapy) moieties in a constant ratio (1:1:1) into a single, reproducible, and structurally homogeneous entity, avoiding nonuniform drug loading and premature leakage as well as the discrete steps of imaging and therapy, which thus is more beneficial for precise therapeutics and future clinical translation.

Cellular Toxicity Mechanisms and the Role of Autophagy in Pt(IV) Prodrug-Loaded Ultrasmall Iron Oxide Nanoparticles Used for Enhanced Drug Delivery

“…Furthermore, after t = 3 h in drug-free media, the concentration was twofold higher (up to 17,400 ± 75 ng Pt/ mg DNA), showing that the platination of mtDNA when using Pt(IV)-FeNPs was also more efficient here than when using cisplatin directly and required, as in the case of nDNA, a time lapse. Therefore, once cisplatin was released from the nanoparticles, the quantity of adducts formed with mtDNA increased by as much as 30-fold compared to nDNA, and this must be considered a significant contribution to cell toxicity, as proposed by other authors [ 19 , 29 ].…”

Mitochondria-Targeted Mesoporous Organic Silica Nanoplatforms for Overcoming Cisplatin Resistance by Disturbing Mitochondrial Redox Homeostasis

“…With mitochondrial GSH depletion, DDP is released from nanoplatforms and attacks mitochondria. Mitochondrial damage can be estimated by MMP and intracellular ATP levels ( Yang et al, 2020 ). Then, we measured the MMP using the fluorescent probe JC-1.…”

The role of non‐coding RNAs in drug resistance of oral squamous cell carcinoma and therapeutic potential

“…Meanwhile, Yang et al. [ 185 ] also developed Pt(IV)‐NPs assembled from biotin‐labeled Pt(IV) prodrug derivative and cyclodextrin‐functionalized IR780. Since IR780 acted as a targeting ligand for mitochondria, Pt(IV)‐NPs could localize in mitochondria and release CDDP, inducing mitochondrial DNA damage, thereby, downregulating GSH level and inhibiting DNA repair mechanisms.…”