Near-infrared light triggered multi-hit therapeutic nanosystem for tumor specific photothermal effect amplified signal pathway regulation and ferroptosis

Abstract

The high therapeutic resistance of tumor is the primary cause behind tumor recurrence and incurability. In recent years, scientists have devoted themselves to find a variety of treatments to solve this problem. Herein, we propose a multi-hit strategy that is based on the biodegradable hollow mesoporous Prussian blue (HMPB)-based nanosystem for tumor-specific therapy that encapsulated the critical heat shock protein 90 (HSP90) inhibitor 17-dimethylamino-ethylamino-17-demethoxydeldanamycin (17-DMAG). The nanosystem was further modified using thermotropic phase transition material star-PEG-PCL (sPP) and hyaluronic acid (HA), which offers near infrared light (NIR) responsive release characteristic, as well as enhanced tumor cell endocytosis. Upon cell internalization of 17-DMAG-HMPB@sPP@HA and under 808 nm laser irradiation, photothermal-conversion effect of HMPB directly kills cells using hyperthermia, which further causes phase transition of sPP to trigger release of 17-DMAG, inhibits HSP90 activity and blocks multiple signaling pathways, including cell cycle, Akt and HIF pathways. Additionally, the down-regulation of GPX4 protein expression by 17-DMAG and the release of ferric and ferrous ions from gradual degradation of HMPB in the endogenous mild acidic microenvironment in tumors promoted the occurrence of ferroptosis. Importantly, the antitumor effect of 17-DMAG and ferroptosis damage were amplified using photothermal effect of HMPB by accelerating release of ferric and ferrous ions, and reducing HSP90 expression in cells, which induced powerful antitumor effect in vitro and in vivo . This multi-hit therapeutic nanosystem helps provide a novel perspective for solving the predicament of cancer treatment, as well as a promising strategy for design of a novel cancer treatment nanoplatform.

Black Silver Nanocubes@Amino Acid-Encoded Highly Branched Gold Shells with Efficient Photothermal Conversion for Tumor Therapy

“…After co-incubation and 808 nm laser irradiation, the cells were stained with calcein AM and PI solutions, which can discern live or dead cells through green or red fluorescence emission, respectively. 53 As shown in Figures 9 and S11, nearly all the three cells were alive after laser irradiation alone and after incubation with the samples without laser irradiation. It was indicated again that the bimetallic nanoparticles had a low effect on the cells, and the 808 nm laser also showed low damage to the cells.…”

Ferroptosis-Driven Nanotherapeutics to Reverse Drug Resistance in Tumor Microenvironment

“…Therefore, the hollow mesoporous PB nanoparticles (HMPB) encapsulated 17-dimethylamino-ethylamino-17-deme-thoxydeldanamycin (17-DMAG), a HSP inhibitor, into its inner cavity and their surfaces were modified with thermotropic phase transition material star-PEG-polycaprolactone (PCL) for laser irradiation. Besides, HA was coated onto the outer layer in order to improve hydrophilicity and enhance CD44 receptor-mediated endocytosis . 17-DMAG, ferric, and ferrous ions would be released after endocytosis, resulting in the down-regulation of several carcinogenic pathways by suppressing HSP90 and ROS accumulation-induced ferroptosis through increasing ferric and ferrous ions, which further inhibits proliferation of cancer cells.…”

“…Besides, HA was coated onto the outer layer in order to improve hydrophilicity and enhance CD44 receptor-mediated endocytosis. 250 17-DMAG, ferric, and ferrous ions would be released after endocytosis, resulting in the down-regulation of several carcinogenic pathways by suppressing HSP90 and ROS accumulation-induced ferroptosis through increasing ferric and ferrous ions, which further inhibits proliferation of cancer cells.…”

Extracellular HSP90α inhibits ferroptosis through GPX4 in NSCLC cells

“…Interestingly, nanoparticles that affect both GPX4 and HSP90 expression have recently been found to have tremendous antitumor effects. The newly synthesized nanoparticle 17-DMAG-HMPB@sPP@HA can downregulate the expression of GPX4, while the photothermal effect of this drug accelerates the degradation and release of iron and ferrous ions, reduces the expression of HSP90, and induces ferroptosis in tumor cells [20]. Therefore, combining ferroptosis inhibitors with other therapeutic approaches seems to be an effective strategy for a more potent induction of ferroptosis [21,22].…”