Laser-activatable oxygen self-supplying nanoplatform for efficiently overcoming colorectal cancer resistance by enhanced ferroptosis and alleviated hypoxic microenvironment

Abstract

Background Colorectal cancer (CRC) is the second most deadly cancer worldwide, with chemo-resistance remaining a major obstacle in CRC treatment. Notably, the imbalance of redox homeostasis-mediated ferroptosis and the modulation of hypoxic tumor microenvironment are regarded as new entry points for overcoming the chemo-resistance of CRC. Methods Inspired by this, we rationally designed a light-activatable oxygen self-supplying chemo-photothermal nanoplatform by co-assembling cisplatin (CDDP) and linoleic acid (LA)-tailored IR820 via enhanced ferroptosis against colorectal cancer chemo-resistance. In this nanoplatform, CDDP can produce hydrogen peroxide in CRC cells through a series of enzymatic reactions and subsequently release oxygen under laser-triggered photothermal to alleviate hypoxia. Additionally, the introduced LA can add exogenous unsaturated fatty acids into CRC cells, triggering ferroptosis via oxidative stress-related peroxidized lipid accumulation. Meanwhile, photothermal can efficiently boost the rate of enzymatic response and local blood flow, hence increasing the oxygen supply and oxidizing LA for enhanced ferroptosis. Results This nanoplatform exhibited excellent anti-tumor efficacy in chemo-resistant cell lines and showed potent inhibitory capability in nude mice xenograft models. Conclusions Taken together, this nanoplatform provides a promising paradigm via enhanced ferroptosis and alleviated hypoxia tumor microenvironment against CRC chemo-resistance. Graphical Abstract

Exploiting cell death and tumor immunity in cancer therapy: challenges and future directions

“…Carrier-free nanocomponents containing sorafenib (Sor) and gambogic acid (GA) deplete GSH, inducing ferroptosis in vitro and in vivo , exhibiting potent antitumor activity ( Lei et al, 2023 ). A photoactivated oxygen self-supplying chemical photothermal nanoplatform enhances ferroptosis and alleviates hypoxia-induced chemoresistance in colorectal cancer (CRC) ( Jiang et al, 2023 ). Phenanthroindolizidine alkaloids, natural products that inhibit various cancers, show promise in overcoming tumor resistance ( Peng et al, 2023 ).…”

Oxygen Self-Supplied Perfluorocarbon-Modified Micelles for Enhanced Cancer Photodynamic Therapy and Ferroptosis

“…14 Subsequently, these ROS engage in reactions with unsaturated fatty acids in lipid membranes, leading to the production of lipid peroxides (LPO). 15,16 The metabolism of LPO requires the catalytic activity of glutathione peroxidase 4 (GPX4). 17 And glutathione (GSH) plays a crucial role as a substrate for GPX4 including aiding in the reduction of LPO through the GPX4 pathway 18 and maintaining the intracellular redox balance.…”

“…Instead, it is characterized by the regulation of intracellular lipid peroxidation, , ferritin deposition, and the intracellular redox reaction. , Specifically, oxygen is initially converted into reactive oxygen species (ROS) within the mitochondria through redox reactions . Subsequently, these ROS engage in reactions with unsaturated fatty acids in lipid membranes, leading to the production of lipid peroxides (LPO). , The metabolism of LPO requires the catalytic activity of glutathione peroxidase 4 (GPX4) . And glutathione (GSH) plays a crucial role as a substrate for GPX4 including aiding in the reduction of LPO through the GPX4 pathway and maintaining the intracellular redox balance. , Consequently, the three common ways for inducing ferroptosis involve the inhibition of GSH production, suppression of GPX4 expression, or the generation of excess ROS through the Fenton reaction. , For instance, various iron- and manganese-based nanomaterials have been designed to induce an intracellular Fenton-like effect, , thereby promoting ferroptosis.…”

RPF2 mediates the CARM1‑MYCN axis to promote chemotherapy resistance in colorectal cancer cells

“…For the treatment of CRC, although cisplatin is no longer the first choice due to its unique distribution preference in ascites, cisplatin still has potential advantages for patients with advanced tumors complicated by ascites ( 16 ). There are still a large number of investigators attempting to develop entirely new regimens for cisplatin in CRC treatment, implying that cisplatin still retains great potential in CRC therapy ( 17 , 18 ). In summary, the present study aimed to refine and validate the above hypotheses and further investigate the related signaling pathway mechanisms, providing a basis for the selection of new chemotherapeutic targets, chemosensitization of chemotherapeutic agents, especially platinum drugs led by cisplatin, as well as the production of new combination chemotherapeutic regimens.…”