Flexible manipulation of the fate of cancer cells through exogenous stimulation-induced metabolic reprogramming could handle the cellular plasticity-derived therapies resistance, which provides an effective paradigm for the treatment of refractory and relapsing tumors in clinical settings. Herein, we demonstrated that moderate heat (45 °C) could significantly regress the expression of antioxidants and trigger specific lipid metabolic reprogramming in cancer cells synergized with iron oxide nanoparticles (Fe 3 O 4 NPs). This metabolic control behavior destroyed the tumor redox homeostasis and produced overwhelming lipid peroxides, consequently sensitizing the tumor to ferroptosis. Based on these findings, a heat-triggered tumor-specific ferroptosis strategy was proposed by the rational design of a polypeptide-modified and 1H-perfluoropentane (1H-PFP)-encapsulated Fe 3 O 4 -containing nanoformulation (GBP@Fe 3 O 4 ). When irradiated by an 808 nm laser, the phase transition of 1H-PFP was triggered by localized moderate heat (45 °C), leading to burst release of Fe 3 O 4 in situ to produce potent reactive oxygen species through the Fenton reaction in the tumor microenvironment. Together with the antioxidant inhibition response and distinctive lipid metabolic reprogramming by heat stress, this oxidative damage was amplified to induce tumor ferroptosis and achieve sufficient antitumor effects. Importantly, we confirmed that ACSBG1, an acyl-CoA synthetase, was the key pro-ferroptotic factor in this heat-induced ferroptosis process. Moreover, knockout of this gene could realize cancer cell death fate conversion from ferroptosis to non-ferroptotic death. This work provides mechanistic insights and practical strategies for heat-triggered ferroptosis in situ to reduce the potential side effects of direct ferroptosis inducers and highlights the key factor in regulating cell fate under heat stress.
Immune responses stimulated by photodynamic therapy (PDT) and photothermal therapy (PTT) are a promising strategy for the treatment of advanced cancer. However, the antitumor efficacy by PDT or PTT alone is less potent and unsustainable against cancer metastasis and relapse. In this study, Gd 3+ and chlorin e6 loaded single‐walled carbon nanohorns (Gd‐Ce6@SWNHs) are developed, and it is demonstrated that they are a strong immune adjuvant, and have high tumor targeting and penetration efficiency. Then, three in vivo mouse cancer models are established, and it is found that sequential PDT and PTT using Gd‐Ce6@SWNHs synergistically promotes systemic antitumor immune responses, where PTT stimulates dendritic cells (DCs) to secrete IL‐6 and TNF‐ α , while PDT triggers upregulation of IFN‐ γ and CD80. Moreover, migration of Gd‐Ce6@SWNHs from the targeted tumors to tumor‐draining lymph nodes sustainably activates the DCs to generate a durable immune response, which eventually eliminates the distant metastases without using additional therapeutics. Gd‐Ce6@SWNHs intervened phototherapies also generate durable and long‐term memory immune responses to tolerate and prevent cancer rechallenge. Therefore, this study demonstrates that sequential PDT and PTT using Gd‐Ce6@SWNHs under moderate conditions elicits cooperative and long‐lasting antitumor immune responses, which are promising for the treatment of patients with advanced metastatic cancers.
GE11-PDA-Pt@USPIOs can relieve tumor hypoxic conditions efficiently and are highly effective for radio-chemotherapy of EGFR-positive tumors.
Tumor combination therapy using nano formulations with multimodal synergistic therapeutic effects shows great potential for complete ablation of tumors. However, targeting tumor metastases with nano structures is a major obstacle for therapy. Therefore, developing a combination therapy system able to target both primary tumors and their metastases at distant sites with synergistic therapy is desirable for the complete eradication of tumors. To this end, a dual chemodrug-loaded theranostic system based on single walled carbon nanohorns (SWNHs) is developed for targeting both primary breast tumors and their lung metastases.Methods: SWNHs were first modified simultaneously with poly (maleic anhydride-alt-1-octadecene) (C18PMH) and methoxypolyethyleneglycol-b-poly-D, L-lactide (mPEG-PLA) via hydrophobic-hydrophobic interactions and π-π stacking. Then cisplatin and doxorubicin (DOX) (2.9:1 molar ratio) were sequentially loaded onto the modified nanohorns in a noninterfering way. After careful examinations of the release profiles of the loaded drugs and the photothermal performance of the dual chemodrug-loaded SWNHs, termed SWNHs/C18PMH/mPEG-PLA-DOX-Pt, the dual drug chemotherapeutic and chemo-photothermal synergetic therapeutic effects on tumor cells were evaluated. Subsequently, the in vivo behavior and tumor accumulation of the drug-loaded SWNHs were studied by photoacoustic imaging (PAI). For chemo-photothermal therapy of tumors, 4T1 tumor bearing mice were intravenously injected with SWNHs/C18PMH/mPEG-PLA-DOX-Pt at a dose of 10 mg/kg b.w. (in SWNHs) and tumors were illuminated by an 808 nm laser (1W/cm2 for 5 min) 24 h post-injection.Results: DOX and cisplatin were loaded onto the modified SWNHs with high efficiency (44 wt% and 66 wt%, respectively) and released in a pH-sensitive, tandem and sustainable manner. The SWNHs/C18PMH/mPEG-PLA-DOX-Pt had a hydrodynamic diameter of 182 ± 3.2 nm, were highly stable in physiological environment, and had both dual drug chemotherapeutic (CI = 0.439) and chemo-photothermal synergistic antitumor effects (CI = 0.396) in vitro. Moreover, the dual drug-loaded SWNHs had a long blood half-life (10.9 h) and could address both the primary breast tumors and their lung metastases after intravenous administration. Consequently, chemo-photothermal combination therapy ablated the primary tumors and simultaneously eradicated the metastatic lung nodules.Conclusion: Our study demonstrates that SWNHs/C18PMH/mPEG-PLA-DOX-Pt is highly potent for chemo-photothermal combination therapy of primary tumors and cocktail chemotherapy of their metastases at a distant site.
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