Chemodynamic and Photothermal Combination Therapy Based on Dual-Modified Metal-Organic Framework for Inducing Tumor Ferroptosis/Pyroptosis.

Single therapy for tumor therapy always exerts limited ability for the constraints on the reaction condition and the unavoidable multidrug resistance, which seriously influences the therapy effect in the clinic. Herein, a combination treatment nanosystem (MP@PI) based on chemodynamic therapy (CDT) and photothermal therapy (PTT) is constructed for triggering ferroptosis/pyroptosis, which is the metal-organic framework (MOF) modified with polydopamine (PDA) and IR820 to loaded with piperlongumine (PL). The MOF and PL respectively served as the iron source and H2O2 source, performing chemodynamic therapy (CDT) for eliciting ferroptosis. Meanwhile the iron source induces pyroptosis in tumor cells. PDA is not only pH responsive to release PL but also CDT-assisted which due to PDA consumes the glutathione to decrease the expression of glutathione peroxide 4. The photosensitizer IR820 exerts photothermal effects under near-infrared light and further facilitates the ferroptosis/pyroptosis. In addation, the MP@PI nanoplatform evokes the immune response in vivo and enhances the antitumor effects further. Overall, MP@PI is a kind of promising cancer therapy strategy through CDT and PTT combination, inducing ferroptosis and pyroptosis.

Reactive oxygen species / photothermal therapy dual-triggered biomimetic gold nanocages nanoplatform for combination cancer therapy via ferroptosis and tumor-associated macrophage repolarization mechanism.

With the continuous development of cancer nanotechnology, an important trend in the research is to combine the broad application prospects of functional nanomaterials with recent biological discoveries and technological advances. Herein, a cancer cell membrane-camouflaged gold nanocage loading doxorubicin (DOX) and l-buthionine sulfoximine (BSO) (denoted as m@Au-D/B NCs) was constructed as an innovative nanoplatform to confer promising cancer combination therapy by evoking effective ferroptosis and immune responses. Briefly, the loading of BSO and DOX could induce ferroptosis through simultaneous effective glutathione (GSH) consumption and reactive oxygen species (ROS) accumulation. Gold nanocages (AuNCs) with distinct anti-tumor application performance was utilized as ideal nanocarrier for drug loading, evoking photothermal effects and photochemical catalysis to generate more ROS under near-infrared (NIR) irradiation. Moreover, m@Au-D/B NCs-mediated photothermal therapy (PTT) combined with ROS production could repolarize the tumor-associated macrophages (TAMs) from pro-tumor (M2) phenotype to anti-tumor (M1) phenotype, thus improving tumor-suppressive immune environment and then promoting the activation of effector cells and release of pro-inflammatory cytokines, in which the antitumor responses were evoked robustly in a methodical approach. The anti-tumor effects in vivo implied that m@Au-D/B NCs could significantly inhibit tumor growth without severe toxicity. Hence, this homotypic targeting nanosystem could offer an auspicious anticancer access by triggering combination cancer therapy via ferroptosis and tumor-associated macrophage repolarization mechanism.

pH-Sensitive Molecular-Switch-Containing Polymer Nanoparticle for Breast Cancer Therapy with Ferritinophagy-Cascade Ferroptosis and Tumor Immune Activation.

Ferritin internalized into tumor cells is degraded and releases iron ions via ferritinophagy. Iron ions participate in Fenton reaction to produce reactive oxygen species for lipid peroxidation and ferroptosis. Inhibition of indoleamine-2,3-dioxygenase (IDO) decreases tryptophan elimination to induce T cells activation for tumor immunosuppression relief. The active tumor targeting nanoparticles containing ferritin and a pH-sensitive molecular-switch (FPBC@SN) are developed to utilize ferritinophagy-cascade ferroptosis and tumor immunity activation for cancer therapy. FPBC@SN disintegrates in acidic cytoplasm and releases sorafenib (SRF) and IDO inhibitor (NLG919). SRF upregulates nuclear receptor coactivator 4 (NCOA4) to induce ferritin and endogenous iron pool degradation by ferritinophagy, then obtained iron ions participate in the Fenton reaction to produce lipid peroxide (LPO). Meanwhile, SRF blocks glutathione synthesis to downregulate glutathione peroxidase 4 (GPX4) which can scavenge LPO as a different pathway from ferritinophagy to promote ferroptosis in tumor cells. NLG919 inhibits IDO to reduce tryptophan metabolism, so immunity in tumors is aroused to anti-tumor. In vitro and in vivo experiments prove FPBC@SN inhibits tumor cell growth and metastasis, indicating the potential of FPBC@SN for breast cancer therapy based on the combination of ferritinophagy-cascade ferroptosis and tumor immunity activation.

Smart biomimetic metal organic frameworks based on ROS-ferroptosis-glycolysis regulation for enhanced tumor chemo-immunotherapy.

Antitumor immunotherapy is limited by low tumor immunogenicity and immunosuppressive microenvironment (TIME), which could be improved by "ROS-ferroptosis-glycolysis regulation" strategy. Herein, a cancer cell membrane coated metal organic framework (MOF) loading with glucose oxidase (GOx) and doxorubicin (DOX) was constructed (denoted as mFe(SS)/DG). Benefiting from the homotypic targeting of cancer cell membrane, the nanoplatform effectively accumulated in tumors. mFe(SS)/DG based on coordination between Fe3+ and disulfide-bearing ligand scavenged GSH and downregulated glutathione peroxide 4 (GPX4) to trigger ferroptosis. GOx catalyzed glucose to generate abundant H2O2 for enhancing Fenton reaction, resulting in excessive ROS in tumors. The ROS burst simultaneously promoted ferroptosis and inhibited glycolysis. Ferroptosis combined with DOX induced immunogenic cell death (ICD) and released tumor antigens to initiate antitumor immunity. Glycolysis repression remodeled TIME by decreasing lactate to solidify and boost the antitumor immunity. The smart biomimetic nanoplatform integrates tumor metabolism and immunity based on ROS-ferroptosis-glycolysis regulation, providing a potential anti-tumor strategy.

Multifunctional ZnO@CuS nanoparticles cluster synergize chemotherapy and photothermal therapy for tumor metastasis.

The poor drug delivery and unsatisfying therapeutic effects remain to be the primary challenges for cancer therapy. Nanosystem that combines multiple functions into a single platform is an ideal strategy. Here, a smart drug delivery nanoplatform (Z@C-D/P) based on ZnO@CuS nanoparticles, loaded with doxorubicin (DOX) and pirfenidone (PFD) was constructed. Importantly, the ß-CD-DMA and PEG-DMA could be activated in the mild acidic tumor microenvironment, then the nanosystem underwent charge reversal and PFD release. PFD could inhibit cancer-associated fibroblasts (CAFs) activation and enhance tumor penetration. And the residual nanostructure ZnO@CuS could trigger cascade amplified ROS generation to induce tumor cell death. The photothermal effect further strengthened the anti-tumor efficacy. Finally, the nanosystem showed remarkable inhibition of tumor growth (89.7%) and lung metastasis. The innovatively designed nanosystem integrating chemotherapy and photothermal effect would provide a promising strategy in breast cancer therapy.

Ferroptosis/pyroptosis dual-inductive combinational anti-cancer therapy achieved by transferrin decorated nanoMOF.

Non-apoptotic cell death such as ferroptosis and pyroptosis has shed new light on cancer treatment, whereas combinational therapy using both these mechanisms has not yet been fully explored. Herein, a dual-inductive nano-system to realize ferroptosis/pyroptosis mediated anti-cancer effects is presented. The nanodrug (Tf-LipoMof@PL) is constructed with a piperlongumine (PL) loaded metal-organic framework (MOF) coated with transferrin decorated pH sensitive lipid layer. Intracellular iron was enriched with an iron-containing MOF, whose endocytosis can be further facilitated by transferrin decorated on the lipid layer, which provides a prerequisite for the occurrence of ferroptosis and pyroptosis. Piperlongumine as the ferroptosis inducer can strengthen the ferroptotic cell death, and provide H2O2 for the dual induction system to increase ROS generation through Fenton reaction. On the basis of validation of both ferroptosis and pyroptosis, the dual-inductive nanodrug demonstrated ideal anticancer effects in the xenograft mice model, which proved that the ferroptosis/pyroptosis dual-inductive nanoplatform could be an effective and promising anticancer modality.

On-demand responsive nanoplatform mediated targeting of CAFs and down-regulating mtROS-PYK2 signaling for antitumor metastasis.

The desmoplastic tumor microenvironment (DTME), including overexpressed stromal cells and extracellular matrix, formed the first barrier for the accumulation and penetration of nanoparticles in tumors, which compromised the therapeutic efficacy and prognosis. In some metastatic cells, overactivity of the tricarboxylic cycle could overload the electron transport chain resulting in increased mtROS production, which triggered the mitochondria-driven tumor migration and metastasis. Hence, we developed HPBC@TRP/NPs for down-regulating the mtROS-PYK2 pathway and remodeling the DTME to inhibit tumor growth and metastasis for the first time. TPP-RSV prodrugs were synthesized and targeted at mitochondria, resulting in the scavenging of mtROS, lower PYK2 expression, and activation of the mitochondria-driven apoptotic pathway. Pirfenidone fully remodeled the DTME through inhibiting the expression of CAFs, hyaluronan and collagen I, thereby reducing IFP, eliminating the immunosuppressive microenvironment by decreasing the expression of TGF-ß, and increasing the infiltration of cytotoxic T lymphocytes. The combination therapy of different mechanisms via targeting the mtROS-PYK2 pathway and CAFs might provide deeper insights into the inhibition of malignant breast cancer growth and metastasis.

Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells via IL-6/STAT3 Pathway Inhibition.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is the most important limiting factor for treatment efficiency in EGFR-mutant non-small cell lung cancer (NSCLC). Much work has linked the epithelial-mesenchymal transition (EMT) to the emergence of drug resistance, consequently, ongoing research has been focused on exploring the therapeutic options to reverse EMT for delaying or preventing drug resistance. Polyphyllin I (PPI) is a natural compound isolated from Paris polyphylla rhizomes and displayed anti-cancer properties. In the current work, we aimed to testify whether PPI could reverse EMT and overcome acquired EGFR-TKI resistance. We exposed HCC827 lung adenocarcinoma cells to erlotinib which resulted in acquired resistance with strong features of EMT. PPI effectively restored drug sensitivity of cells that obtained acquired resistance. PPI reversed EMT and decreased interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway activation in erlotinib-resistant cells. Moreover, addition of IL-6 partially abolished the sensitization response of PPI. Furthermore, co-treatment of erlotinib and PPI completed abrogation of tumor growth in xenografts, which was associated with EMT reversal. In conclusion, PPI serves as a novel solution to conquer the EGFR-TKI resistance of NSCLC via reversing EMT by modulating IL-6/STAT3 signaling pathway. Combined PPI and erlotinib treatment provides a promising future for lung cancer patients to strengthen drug response and prolong survival.