Cancer stem cells (CSCs) play critical roles in tumor growth, metastasis, and chemoresistance. Although several small-molecule inhibitors designed to inhibit CSCs have been investigated in clinical trials, their inadequate tumor targeting and potential off-target side effects have led to poor outcomes. A CD44-targeted virus-mimicking nanomedicine encapsulating the BMI1 inhibitor PTC209 (PTC209@VNP-HA) was designed to treat head and neck squamous cell carcinoma (HNSCC). We used a dendritic mesoporous silica nanoparticle (MSN) as the core for virus-mimicking nanoparticle (VNP) formation after adding shell particles to the MSN surface. The VNP surface was then modified with hyaluronic acid (HA), and PTC209 was adsorbed by mesopores to form PTC209@VNP-HA. In this system, HA is used to target CD44⁺ CSCs. The rough surface of VNP-HA provided better drug delivery efficiency than smooth nanoparticles modified with HA. VNP-HA enhanced the cancer inhibitory effect of PTC209 12-fold compared to the administration of free PTC209, leading to significantly higher bioavailability of PTC209. Both in vitro and in vivo assays showed that PTC209@VNP-HA inhibited cancer stemness, proliferation, and metastasis in HNSCC. Mechanistically, this inhibitory effect is closely associated with DNA damage/apoptosis signaling. Using a series of preclinical models in murine systems, we confirmed that PTC209@VNP-HA eliminated BMI1⁺ CSCs, and greatly inhibited the proliferation and metastasis of HNSCC when combined with cisplatin. This study investigated PTC209@VNP-HA as a novel and potentially transformative HNSCC treatment option that eliminates CSCs, prevents metastasis, and overcomes cisplatin resistance.

2025-04-01·ACS Nano

A Hybrid Manganese Nanoparticle Simultaneously Eliminates Cancer Stem Cells and Activates STING Pathway to Potentiate Cancer Immunotherapy

Article

作者: Cai, Ting ; Diao, Pengfei ; Lv, Pin ; Yang, Yuhan ; Wang, Yuhan ; Cheng, Jie ; Wu, Yaping ; Wang, Dongmiao ; Li, Jin ; Peng, Yayun

Current immunotherapies such as immune checkpoint blockades (ICBs) have revolutionized oncotherapy regime; however, their responsiveness and efficiencies among patients with head and neck squamous cell carcinoma (HNSCC) remain quite limited. The existence of therapeutic-refractory cancer stem cells (CSCs) and inadequate activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) signaling pathway greatly contribute to immune evasion and immunotherapeutic resistance. Herein, we sought to develop a nanocomplex for HNSCC therapy by simultaneous CSCs eradication and STING activation. PTC209/MnO₂@BSA (bovine serum albumin) nanoparticles (PMB NPs) synthesized via a facile and green process are reported, wherein the released manganese (Mn) ions under acidic tumor microenvironment significantly enhance cGAS-STING signals and facilitate the dendritic cells maturation to unleash the T-cell-mediated immune response. Meanwhile, PTC209 released from PMB NPs targets BMI1⁺ CSCs to suppress cancer stemness and epithelial-mesenchymal transition (EMT) and elicits apoptosis to further potentiate Mn-based metalloimmunotherapy. Both in vitro and in vivo experiments elucidate that PMB NPs function as designed, exerting powerful immunotherapeutic and chemotherapeutic impacts to impede HNSCC growth and metastasis as well as bolster anti-PD-1-based ICB. Collectively, our findings provide a promising therapeutic strategy against HNSCC by combinational CSCs elimination and STING activation via metalloimmunotherapy.

2025-01-01·Toxicology Letters

Activation of Wnt/β-catenin signaling to increase B lymphoma Moloney murine leukemia virus insertion region 1 by lithium chloride attenuates the toxicity of cisplatin in the HEI-OC1 auditory cells

Article

作者: Chen, Chao ; Xu, Yingpeng ; Lu, Chen ; Sun, Chen ; Dai, Dingyuan ; Li, Qi

Cisplatin is widely used in anti-tumor therapy, but the ototoxicity caused by high-dose cisplatin often limits its efficacy, and the specific mechanism of cisplatin-induced cochlear damage is still not perfect. The Wnt/β-catenin signaling pathway is closely related to aging, embryonic development, and apoptosis. Meanwhile, B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1) plays a certain role in the evolution and development of the inner ear and the occurrence and development of inner ear-related diseases. Our study intends to explore the role and specific mechanism of the Wnt/β-catenin signaling pathway and BMI1 in improving cisplatin ototoxicity. The appropriate experimental concentrations for each drug were selected by CCK-8 cell proliferation assay and Western Blot to detect apoptosis. The lentivirus transfection of HEI-OC1 cochlear hair cells was used to overexpress BMI1. Western Blot, qPCR, and immunofluorescence detected the activation of each component of BMI1 and Wnt/β-catenin signaling pathway in each experimental model. Wnt/β-catenin signaling pathway and BMI1 are jointly involved in cisplatin-induced cell injury. Low lithium chloride (LiCl) concentrations activated the Wnt/β-catenin pathway, increased BMI1 expression, and reduced cisplatin-induced hair cell injury. In contrast, overexpression of BMI1 inhibited the Wnt/β-catenin pathway and reduced hair cell injury. Meanwhile, the increased cisplatin-induced damage to hair cells by inhibiting BMI1 could not be rescued by LiCl. In conclusion, LiCl can ameliorate cisplatin ototoxicity by elevating BMI1 expression through activation of the Wnt/β-catenin pathway. Overexpression of BMI1 inhibits the Wnt/β-catenin pathway and reduces cisplatin-induced hair cell damage.

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适应症	最高研发状态	国家/地区	公司	日期
类风湿关节炎	临床前	中国	南京医科大学第一附属医院	2024-02-01
结直肠癌	临床前	美国	PTC Therapeutics, Inc.	2014-01-01
结直肠癌	临床前	加拿大	University of Toronto	2014-01-01
结直肠癌	临床前	加拿大	University Health Network	2014-01-01