Asian Journal of Pharmaceutical Sciences
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2025
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IF 11.9
Wei-Ran Cao,Xue Zhang,Jia-Xuan Chen,Lu Sun,Hui-Ning He,Fei Yu
Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation. Compared to the broadly used method of inducing DNA replication arrest to kill cancer, inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities, increase intracellular accumulation of toxic drugs, eventually sensitize chemotherapy and even reverse drug resistance. Breaking the balance of glutathione (GSH) and reactive oxygen species (ROS) contents have been proven efficient in destroying mitochondria respectively. Herein, apigenin, a GSH efflux reagent, and 2′-deoxy-5-fluorouridine 5′-monophosphate sodium salt (FdUMP) that could induce toxic ROS were co-delivered by constructed lipid nanoparticles, noted as Lip@AF. An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity (noted as αCD276-Lip@AF) to enhance the recognition of immune cells to tumor. Results showed that the redox balance was destroyed, leading to severe injury to mitochondria and cell membrane. Furthermore, synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed. Eventually, significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis, apoptosis and pyroptosis. In vivo , strengthen tumor growth inhibition was achieved by αCD276-Lip@AF with high biosafety, providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.
研究领域:
肿瘤学
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药理学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
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2026
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IF 14.1
Chao Wang,Chenxuan Zhao,Yesong Yao,Zhiwen Zou,Anxin Shi,Zhuo Feng,Mingkang Yang,Yue Yu,Yang Liu,Xuehui Rui,Jinhui Wu
Intracellular nucleotide imbalance between ribonucleotides and deoxyribonucleotides can trigger cytosolic mitochondrial DNA (mtDNA) release and subsequent activation of the cGAS–STING pathway. However, fluoropyrimidine-induced nucleotide imbalance is constrained by their metabolic instability. Here, we leverage ribonucleotides to amplify floxuridine (FUDR)-induced mtDNA release and cGAS–STING activation for enhanced cancer chemoimmunotherapy. We identified that cytidine monophosphate (CMP) significantly enhances FUDR-mediated activation of the mtDNA-driven cGAS–STING pathway, inducing over 300-fold upregulation of the interferon gene Ifnb1 and initiating STING-dependent antitumor immunity. Genome-wide CRISPR-Cas9 screening identified five pyrimidine-metabolizing enzymes (CMPK1, CMPK2, TYMP, UPP1, and UPP2) that are responsible for the metabolic instability of floxuridine monophosphate (FdUMP). CMP and its intracellular metabolites can metabolically block these enzymes, thereby increasing the peak intracellular concentration of FdUMP by over 500-fold and extending its half-life by more than 20-fold, which in turn promotes sustained intracellular nucleotide imbalance. To translate this mechanism into therapy, we co-encapsulated FdUMP and CMP into hybrid lipid nanoparticles (FC-NPs). FC-NPs robustly activated STING-dependent antitumor immunity, achieving remarkable therapeutic efficacy in multiple murine colorectal cancer (CRC) models. Our study not only addresses the long-standing issue of fluoropyrimidine metabolic instability but also reveals a novel ribonucleotide-mediated immunomodulatory mechanism, providing a promising strategy to potentiate chemoimmunotherapy in CRC.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Weiran Cao,Xue Zhang,Rui Li,Zijie Li,An Lu,Fei Yu,Lu Sun,Jiancheng Wang,Zhiyu Wang,Huining He
FOLFOX regimen, composed of folinic acid, 5-fluorouracil (5-FU) and oxaliplatin (OXP), has been used as clinical standard therapeutic regimen in treatments of colorectal cancer (CRC) and esophageal squamous cell carcinoma (ESCC). To further improve its therapeutic outcomes, FOLFOX was combined with anti-PD-1 antibody to form an advanced chemo-immune combination strategy, which has been proven more efficient in controlling cancer progression and prolonging patients' survival in various clinical trials. However, bad tumor accumulation, relative high toxicity, numerous treatment cycles with high fees and low compliance as well as drug resistance seriously limit the prognosis of FOLFOX regimen. The “all-in-one” formulations, which could precisely delivery multidrug regimen into tumor sites and cells, showed a promising application prospect for targeted drug delivery as well as reducing side effects. However, the design and preparation of the “all-in-one” formulation with high drug encapsulation efficiencies for all drugs was still challenging. Herein, a lipid core-shell nanoparticle codelivery platform was designed for simultaneous encapsulation of variant FOLFOX composed of miriplatin (MiPt), 5-Fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP), calcium folinate ( CF ) and PD-L1 siRNA (siPD-L1) with high efficiencies, and their synergistic anti-tumor mechanisms were studied, respectively. MiPt, a precursor of OXP, was validated capable of inducing efficient immunogenic cell death (ICD) in this work. Additionally, ICD-mediated release of damage associated molecular patterns functionalized synergistically with PD-L1 silence by siPD-L1 to overcome chemoresistance, reverse suppressive tumor microenvironment and recruit more CD8 + T cells. FdUMP, as the intracellular active form of 5-FU, could induce large amounts of reactive oxygen species to enhance the ICD. CF worked as the sensitizer of FdUMP. The enhanced long-term anti-tumor effect of the prepared “all-in-one” formulation compared to free drug regimen and other controls, was verified in heterotopic CRC mice models and ESCC mice models, providing new thoughts for researchers and showing a promising prospect of translation into clinical applications.
研究领域:
纳米技术
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癌症研究
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药学
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免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）