Acidic tumor microenvironment-sensitive liposomes enhance colorectal cancer therapy by acting on both tumor cells and cancer-associated fibroblasts

Li, Chenglei; Li, Zhaohuan; Gong, Xue; Liu, Jianhao; Zheng, Tingyue; Wang, Fangqing; Wu, Jingliang; Zhang, Bo

doi:10.1039/d1nr01506k

Cited by 12 publications

(5 citation statements)

References 49 publications

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“…This observation was consistent with the results of prior studies involving B16, CT26, and 4T1 tumors mixed with NIH3T3 fibroblasts. 14 – 16 Western blotting revealed that FAP was highly expressed in the NIH3T3-FAP cell line, whereas was not expressed in MC38 and CT26 cells (Fig. 1b ).…”

Section: Resultsmentioning

confidence: 99%

Antitumor efficacy and potential mechanism of FAP-targeted radioligand therapy combined with immune checkpoint blockade

Zhao,

Pang,

Zhou

et al. 2024

Sig Transduct Target Ther

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Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that 68Ga/177Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with 177Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of 177Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8+ T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that 177Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with 177Lu-LNC1004 for cancer patients with FAP-positive tumors.

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Section: Resultsmentioning

confidence: 99%

Antitumor efficacy and potential mechanism of FAP-targeted radioligand therapy combined with immune checkpoint blockade

Zhao,

Pang,

Zhou

et al. 2024

Sig Transduct Target Ther

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“…Recent research has shown that the normal fibroblasts could be activated by tumor cells. , To mimic the hepatoma TME in vitro, LX-2 cells were incubated with the condition medium of 7402 cells for 24 h. A cellular immunofluorescence assay was performed to explore whether the cocultured model was established successfully. Briefly, LX-2 cells were seeded into cover-glass bottom dishes and treated with the 7402 cell condition medium for 24 h. Then, the solutions were removed, and the cells were treated with various formulations.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous research reported that liposomes were safe carriers for drug delivery due to their biocompatible and lower cytotoxicity. 32 In this study, the in vitro cytotoxicity of various formulations was assessed using the MTT assay. As shown in Figure 4A,B, all the drug formulations showed concentration-dependent cytotoxicity.…”

Section: Combination Therapy Inhibits the Activation Ofmentioning

confidence: 99%

Dual-Ligand-Modified Nanoscale Liposomes Loaded with Curcumin and Metformin Inhibit Drug Resistance and Metastasis of Hepatocellular Carcinoma

Gong

Wen

et al. 2022

ACS Appl. Nano Mater.

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In the tumor microenvironment (TME), the cross-talk between tumor cells and hepatic stellate cells (HSCs) could facilitate tumor drug resistance and metastasis, leading to poor prognosis in the patients with hepatocellular carcinoma (HCC). Herein, blocking the cross-talk would be an effective antitumor strategy. In this study, nanoscale dual-ligand-modified multifunctional liposomes (CMDLs) were prepared for the codelivery of curcumin and metformin. To mimic a real TME, the “HSC + HCC” cell cocultured model and “m-HSC–HCC” coimplanted model were established to evaluate the antitumor effect in vitro and in vivo, respectively. These models have been proven to be more efficient for antitumor analysis than tumor cells alone. Compared to free drugs, CMDLs well strengthened drug internalization and drug retention in vitro. Notably, the combined drug formulations, especially CMDLs, exhibited a greater proapoptotic effect than single treatment groups. Furthermore, the in vivo antitumor studies showed that CMDLs exhibited low extracellular matrix deposition, less tumor angiogenesis, and superior anti-HCC efficacy than the other groups in both subcutaneous H22 cells and “m-HSC + H22” coimplanted mice models. The antitumor mechanisms revealed that the combination therapy based on the nanoscale CMDLs could not only inhibit the activation of HSCs by blocking the TGF-β/Smad2 pathway but also block tumor metastasis by reversing epithelial mesenchymal transformation of HCC, which provides a promising approach for anti-HCC therapy.

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“…In recent years, tumor microenvironment (TME) responsive liposomes have received attention from many researchers [ 77 ]. These liposomes underwent a conformational change when exposed to microenvironmental stimuli (such as pH, reactive oxygen species (ROS), temperature, magnetic field or enzyme) in order to achieve specific release of the CRISPR/Cas9 system and improve gene editing efficiency [ 78 ].…”

Section: Kinds Of Nps-based Crispr/cas9 Systemmentioning

confidence: 99%

Research Progress on Nanoparticles-Based CRISPR/Cas9 System for Targeted Therapy of Tumors

et al. 2022

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Cancer is a genetic mutation disease that seriously endangers the health and life of all human beings. As one of the most amazing academic achievements in the past decade, CRISPR/Cas9 technology has been sought after by many researchers due to its powerful gene editing capability. CRISPR/Cas9 technology shows great potential in oncology, and has become one of the most promising technologies for cancer genome-editing therapeutics. However, its efficiency and the safety issues of in vivo gene editing severely limit its widespread application. Therefore, developing a suitable delivery method for the CRISPR/Cas9 system is an urgent problem to be solved at present. Rapid advances in nanomedicine suggest nanoparticles could be a viable option. In this review, we summarize the latest research on the potential use of nanoparticle-based CRISPR/Cas9 systems in cancer therapeutics, in order to further their clinical application. We hope that this review will provide a novel insight into the CRISPR/Cas9 system and offer guidance for nanocarrier designs that will enable its use in cancer clinical applications.

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Acidic tumor microenvironment-sensitive liposomes enhance colorectal cancer therapy by acting on both tumor cells and cancer-associated fibroblasts

Abstract: Cancer-associated fibroblasts (CAFs) play a crucial role in facilitating tumor invasion and metastasis, which act as the “soils” in tumor microenvironment (TME). Accordingly, it would be a promising strategy to...

Cited by 12 publications

References 49 publications

Antitumor efficacy and potential mechanism of FAP-targeted radioligand therapy combined with immune checkpoint blockade

Antitumor efficacy and potential mechanism of FAP-targeted radioligand therapy combined with immune checkpoint blockade

Dual-Ligand-Modified Nanoscale Liposomes Loaded with Curcumin and Metformin Inhibit Drug Resistance and Metastasis of Hepatocellular Carcinoma

Research Progress on Nanoparticles-Based CRISPR/Cas9 System for Targeted Therapy of Tumors

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