ABSTRACT
Liver cancer, which is well-known to us as one of human most prevalent malignancies across the globe, poses a significant risk to live condition and life safety of individuals in every region of the planet. It has been shown that immune checkpoint treatment may enhance survival benefits and make a significant contribution to patient prognosis, which makes it a promising and popular therapeutic option for treating liver cancer at the current time. However, there are only a very few numbers of patients who can benefit from the treatment and there also exist adverse events such as toxic effects and so on, which is still required further research and discussion. Fortunately, the clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9) provides a potential strategy for immunotherapy and immune checkpoint therapy of liver cancer. In this review, we focus on elucidating the fundamentals of the recently developed CRISPR/Cas9 technology as well as the present-day landscape of immune checkpoint treatment which pertains to liver cancer. What's more, we aim to explore the molecular mechanism of immune checkpoint treatment in liver cancer based on CRISPR/Cas9 technology. At last, its encouraging and powerful potential in the future application of the clinic is discussed, along with the issues that already exist and the difficulties that must be overcome. To sum up, our ultimate goal is to create a fresh knowledge that we can utilize this new CRISPR/Cas9 technology for the current popular immune checkpoint therapy to overcome the treatment issues of liver cancer.
Subject(s)
CRISPR-Cas Systems , Gene Editing , Liver Neoplasms , Humans , Liver Neoplasms/therapy , Liver Neoplasms/genetics , Liver Neoplasms/immunology , Gene Editing/methods , Immunotherapy/methods , Immune Checkpoint Inhibitors/therapeutic use , AnimalsABSTRACT
The heterogeneity of hepatocellular carcinoma (HCC) and the complexity of the tumor microenvironment (TME) pose challenges to efficient drug delivery and the antitumor efficacy of combined or synergistic therapies. Herein, a metal-coordinated carrier-free nanodrug (named as USFe3+ LA NPs) was developed for ferroptosis-mediated multimodal synergistic anti-HCC. Natural product ursolic acid (UA) was incorporated to enhance the sensitivity of tumor cells to sorafenib (SRF). Surface decoration of cell penetration peptide and epithelial cell adhesion molecule aptamer facilitated the uptake of USFe3+ LA NPs by HepG2 cells. Meanwhile, Fe3+ ions could react with intracellular hydrogen peroxide, generating toxic hydroxyl radical (·OH) for chemodynamical therapy (CDT) and amplified ferroptosis by cystine/glutamate antiporter system (System Xc-), which promoted the consumption of glutathione (GSH) and inhibited the expression of glutathione peroxidase 4 (GPX4). Notably, these all-in-one nanodrugs could inhibit tumor metastasis and induced immunogenic cell death (ICD). Last but not least, the nanodrugs demonstrated favorable biocompatibility, augmenting the immune response against the programmed death-ligand 1 (PD-L1) by increasing cytotoxic T cell infiltration. In vivo studies revealed significant suppression of tumor growth and distant metastasis. Overall, our work introduced a novel strategy for applications of metal-coordinated co-assembled carrier-free nano-delivery system in HCC combination therapy, especially in the realms of cancer metastasis prevention and immunotherapy.
Subject(s)
Carcinoma, Hepatocellular , Ferroptosis , Liver Neoplasms , Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Pharmaceutical Preparations , Liver Neoplasms/drug therapy , Combined Modality Therapy , Cell Line, Tumor , Tumor MicroenvironmentABSTRACT
Both ursolic acid (UA) and sorafenib (Sora) have been generally utilized in cancer treatment, and the combination of the two has also shown a good anti-tumor effect. However, single-agent therapy for Hepatocellular carcinoma (HCC) has the disadvantages of multi-drug resistance, poor water solubility and low bioavailability, and the application of traditional nanocarrier materials is limited due to their low drug loading and low carrier-related toxicity. Therefore, we prepared US NPs with different proportions of UA and Sora by solvent exchange method for achieving synergistic HCC therapy. US NPs had suitable particle size, good dispersibility and storage stability, which synergistically inhibited the proliferation of HepG2 cells, SMMC7721 cells and H22 cells. In addition, we also proved that US NPs were able to suppress the migration of HepG2 cells and SMMC7721 cells and reduce the adhesion ability and colony formation ability of these cells. According to the results, US NPs could degrade the membrane potential of mitochondrial, participate in cell apoptosis, and synergistically induce autophagy. Collectively, the carrier-free US NPs provide new strategies for HCC treatment and new ideas for the development of novel nano-drug delivery systems containing UA and Sora.
Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Liver Neoplasms , Nanoparticles , Humans , Sorafenib/pharmacology , Sorafenib/therapeutic use , Carcinoma, Hepatocellular/pathology , Ursolic Acid , Pharmaceutical Preparations , Liver Neoplasms/pathology , Cell Line, TumorABSTRACT
The effectiveness of chemotherapeutic agents for hepatocellular carcinoma (HCC) is unsatisfactory because of tumor heterogeneity, multidrug resistance, and poor target accumulation. Therefore, multimodality-treatment with accurate drug delivery has become increasingly popular. Herein, a cell penetrating peptide-aptamer dual modified-nanocomposite (USILA NPs) was successfully constructed by coating a cell penetrating peptide and aptamer onto the surface of sorafenib (Sora), ursolic acid (UA) and indocyanine green (ICG) condensed nanodrug (USI NPs) via one-pot assembly for targeted and synergistic HCC treatment. USILA NPs showed higher cellular uptake and cytotoxicity in HepG2 and H22 cells, with a high expression of epithelial cell adhesion molecule (EpCAM). Furthermore, these NPs caused more significant mitochondrial membrane potential reduction and cell apoptosis. These NPs could selectively accumulate at the tumor site of H22 tumor-bearing mice and were detected with the help of ICG fluorescence; moreover, they retarded tumor growth better than monotherapy. Thus, USILA NPs can realize the targeted delivery of dual drugs and the integration of diagnosis and treatment. Moreover, the effects were more significant after co-administration of iRGD peptide, a tumor-penetrating peptide with better penetration promoting ability or programmed cell death ligand 1 (PD-L1) antibody for the reversal of the immunosuppressive state in the tumor microenvironment. The tumor inhibition rates of USILA NPs + iRGD peptide or USILA NPs + PD-L1 antibody with good therapeutic safety were 72.38 % and 67.91 % compared with control, respectively. Overall, this composite nanosystem could act as a promising targeted tool and provide an effective intervention strategy for enhanced HCC synergistic treatment.