scholarly journals Dual-functional Liposomes with Carbonic Anhydrase IX Antibody and BR2 Peptide Modification Effectively Improve Intracellular Delivery of Cantharidin to Treat Orthotopic Hepatocellular Carcinoma Mice

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3332 ◽  
Author(s):  
Zhang ◽  
Lin ◽  
Chan ◽  
Liu ◽  
Lu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Carbonic Anhydrase ◽  
Therapeutic Potential ◽  
Intracellular Delivery ◽  
Carbonic Anhydrase Ix ◽  
Ca Ix ◽  
Dual Functional ◽  
Peptide Modification

Liposomal nanotechnology has a great potential to overcome the current major problems of chemotherapy. However, the lack of penetrability and targetability retards the successful delivery of liposomal carriers. Previously, we showed that BR2 peptide modification endowed cantharidin-loaded liposomes with intracellular penetration that enhanced the drug cytotoxic effects. Here, we aimed to improve the targeting delivery of drugs into cancer cells via highly expressed carbonic anhydrase IX (CA IX) receptors by modifying our previous catharidin-loaded BR2-liposomes with anti-CA IX antibody. A higher cellular uptake of dual-functional liposomes (DF-Lp) than other treatments was observed. Induction of CA IX over-expressing resulted in a higher cellular binding of DF-Lp; subsequently, blocking with excess antibodies resulted in a decreased cancer-cell association, indicating a specific targeting property of our liposomes towards CA IX expressed cells. After 3h tracking, most of the liposomes were located around the nucleus which confirmed the involvement of targeting intracellular delivery. Cantharidin loaded DF-Lp exhibited enhanced cytotoxicity in vitro and was most effective in controlling tumor growth in vivo in an orthotopic hepatocellular carcinoma model compared to other groups. Collectively, our results presented the advantage of the BR2 peptide and CA IX antibody combination to elevate the therapeutic potential of cantharidin loaded DF-liposomes.

Novel Humanized Monoclonal Antibodies for Targeting Hypoxic Human Tumors via Two Distinct Extracellular Domains of Carbonic Anhydrase IX

2021 ◽  
Author(s):  
Miriam Zatovicova ◽  
Ivana Kajanova ◽  
Monika Barathova ◽  
Martina Takacova ◽  
Martina Labudova ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Cancer Progression ◽  
Standard Therapy ◽  
Catalytic Domain ◽  
Conformational Epitope ◽  
Carbonic Anhydrase Ix ◽  
Acidic Environment ◽  
Primary Tumors ◽  
Ca Ix

Abstract Background Hypoxia in the tumor microenvironment (TME) is often the main factor in the cancer progression. Moreover, low levels of oxygen in tumor tissue may signal that the first or second-line therapy will not be successful. This knowledge triggers the inevitable search for different kinds of treatment that will successfully cure aggressive tumors. Due to its exclusive expression on cancer cells, carbonic anhydrase IX belongs to the group of the most precise targets in hypoxic tumors. CA IX possesses several exceptional qualities that predetermine its crucial role in targeted therapy. Its expression on the cell membrane makes it an easily accessible target, while its absence in healthy corresponding tissues makes the treatment practically harmless. The presence of CA IX in solid tumors causes an acidic environment that may lead to the failure of standard therapy. Methods Parental mouse hybridomas (IV/18 and VII/20) were humanized to antibodies which were subsequently named CA9hu-1 and CA9hu-2. From each hybridoma we obtained 25 clones. Each clone was tested for ADCC and CDC activity, affinity, extracellular pH measurement, multicellular aggregation analysis and real-time monitoring of invasion with xCELLigence system. ResultsBoth CA9hu-1 and CA9hu-2 are IgG1 antibodies and they were both examined in vivo. Here we describe anti-CAIX antibodies that can reverse the failure of standard therapy as a result of an acidic environment by modulating the TME. CA9hu-1 is directed at the conformational epitope of the catalytic domain, while CA9hu-2 targets the sequential epitope of the proteo-glycan domain. They are both able to induce an immune response, have high affinity, as well as ADCC and CDC activity. While the first one internalizes after binding to the antigen, the second one is able to reduce metastases formation. More importantly, they have both proved the ability to block the acidification of the extracellular environment. ConclusionCA9hu-1 and CA9hu-2 are the very first humanized antibodies against CA IX that are likely to become suitable therapies for hypoxic tumors. These antibodies can be applied in the treatment therapy of primary tumors and suppression of metastases formation.

scholarly journals Correlation of In Vivo and In Vitro Measures of Carbonic Anhydrase IX Antigen Expression in Renal Masses Using Antibody 124I-cG250

2011 ◽  
Vol 52 (4) ◽  
pp. 535-540 ◽  
Author(s):  
D. A. Pryma ◽  
J. A. O'Donoghue ◽  
J. L. Humm ◽  
A. A. Jungbluth ◽  
L. J. Old ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Antigen Expression ◽  
Carbonic Anhydrase Ix ◽  
Renal Masses

scholarly journals Synergistic antitumor effect of resveratrol and sorafenib on hepatocellular carcinoma through PKA/AMPK/eEF2K pathway

2021 ◽  
Author(s):  
Meili Gao ◽  
Chun Deng ◽  
Fan Dang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Tumor Response ◽  
Therapeutic Potential ◽  
Combined Treatment ◽  
In Vivo Studies ◽  
Antitumor Effects ◽  
Protein Levels

Although sorafenib (Sor) is the only effective drug for hepatocellular carcinoma (HCC), its therapeutic potential to date is mainly limited to the low tumor response. This study was designed to explore whether resveratrol (Res) could potentiate the anticancerous activity of Sor. We used HepG2 and Huh7 HCC cell lines and BALB/c nude mice for in vitro and in vivo studies, respectively. The cultured cell lines and tumor induction in the mice were treated with different concentrations of Res and Sor alone, and the combination of Res and Sor to observe the antitumor effects. Significant inhibitory effects were observed in the combined treatment of Res and Sor compared to Res and Sor alone treatments both in vitro and in vivo as demonstrated by significantly high number of S phase cells and apoptotic cells. Moreover, these findings were accompanied by the reduction of CDK2, CDC25A, PKA, p-AMPK, and eEF2K protein levels and the increment of cyclin A, cleavage caspase-3, caspase-8, and caspase-9 protein levels. The combinational treatment exhibited more significant anticancerous effect than the Res and Sor alone treatments in mice-bearing HepG2 xenograft. Overall, our results suggest that PKA/AMPK/eEF2K pathway is involved in the synergistic anticancerous activity of Res and Sor combination treatment in HCC cells. Thus, Res and Sor combination therapy may be promising in increasing the tumor response of Sor in the future.

Bioinformatic analysis of RHO family of GTPases identifies RAC1 pharmacological inhibition as a new therapeutic strategy for hepatocellular carcinoma

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321454
Author(s):  
Juan Bayo ◽  
Esteban J Fiore ◽  
Luciana María Dominguez ◽  
María Jose Cantero ◽  
Matias S Ciarlantini ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Stellate Cell ◽  
Underlying Mechanism ◽  
Intrahepatic Metastasis ◽  
Clinical Prognosis ◽  
Rho Family

ObjectiveThe RHO family of GTPases, particularly RAC1, has been linked with hepatocarcinogenesis, suggesting that their inhibition might be a rational therapeutic approach. We aimed to identify and target deregulated RHO family members in human hepatocellular carcinoma (HCC).DesignWe studied expression deregulation, clinical prognosis and transcription programmes relevant to HCC using public datasets. The therapeutic potential of RAC1 inhibitors in HCC was study in vitro and in vivo. RNA-Seq analysis and their correlation with the three different HCC datasets were used to characterise the underlying mechanism on RAC1 inhibition. The therapeutic effect of RAC1 inhibition on liver fibrosis was evaluated.ResultsAmong the RHO family of GTPases we observed that RAC1 is upregulated, correlates with poor patient survival, and is strongly linked with a prooncogenic transcriptional programme. From a panel of novel RAC1 inhibitors studied, 1D-142 was able to induce apoptosis and cell cycle arrest in HCC cells, displaying a stronger effect in highly proliferative cells. Partial rescue of the RAC1-related oncogenic transcriptional programme was obtained on RAC1 inhibition by 1D-142 in HCC. Most importantly, the RAC1 inhibitor 1D-142 strongly reduce tumour growth and intrahepatic metastasis in HCC mice models. Additionally, 1D-142 decreases hepatic stellate cell activation and exerts an anti-fibrotic effect in vivo.ConclusionsThe bioinformatics analysis of the HCC datasets, allows identifying RAC1 as a new therapeutic target for HCC. The targeted inhibition of RAC1 by 1D-142 resulted in a potent antitumoural effect in highly proliferative HCC established in fibrotic livers.

scholarly journals Antibody-pHPMA functionalised fluorescent silica nanoparticles for colorectal carcinoma targeting

RSC Advances ◽  
2018 ◽  
Vol 8 (39) ◽  
pp. 21679-21689 ◽  
Author(s):  
Denisa Lizoňová ◽  
Monika Majerská ◽  
Vlastimil Král ◽  
Michal Pechar ◽  
Robert Pola ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Carbonic Anhydrase ◽  
Colorectal Carcinoma ◽  
Silica Nanoparticles ◽  
Tumour Cells ◽  
Carbonic Anhydrase Ix ◽  
Fluorescent Silica Nanoparticles

Nanoparticles functionalised with pHPMA and monoclonal antibody IgG M75 show specific adhesion to tumour cells expressing carbonic anhydrase IX bothin vitroandin vivo.

In vitro and in vivo antitumor activities of a small and novel synthetic molecule: A potential therapy for hepatocellular carcinoma.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 300-300
Author(s):  
K. I. Batarseh
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Therapeutic Potential ◽  
Statistical Tests ◽  
Xenograft Model ◽  
Growth Delay ◽  
Antitumor Activities ◽  
Immunodeficient Mice

300 Background: A small (molecular weight of 275) and novel pharmaceutically silver (I)-tartaric acid complex given the title name aliargentumycine was recently synthesized and the results on its in vitro cytotoxicity and mechanism of action on solid and hematopoietic malignancies were reported. Here the therapeutic potential of aliargentumycine on hepatocellular carcinoma was investigated. Methods: The in vitro and in vivo antitumor activities of aliargentumycine were studied on human HepG-2 xenograft model grown subcutaneously in female immunodeficient mice. Aliargentumycine was administered intratumorally, intravenously and orally twice a week at various concentrations. Results: The IC50 of aliargentumycine was found to be 1.49 ± 0.067 mg/ml, which is comparable to the value of 1.04 ± 0.07 mg/ml for doxorubicin, and almost half the value of 2.87 ± 1.02 mg/ml for sorafenib tosylate. The in vivo results demonstrated excellent statistically significant antitumor activities for the intratumoral, intravenous and oral routes of administration with Pi.t. < 0.00001, Pi.v. < 0.005 and Pp.o. < 0.003, respectively. Some animals showed complete tumor remission (tumor-free), and no tumor re-growth was observed even after treatment was stopped. Nonlinear regression on the data revealed that aliargentumycine results in significant tumor growth delay. All treated animals did not show any commonly observed signs of toxicity, including no body weight loss (p > 0.05). Mantel-Cox statistical tests revealed that there were significant tumor growth delays (p < 0.05) and survival advantages (p < 0.05). Conclusions: These promising findings might have great therapeutic potential on the future clinical treatment of hepatocellular carcinoma using aliargentumycine. No significant financial relationships to disclose.

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