scholarly journals Effect of PEGylation on assembly morphology and cellular uptake of poly ethyleneimine-cholesterol conjugates for delivery of sorafenib tosylate in hepatocellular carcinoma

Bioimpacts ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 241-252 ◽  
Author(s):  
Maryam Monajati ◽  
Shirin Tavakoli ◽  
gholam hossein yousefi ◽  
Samira Sadat Abolmaali ◽  
AliMohammad Tamaddon
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cellular Uptake ◽  
Drug Loading ◽  
Spherical Shape ◽  
Chemotherapeutic Agents ◽  
Log P ◽  
Specific Cytotoxicity ◽  
The Impact

Introduction: Sorafenib (SFB) is an FDA-approved chemotherapeutic agent with a high partition coefficient (log P = 4.34) for monotherapy of hepatocellular carcinoma (HCC). The oral bioavailability is low and variable, so it was aimed to study the application of the polymeric nanoassembly of cholesterol conjugates of branched polyethyleneimine (PEI) for micellar solubilization of SFB and to investigate the impact of the polymer PEGylation on the physicochemical and cellular characteristics of the lipopolymeric dispersions. Methods: Successful synthesis of cholesterol-PEI lipopolymers, either native or PEGylated, was confirmed by FTIR, 1H-NMR, pyrene assay methods. The nanoassemblies were also characterized in terms of morphology, particle size distribution and zeta-potential by TEM and dynamic light scattering (DLS). The SFB loading was optimized using general factorial design. Finally, the effect of particle characteristics on cellular uptake and specific cytotoxicity was investigated by flow cytometry and MTT assay in HepG2 cells. Results: Transmission electron microscopy (TEM) showed that PEGylation of the lipopolymers reduces the size and changes the morphology of the nanoassembly from rod-like to spherical shape. However, PEGylation of the lipopolymer increased critical micelle concentration (CMC) and reduced the drug loading. Moreover, the particle shape changes from large rods to small spheres promoted the cellular uptake and SFB-related cytotoxicity. Conclusion: The combinatory effects of enhanced cellular uptake and reduced general cytotoxicity can present PEGylated PEI-cholesterol conjugates as a potential carrier for delivery of poorly soluble chemotherapeutic agents such as SFB in HCC that certainly requires further investigations in vitro and in vivo.

scholarly journals The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroaki Kanzaki ◽  
Tetsuhiro Chiba ◽  
Junjie Ao ◽  
Keisuke Koroki ◽  
Kengo Kanayama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Erk Signaling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antitumor Effects ◽  
The Impact

AbstractFGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

Enhanced 5-fluorouracil cytotoxicity in high COX-2 expressing hepatocellular carcinoma cells by wogonin via the PI3K/Akt pathway

2013 ◽  
Vol 91 (4) ◽  
pp. 221-229 ◽  
Author(s):  
Li Zhao ◽  
Yun-Ying Sha ◽  
Qing Zhao ◽  
Jing Yao ◽  
Bin-Bin Zhu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Human Tumor ◽  
Inhibitory Effect ◽  
Chemotherapeutic Agents ◽  
Carcinoma Cells ◽  
Antitumor Effects ◽  
Synergistic Inhibitory Effect ◽  
Cox 2

Combination therapies may increase the antitumor effects and reduce the adverse effects for the treatment of hepatocellular carcinoma. In this study, we determined the effects of 5-fluorouracil alone or in combination with wogonin in vitro and in vivo, and we investigated the possible mechanisms. The combination of these 2 drugs led to a decrease in survival and a significant synergistic inhibitory effect on high COX-2 expression in SMMC-7721 hepatocellular carcinoma (HCC) cells. Furthermore, the results show that this combination inhibits COX-2 expression and increases sensitivity to chemotherapeutic agents partly through regulating the PI3K/Akt signaling pathway. Moreover, the combination treatment caused a significant growth inhibition of human tumor xenografts in vivo. In conclusion, wogonin may increase the cytotoxicity of some antineoplastic agents and it can be used in combination with these agents as a novel therapeutic regimen for HCC treatment.

scholarly journals ACOX2 is a prognostic marker and impedes the progression of hepatocellular carcinoma via PPARα pathway

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qifan Zhang ◽  
Yunbin Zhang ◽  
Shibo Sun ◽  
Kai Wang ◽  
Jianping Qian ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Prognostic Significance ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Cell Counting ◽  
Peroxisomal Enzyme ◽  
The Impact

AbstractHepatocellular carcinoma (HCC) has been extensively studied as one of the most aggressive tumors worldwide. However, its mortality rate remains high due to ideal diagnosis and treatment strategies. Uncovering novel genes with prognostic significance would shed light on improving the HCC patient’s outcome. In our study, we applied data-independent acquisition (DIA) quantitative proteomics to investigate the expression landscape of 24 paired HCC patients. A total of 1029 differentially expressed proteins (DEPs) were screened. Then, we compared DEPs in our cohort with the differentially expressed genes (DEGs) in The Cancer Genome Atlas, and investigated their prognostic significance, and found 183 prognosis-related genes (PRGs). By conducting protein–protein interaction topological analysis, we identified four subnetworks with prognostic significance. Acyl-CoA oxidase 2 (ACOX2) is a novel gene in subnetwork1, encodes a peroxisomal enzyme, and its function in HCC was investigated in vivo and in vitro. The lower expression of ACOX2 was validated by real-time quantitative PCR, immunohistochemistry, and Western blot. Cell Counting Kit-8 assay, wound healing, and transwell migration assay were applied to evaluate the impact of ACOX2 overexpression on the proliferation and migration abilities in two liver cancer cell lines. ACOX2 overexpression, using a subcutaneous xenograft tumor model, indicated a tumor suppressor role in HCC. To uncover the underlying mechanism, gene set enrichment analysis was conducted, and peroxisome proliferator-activated receptor-α (PPARα) was proposed to be a potential target. In conclusion, we demonstrated a PRG ACOX2, and its overexpression reduced the proliferation and metastasis of liver cancer in vitro and in vivo through PPARα pathway.

scholarly journals Self-amplification of oxidative stress with tumour microenvironment-activatable iron-doped nanoplatform for targeting hepatocellular carcinoma synergistic cascade therapy and diagnosis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Qiao-Mei Zhou ◽  
Yuan-Fei Lu ◽  
Jia-Ping Zhou ◽  
Xiao-Yan Yang ◽  
Xiao-Jie Wang ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Hepatocellular Carcinoma ◽  
Hydrogen Peroxide ◽  
Cell Death ◽  
Magnetic Resonance ◽  
Tumour Microenvironment ◽  
Chemotherapeutic Agents ◽  
Resonance Imaging

Abstract Background Hepatocellular carcinoma is insensitive to many chemotherapeutic agents. Ferroptosis is a form of programmed cell death with a Fenton reaction mechanism. It converts endogenous hydrogen peroxide into highly toxic hydroxyl radicals, which inhibit hepatocellular carcinoma progression. Methods The morphology, elemental composition, and tumour microenvironment responses of various organic/inorganic nanoplatforms were characterised by different analytical methods. Their in vivo and in vitro tumour-targeting efficacy and imaging capability were analysed by magnetic resonance imaging. Confocal microscopy, flow cytometry, and western blotting were used to investigate the therapeutic efficacy and mechanisms of complementary ferroptosis/apoptosis mediated by the nanoplatforms. Results The nanoplatform consisted of a silica shell doped with iron and disulphide bonds and an etched core loaded with doxorubicin that generates hydrogen peroxide in situ and enhances ferroptosis. It relied upon transferrin for targeted drug delivery and could be activated by the tumour microenvironment. Glutathione-responsive biodegradability could operate synergistically with the therapeutic interaction between doxorubicin and iron and induce tumour cell death through complementary ferroptosis and apoptosis. The nanoplatform also has a superparamagnetic framework that could serve to guide and monitor treatment under T2-weighted magnetic resonance imaging. Conclusion This rationally designed nanoplatform is expected to integrate cancer diagnosis, treatment, and monitoring and provide a novel clinical antitumour therapeutic strategy. Graphical Abstract

In Vitro and In Vivo Evaluation of Novel DTX-Loaded Multifunctional Heparin-Based Polymeric Micelles Targeting Folate Receptors and Endosomes

2020 ◽  
Vol 15 (4) ◽  
pp. 341-359
Author(s):  
Moloud Kazemi ◽  
Jaber Emami ◽  
Farshid Hasanzadeh ◽  
Mohsen Minaiyan ◽  
Mina Mirian ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Antitumor Activity ◽  
Cellular Uptake ◽  
Folate Receptor ◽  
Chemotherapeutic Agents ◽  
Water Soluble ◽  
Growth Monitoring ◽  
Tumor Bearing

Background: The development of biocompatible tumor-targeting delivery systems for anticancer agents is essential for efficacious cancer chemotherapy. Nanoparticles, as drug delivery cargoes for cancer therapy, are rapidly improving to overcome the limitations of conventional chemotherapeutic agents. Heparin–modified nanoparticles are currently being considered as one of the favorable carriers for the delivery of chemotherapeutics to cancer tissues. Objective: This study was aimed at evaluating the in vitro and in vivo antitumor activity of a novel targeted, pH-sensitive, heparin-based polymeric micelle loaded with the poorly water-soluble anticancer drug, docetaxel (DTX). The micelles could overcome the limited water solubility, non-specific distribution, and insufficient drug concentration in tumor tissues. Methods: DTX-loaded folate targeted micelles were prepared and evaluated for physicochemical properties, drug release, in vitro cellular uptake and cytotoxicity in folate receptor-positive and folate receptor-negative cells. Furthermore, the antitumor activity of DTX-loaded micelles was evaluated in the tumor-bearing mice. Some related patents were also studied in this research. Results: The heparin-based targeted micelles exhibited higher in vitro cellular uptake and cytotoxicity against folate receptor over-expressed cells due to the specific receptor-mediated endocytosis. DTX-loaded micelles displayed greater antitumor activity, higher anti-angiogenesis effects, and lower systemic toxicity compared with free DTX in a tumor-induced mice model as confirmed by tumor growth monitoring, immunohistochemical evaluation, and body weight shift. DTX-loaded targeting micelles demonstrated no considerable toxicity on major organs of tumor-bearing mice compared with free DTX. Conclusion: Our results indicated that DTX-loaded multifunctional heparin-based micelles with desirable antitumor activity and low toxicity possess great potential as a targeted drug delivery system in the treatment of cancer.

Leukemia Stem/Progenitor Cells From AML Patients Treated With The Multi-Kinase Inhibitor TG02 Demonstrate Increased Proliferation and Are Sensitized To Chemotherapeutic Agents

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3892-3892 ◽  
Author(s):  
Monica L. Guzman ◽  
Wen Xie ◽  
Jeanne P. De Leon ◽  
Francis Burrows ◽  
Eric J. Feldman ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Peripheral Blood ◽  
Colony Formation ◽  
Kinase Inhibitor ◽  
Chemotherapeutic Agents ◽  
Positive Staining ◽  
Annual Meeting Abstract ◽  
The Impact

Abstract TG02 is a multi-kinase inhibitor that targets cyclin-dependent kinases (CDKs), ERK5, JAK2, and Flt3. In vitro studies of TG02 have shown robust induction of apoptosis in both acute myeloid leukemia (AML) cell lines and primary cells (Goh et al, 2011). Leukemia stem cells (LSCs) comprise a largely quiescent, highly chemotherapy-resistant cell population and are believed to initiate and maintain AML, as well as contribute to its poor prognosis. Thus, we sought to investigate the impact of TG02 on LSCs collected from patients with relapsed/refractory AML enrolled in a phase I dose escalation trial. Patients ≥ 18 years with advanced hematological malignancies or newly diagnosed AML pts ≥ 65 years unfit for intensive therapy were enrolled onto daily (A) and intermittent (B, 5 days on 2 days off X 2 weeks) schedules in 28-day cycles. Pts had acceptable organ function and ECOG PS 0-2. Dose levels were 10 - 70 mg on arm A and 30 - 150 mg on arm B. We evaluated immunophenotypically defined leukemia stem and progenitor cells (LSPCs) by flow cytometry, cell cycle status and colony forming assays. A total of 16 patients were evaluated with treatment doses ranging from 10-150 mg of TG02. Clinically, treatment with TG02 did not have an effect in AML tumor burden, and most patients at our center only received one cycle of treatment (Roboz et al ASCO 2012 Annual Meeting Abstract #6557, J Clin. Oncol. 30, 2012). However, we found that 8 patient samples showed increased LSPCs in both the bone marrow and peripheral blood. Interestingly, we observed an increase in LSPC cell proliferation, as determined by Ki-67 positive staining. AML colony forming assays also showed increased colony formation (n=5) after one cycle of treatment, which suggests an increase in the frequency of LSPCs. The increase in colony formation in peripheral blood samples suggests mobilization of LSPCs from the marrow into the circulation. Thus, we hypothesized that exposure to TG02 in vivo may result in sensitization to other chemotherapeutic agents, such as Ara-C. We evaluated the effects of Ara-C and other chemotherapeutics, such as vincristine, in primary AML cells obtained from patients before and after treatment with TG02. We found that in vivo exposure to TG02 resulted in significantly increased sensitivity to Ara-C in vitro in 3 out of 4 samples tested Together, our data suggest that TG02 induces an effect in LSCs resulting in increased proliferation and, thus, sensitization to other chemotherapeutic drugs, such as Ara-C. Importantly, although no patients at our center receiving single agent TG02 met the criteria for an objective response, by performing correlative studies in association with the clinical trial, we found the TG02 has a marked effect in AML LSCs that could potentially be exploited by combining it with other agents. Disclosures: Burrows: Tragara Pharmaceuticals: Employment, Equity Ownership. Feldman:Tragara Pharmaceuticals: Consultancy.

scholarly journals Mesenchymal Stromal Cells for Antineoplastic Drug Loading and Delivery

Medicines ◽  
2017 ◽  
Vol 4 (4) ◽  
pp. 87 ◽  
Author(s):  
Francesco Petrella ◽  
Isabella Rimoldi ◽  
Stefania Rizzo ◽  
Lorenzo Spaggiari
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Targeted Delivery ◽  
Drug Loading ◽  
Tumour Microenvironment ◽  
Chemotherapeutic Agents ◽  
Immunomodulatory Activity ◽  
Neoplastic Cells

Mesenchymal stromal cells are a population of undifferentiated multipotent adult cells possessing extensive self-renewal properties and the potential to differentiate into a variety of mesenchymal lineage cells. They express broad anti-inflammatory and immunomodulatory activity on the immune system and after transplantation can interact with the surrounding microenvironment, promoting tissue healing and regeneration. For this reason, mesenchymal stromal cells have been widely used in regenerative medicine, both in preclinical and clinical settings. Another clinical application of mesenchymal stromal cells is the targeted delivery of chemotherapeutic agents to neoplastic cells, maximizing the cytotoxic activity against cancer cells and minimizing collateral damage to non-neoplastic tissues. Mesenchymal stem cells are home to the stroma of several primary and metastatic neoplasms and hence can be used as vectors for targeted delivery of antineoplastic drugs to the tumour microenvironment, thereby reducing systemic toxicity and maximizing antitumour effects. Paclitaxel and gemcitabine are the chemotherapeutic drugs best loaded by mesenchymal stromal cells and delivered to neoplastic cells, whereas other agents, like pemetrexed, are not internalized by mesenchymal stromal cells and therefore are not suitable for advanced antineoplastic therapy. This review focuses on the state of the art of advanced antineoplastic cell therapy and its future perspectives, emphasizing in vitro and in vivo preclinical results and future clinical applications.

scholarly journals Amphiphilic Polymeric Micelles Based on Deoxycholic Acid and Folic Acid Modified Chitosan for the Delivery of Paclitaxel

2018 ◽  
Vol 19 (10) ◽  
pp. 3132 ◽  
Author(s):  
Liang Li ◽  
Na Liang ◽  
Danfeng Wang ◽  
Pengfei Yan ◽  
Yoshiaki Kawashima ◽  
...  
Keyword(s):  
Folic Acid ◽  
Deoxycholic Acid ◽  
Polymeric Micelles ◽  
Drug Loading ◽  
Amorphous State ◽  
Spherical Shape ◽  
Water Soluble ◽  
Proton Nuclear Magnetic Resonance

The present investigation aimed to develop a tumor-targeting drug delivery system for paclitaxel (PTX). The hydrophobic deoxycholic acid (DA) and active targeting ligand folic acid (FA) were used to modify water-soluble chitosan (CS). As an amphiphilic polymer, the conjugate FA-CS-DA was synthesized and characterized by Proton nuclear magnetic resonance (1H-NMR) and Fourier-transform infrared spectroscopy (FTIR) analysis. The degree of substitutions of DA and FA were calculated as 15.8% and 8.0%, respectively. In aqueous medium, the conjugate could self-assemble into micelles with the critical micelle concentration of 6.6 × 10−3 mg/mL. Under a transmission electron microscope (TEM), the PTX-loaded micelles exhibited a spherical shape. The particle size determined by dynamic light scattering was 126 nm, and the zeta potential was +19.3 mV. The drug loading efficiency and entrapment efficiency were 9.1% and 81.2%, respectively. X-Ray Diffraction (XRD) analysis showed that the PTX was encapsulated in the micelles in a molecular or amorphous state. In vitro and in vivo antitumor evaluations demonstrated the excellent antitumor activity of PTX-loaded micelles. It was suggested that FA-CS-DA was a safe and effective carrier for the intravenous delivery of paclitaxel.

scholarly journals Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Jacopo Gavini ◽  
Noëlle Dommann ◽  
Manuel O. Jakob ◽  
Adrian Keogh ◽  
Laure C. Bouchez ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Antitumor Effect ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Resistance Mechanisms ◽  
Chemotherapeutic Agents ◽  
Anti Cancer

Abstract Lysosomal sequestration of anti-cancer compounds reduces drug availability at intracellular target sites, thereby limiting drug-sensitivity and inducing chemoresistance. For hepatocellular carcinoma (HCC), sorafenib (SF) is the first line systemic treatment, as well as a simultaneous activator of autophagy-induced drug resistance. The purpose of this study is to elucidate how combination therapy with the FDA-approved photosensitizer verteporfin (VP) can potentiate the antitumor effect of SF, overcoming its acquired resistance mechanisms. HCC cell lines and patient-derived in vitro and in vivo preclinical models were used to identify the molecular mechanism of action of VP alone and in combination with SF. We demonstrate that SF is lysosomotropic and increases the total number of lysosomes in HCC cells and patient-derived xenograft model. Contrary to the effect on lysosomal stability by SF, VP is not only sequestered in lysosomes, but induces lysosomal pH alkalinization, lysosomal membrane permeabilization (LMP) and tumor-selective proteotoxicity. In combination, VP-induced LMP potentiates the antitumor effect of SF, further decreasing tumor proliferation and progression in HCC cell lines and patient-derived samples in vitro and in vivo. Our data suggest that combination of lysosome-targeting compounds, such as VP, in combination with already approved chemotherapeutic agents could open a new avenue to overcome chemo-insensitivity caused by passive lysosomal sequestration of anti-cancer drugs in the context of HCC.

scholarly journals Suppression of CD13 Enhances the Cytotoxic Effect of Chemotherapeutic Drugs in Hepatocellular Carcinoma Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Shengping Ji ◽  
Yuqian Ma ◽  
Xiaoyan Xing ◽  
Binbin Ge ◽  
Yutian Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chemotherapy Resistance ◽  
Chemotherapeutic Agents ◽  
Ros Generation ◽  
Cancer Resistance ◽  
Ros Scavenging ◽  
Chemotherapy Agent ◽  
Hepatocarcinoma Cells

Multidrug resistance (MDR) of hepatocellular carcinoma (HCC) is a serious problem that directly hinders the effect of chemotherapeutics. In this study, we mainly explore the molecular mechanism of ROS-induced CD13 expression using hepatocarcinoma cells as the research object. We show that the drug of fluorouracil (5FU), epirubicin (EPI) and gemcitabine (GEM) can induce ROS generation, activate Ets2 and promote CD13 expression. Meanwhile, CD13 can activate NRF1 and up-regulate ROS scavenging genes transcription, such as SOD1, GPX1, GPX2 and GPX3, leading to down-regulation of intracellular ROS level and reducing the sensitivity of cells to chemotherapy agent. We also detected the anti-tumor effect of the combination therapy, CD13 inhibitor ubenimex and a variety of conventional anti-cancer drugs, such as 5FU, EPI, GEM, pemetrexed (Pem) and paclitaxel (PTX) were employed in combination. Ubenimex enhances the sensitivity of different chemotherapeutic agents and cooperates with chemotherapeutic agents to suppress tumor growth in vitro and in vivo. In general, overexpression of CD13 can lead to chemotherapy resistance, and CD13 inhibitor can reverse this effect. Combination of chemotherapy agent and ubenimex will become a potential treatment strategy for liver cancer resistance.

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