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Hepatocellular carcinoma (HCC) and type 2 diabetes mellitus (T2DM) are common clinical conditions, and T2DM is an independent risk factor for HCC. Sorafenib and lenvatinib, two multi-targeted tyrosine kinase inhibitors, are first-line therapies for advanced HCC, while canagliflozin, a sodium-glucose co-transporter 2 inhibitor, is widely used in the treatment of T2DM. Here, we developed an ultra-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of canagliflozin, sorafenib, and lenvatinib, and investigated the pharmacokinetic drug interactions between canagliflozin and sorafenib or lenvatinib in rats. The animals were randomly divided into five groups. Groups I-III were gavage administrated with sorafenib, lenvatinib, and canagliflozin, respectively. Group IV received sorafenib and canagliflozin; while Group V received lenvatinib and canagliflozin. The area under the plasma concentration-time curves (AUC) and maximum plasma concentrations (C max ) of canagliflozin increased by 37.6% and 32.8%, respectively, while the apparent volume of distribution (V z/F ) and apparent clearance (CL z/F ) of canagliflozin significantly decreased (30.6% and 28.6%, respectively) in the presence of sorafenib. Canagliflozin caused a significant increase in AUC and C max of lenvatinib by 28.9% and 36.2%, respectively, and a significant decrease in V z/F and CL z/F of lenvatinib by 52.9% and 22.7%, respectively. In conclusion, drug interactions exist between canagliflozin and sorafenib or lenvatinib, and these findings provide a reference for the use of these drugs in patients with HCC and T2DM.

In addition to early detection, early diagnosis, and early surgery, it is of great significance to use new strategies for the treatment of hepatocellular carcinoma (HCC). Studies showed that the combination of sorafenib (SFN) and triptolide (TPL) could reduce the clinical dose of SFN and maintain good anti-HCC effect. But the solubility of SFN and TPL in water is low and both drugs have certain toxicity. Therefore, we constructed a biomimetic nanosystem based on cancer cell-platelet (PLT) hybrid membrane camouflage to co-deliver SFN and TPL taking advantage of PLT membrane with long circulation functions and tumor cell membrane with homologous targeting. The biomimetic nanosystem, SFN and TPL loaded cancer cell-PLT hybrid membrane-camouflaged liquid crystalline lipid nanoparticles ((SFN + TPL)@CPLCNPs), could simultaneously load SFN and TPL at the molar ratio of SFN to TPL close to 10:1. (SFN + TPL)@CPLCNPs achieved long circulation function and tumor targeting at the same time, promoting tumor cell apoptosis, inhibiting tumor growth, and achieving a better "synergy and attenuation effect", which provided new ideas for the treatment of HCC., (© 2021. The Author(s).)

Sorafenib improves outcomes in adult hepatocellular carcinoma; however, hand foot skin reaction (HFSR) is a dose limiting toxicity of sorafenib that limits its use. HFSR has been associated with sorafenib systemic exposure. The objective of this study was to use modeling and simulation to determine whether using pharmacokinetically guided dosing to achieve a predefined sorafenib target range could reduce the rate of HFSR. Sorafenib steady-state exposures (area under the concentration curve from 0 to 12-h [AUC 0->12 h ]) were simulated using published sorafenib pharmacokinetics at either a fixed dosage (90 mg/m 2 /dose) or a pharmacokinetically guided dose targeting an AUC 0->12 h between 20 and 55 h µg/ml. Dosages were either rounded to the nearest quarter of a tablet (50 mg) or capsule (10 mg). A Cox proportional hazard model from a previously published study was used to quantify HFSR toxicity. Simulations showed that in-target studies increased from 50% using fixed doses with tablets to 74% using pharmacokinetically guided dosing with capsules. The power to observe at least 4 of 6 patients in the target range increased from 33% using fixed dosing with tablets to 80% using pharmacokinetically guided with capsules. The expected HFSR toxicity rate decreased from 22% using fixed doses with tablets to 16% using pharmacokinetically guided dosing with capsules. The power to observe less than 6 of 24 studies with HFSR toxicity increased from 51% using fixed dosing with tablets to 88% using pharmacokinetically guided with capsules. Our simulations provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Sorafenib is an anticancer drug used in the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. It is a substrate for the human OATP1B1. This study is aimed at assessing the role of OATP1B1 in transportation and uptake of sorafenib in hepatocellular carcinoma and how OATP1B1 affects the pharmacodynamics of sorafenib in vitro and in vivo., Methods: Sorafenib transport was measured in HepG2, HepG2-OATP1B1∗1a, HepG2-OATP1B1∗1b, HepG2-OATP1B1∗15, LO2, LO2-OATP1B1∗1a, LO2-OATP1B1∗1b, and LO2-OATP1B1∗15 cells, as well as in HepG2 cells transfected with miR-148a mimics. The viability and apoptosis rate of cells treated with sorafenib were evaluated. A liver cancer rat model was established to explore the pharmacokinetics and pharmacodynamics of sorafenib after overexpression of Oatp2., Results: Changes in expression and genetic mutations of OATP1B1 significantly affected the uptake of sorafenib in HepG2 and LO2 transgenic cells, and the uptake of sorafenib was higher in HepG2 than LO2. Genetic mutations of OATP1B1 significantly affected the cell viability and apoptosis rate of HepG2 cells after sorafenib treatment. Compared to control group, the uptake of sorafenib in miR-148a mimic-transfected HepG2 cells was decreased, and the cell viability was increased. PCN significantly increased the expression of Oatp2 and affected the pharmacokinetics of sorafenib. Vascular endothelial growth factor levels and microvascular density in tumor-adjacent tissues decreased significantly, suggesting that increased Oatp2 expression improves the treatment effect of sorafenib in a rat model of liver cancer., Conclusions: OATP1B1 plays an important role in the pharmacokinetics and pharmacodynamics of sorafenib in hepatocellular carcinoma., Competing Interests: We declare that they have no conflicts of interest., (Copyright © 2021 Jinhua Wen and Menghua Zhao.)

Sorafenib (SR) is one of the most potent UGT (1A1, 1A9) inhibitors (in in vitro tests). The inhibition of UGT1A1 may cause hyperbilirubinaemia, whereas the inhibition of UGT1A9 and 1A1 may result in drug-drug interactions (DDIs). Tapentadol (TAP) is a synthetic μ-opioid agonist and is used to treat moderate to severe acute pain. Tapentadol is highly glucuronidated by the UGT1A9 and UGT2B7 isoenzymes. The aim of the study was to assess the DDI between SR and TAP. Wistar rats were divided into three groups, with eight animals in each. The rats were orally treated with SR (100 mg/kg) or TAP (4.64 mg/kg) or in combination with 100 mg/kg SOR and 4.64 TAP mg/kg. The concentrations of SR and sorafenib N-oxide, TAP and tapentadol glucuronide were respectively measured by means of high-performance liquid chromatography (HPLC) with ultraviolet detection and by means of ultra-performance liquid chromatography-tandem mass spectrometry. The co-administration of TAP with SR caused TAP maximum plasma concentration (C max ) to increase 5.3-fold whereas its area under the plasma concentration-time curve (AUC 0-∞ ) increased 1.5-fold. The tapentadol glucuronide C max increased 5.3-fold and whereas its AUC 0-∞ increased 2.0-fold. The tapentadol glucuronide/TAP AUC 0-∞ ratio increased 1.4-fold (p = 0.0118). TAP also increased SR C max 1.9-fold, whereas its AUC 0-∞ increased 1.3-fold. The sorafenib N-oxide C max increased 1.9-fold whereas its AUC 0-∞ increased 1.3-fold. The sorafenib N-oxide/SR AUC 0-t ratio increased 1.4-fold (p = 0.0127). The results show that the co-administration of sorafenib and tapentadol increases the exposure to both drugs and changes their metabolism. In consequence, the pharmacological effect may be intensified, but the toxicity may increases, too., (Copyright © 2020. Published by Elsevier Masson SAS.)

Aim: To predict the impact of the different CYP2C9 and VKORC1 genotypes on warfarin-sorafenib interactions in whites and Asians. Materials & methods: The influences of the CYP2C9*1/*3 and VKORC1 -1639 A/A genotypes on increases in anticoagulation responses (international normalized ratio [INR]) in the presence of sorafenib were predicted using the population pharmacokinetic/pharmacodynamic (PK/PD) model in whites and Asians. Results: INRs were predicted to be 2.0-2.1- versus 1.8-1.9-times higher in the presence of sorafenib in the CYP2C9 ( *1/*1 vs *1/*3 ) groups than those for warfarin alone in both whites and Asians. INRs were also predicted to be 2.1-2.2- versus 1.9-2.1-times higher in the VKORC1 (GG or GA vs AA) groups. Conclusion: Warfarin-sorafenib interactions might be similar irrespective of CYP2C9 and VKORC1 genotypes or ethnicity.

To evaluate the effect and mechanism of radiotherapy (RT)-sorafenib pharmacokinetics (PK) in different regimens with conventional or high dose irradiation. Between February 2012 and December 2018, 43 patients with portal vein tumor thrombosis treated with sorafenib plus conventional RT (58%) or stereotactic body radiation therapy (SBRT, 42%) were retrospectively reviewed. In vivo and in vitro studies of concurrent and sequential RT with sorafenib were designed. SBRT resulted in a 3-fold increase in complete recanalization compared to conventional RT group (28% vs. 8%, p = 0.014). Compared to the control group, the area under the concentration vs. time curve (AUC) of sorafenib was increased in the concurrent RT 2Gy and RT 9Gy groups and the sequential RT 9Gy group by 132% (p = 0.046), 163% (p = 0.038) and 102% (p = 0.018), respectively; and was decreased by 59% in the sequential RT 2Gy group (p = 0.036). Sequential RT 2Gy and RT 9Gy increased CYP3A4 activity by 82% (p = 0.028) and 203% (p = 0.0004), respectively, compared to that with the corresponding concurrent regimen. SBRT produced better recanalization than conventional RT with sorafenib. The AUC of sorafenib was modulated by RT. P-gp expression was not influenced by RT. The sequential RT regimen increased CYP3A4 activity that may increase the RT-sorafenib synergy effect and overall sorafenib activity. The biodistribution of sorafenib was modulated by local RT with the different regimens.

Background/aim: Sorafenib results in several adverse events, the mechanism and predictors of which are unknown. Recently, it was reported that metabolism by microbiome changes the structure and effects of drugs. The blood levels of sorafenib may be affected by enterohepatic recycling of sorafenib due to microbial enzymes in the gut. We evaluated the relationship between adverse events caused by sorafenib treatment and microbiome in patients with advanced hepatocellular carcinoma., Materials and Methods: Twenty-five patients were classified into two groups based on the presence of hand-foot syndrome (HFS) or diarrhea within 12 weeks post-sorafenib treatment. Before sorafenib treatment, the fecal samples were analyzed targeting the V3-V4 region of 16s ribosomal RNA. Microbiome and predicted functional gene were compared between two groups., Results: The non-HFS group had a richer abundance of Veillonella, Bacillus, Enterobacter, Faecalibacterium, Lachnospira, Dialister, and Anaerostipes than the HFS group at genus level. Carotenoid biosynthesis and bacterial invasion of epithelial cells were enriched in the HFS group. The former three bacteria are classified as oral-origin bacteria, and the two predicted functions are associated with dysbiosis. The non-diarrhea group had a higher abundance of Butyricimonas and a lower abundance of Citrobacter, Peptostreptococcus, and Staphylococcaceae than the diarrhea group. Eight categories of predicted functional genes were detected with differences between the two groups., Conclusion: The non-HFS group had a higher relative abundance of oral-origin bacteria, which likely led to more robust dysbiosis in the gut. This dysbiosis may affect enterohepatic recycling. Additionally, the metabolism of these short-chain fatty acids in the gut may be different between the diarrhea and non-diarrhea groups., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Tumor microenvironment is closely related to the occurrence and development of liver cancer. Tumor-associated macrophages (TAMs) are an important part of tumor microenvironment promoting tumor deterioration and metastasis by inhibiting immune cells. Previous studies showed that PI3Kγ inhibitor could reverse the phenotype of TAMs, relieve immunosuppression and sensitize chemotherapy drugs, suggesting that the combination of PI3Kγ inhibitor and chemotherapeutics is likely to bring new breakthroughs in the treatment of liver cancer. Based on it, this paper builds HES-TG100-115-CDM-PEG micelles with tumor microenvironment responsiveness that simultaneously loaded sorafenib and TG100-115 to synergistically treat liver cancer. Pharmacokinetic study showed that the prepared micelles had longer half-life than that of the free drug solutions, which was favorable for high propensity of extravasation through tumor vascular fenestrations. Under low pH and high α-amylasereductive conditions, micelles could depolymerize quickly due to the sensitivity of bonds and enhance significantly cytotoxic activity against Hep-3B liver cancer cell. Additionally, micelles demonstrated higher levels of antitumor efficiency and better tolerance against nude mouse with Hep-3B cell than the free drug solutions. These findings reveal that HES-TG100-115-CDM-PEG micelles are a promising drug delivery system in clinical comprehensive therapy of liver cancer.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world with increasing incidence. Chemotherapy is required for HCC patients after receiving surgical resection. Serious off-target induced side effects and systemic toxicity limit the clinical utility of drugs. Targeting therapeutic nanomedicine is an innovative strategy for enhancing drug delivery efficiency and reducing side effects. Here, we successfully formulated nanocarriers to encapsulate sorafenib, an FDA approved drug for treatment of HCC. Sorafenib is encapsulated with an entrapment efficiency >80% over 20 days. The effective aqueous solubility is improved over 1900-fold. The release ratio in vitro is characterized by a half-life of T 1/2  = 22.7 h. The peak target-to-background ratio for nanocarrier uptake by tumor occurs at 24 h post-injection, and is significantly greater for the target peptide versus controls. Ex vivo biodistribution confirms the in vivo results. Tumor regression is significantly greater for the target peptide versus controls after 21 days of therapy. No acute toxicity is found by blood chemistry or necropsy. In summary, a peptide specific for GPC3 has been identified, and used to modify the surface of a nanocarrier that encapsulates sorafenib with high entrapment efficiency. Regression of HCC xenograft tumors showed promise for targeted drug delivery., (Copyright © 2019. Published by Elsevier B.V.)

Iced teas (ITs), also known as ready-to-drink teas, have gained much popularity among many nations. The modulatory effect of tea beverages on CYP3A4 increases the possibility of their potential interactions with many coadministered medications. Being a substrate of CYP3A4, sorafenib (SOR), the first-line therapy for the treatment of hepatocellular carcinoma, shows a great probability to exhibit pharmacokinetic (PK) interaction with ITs. For this purpose, different groups of Wistar rats were given oral doses of SOR (40 mg/kg), along with different types of ITs. The concentration of SOR in rat plasma was determined using UPLC-MS/MS. Chromatographic analysis was performed on a C18 analytical column, Acquity UPLC BEH™ (100 × 1.0 mm, i.d., 1.7  μ m particle size), using erlotinib (ERL) as an internal standard. Isocratic elution was performed with a mobile phase consisting of two solvents: solvent A (water with 0.1% formic acid) and solvent B (acetonitrile with 0.1% formic acid), in a ratio of 30 : 70, v/v, respectively. Quantitation was performed using MRM of the transitions from protonated precursor ions [M+H] + to product ions at m/z 465.12 > 252.02 (SOR) and m/z 394.29 > 278.19 (ERL). The method was fully validated as per the FDA guidance for bioanalytical method validation in the concentration range of 2.5-500 ng/mL. Different PK parameters were calculated for SOR in all rat groups and groups administered with ITs and SOR, compared with groups with simply water and SOR. Experimental data revealed that ITs caused a general reduction in SOR bioavailability; an approximate reduction of 30% was recorded for all types of tested ITs. These data indicate that ITs could affect the PK profile of SOR in rats., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2019 Hadir M. Maher et al.)

Purpose: Over the past 30 years, no consistent survival benefits have been recorded for anticancer agents of advanced hepatocellular carcinoma (HCC), except for the multikinase inhibitor sorafenib (Nexavar ® ), which clinically achieves only ~3 months overall survival benefit. This modest benefit is attributed to limited aqueous solubility, slow dissolution rate and, consequently, limited absorption from the gastrointestinal tract. Thus, novel formulation modalities are in demand to improve the bioavailability of the drug to attack HCC in a more efficient manner. In the current study, we aimed to design a novel sorafenib-loaded carbon nanotubes (CNTs) formula that is able to improve the therapeutic efficacy of carried cargo against HCC and subsequently investigate the antitumour activity of this formula., Materials and Methods: Sorafenib was loaded on functionalized CNTs through physical adsorption, and an alginate-based method was subsequently applied to microcapsulate the drug-loaded CNTs (CNTs-SFN). The therapeutic efficacy of the new formula was estimated and compared to that of conventional sorafenib, both in vitro (against HepG2 cells) and in vivo (in a DENA-induced HCC rat model)., Results: The in vitro MTT anti-proliferative assay revealed that the drug-loaded CNTs formula was at least two-fold more cytotoxic towards HepG2 cells than was sorafenib itself. Moreover, the in vivo animal experiments proved that our innovative formula was superior to conventional sorafenib at all assessed end points. Circulating AFP-L3% was significantly decreased in the CNTs-SFN-MCs-treated group (14.0%) in comparison to that of the DENA (40.3%) and sorafenib (38.8%) groups. This superiority was further confirmed by Western blot analysis and immunofluorescence assessment of some HCC-relevant biomarkers., Conclusion: Our results firmly suggest the distinctive cancer-suppressive nature of CNTs-SFN-MCs, both against HepG2 cells in vitro and in a DENA-induced HCC rat model in vivo, with a preferential superiority over conventional sorafenib., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Elsayed et al.)

Sorafenib is an oral multikinase inhibitor approved for the treatment of differentiated thyroid carcinoma (DTC), renal cell carcinoma, and hepatocellular carcinoma. In the phase III DECISION trial in patients with DTC, sorafenib exposure and the incidence of some adverse events (AEs) were higher than in previous trials; therefore, we analyzed exposure-response relationships, including progression-free survival (PFS) and selected AEs in patients with DTC. A novel, stratified prediction-corrected visual predictive check (pc-VPC) was developed to show robustness of the exposure-response relationships. Time-to-event simulations confirmed the benefit of the recommended dosing schedule of 800 mg/day: initial doses of 800 mg/day were associated with the highest PFS, whereas lower doses (600 or 400 mg/day) were associated with improved tolerability but reduced PFS. A simulated dose-reduction strategy of 800 mg/day for an initial two cycles followed by dose reductions seemed likely to maintain efficacy while possibly mitigating selected AEs (e.g., diarrhea and hand-foot skin reactions)., (© 2019 Bayer AG. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Sorafenib is approved as a standard therapy for advanced hepatocellular carcinoma (HCC), but its clinical application is limited due to moderate therapeutic efficacy and high incidence of acquired resistance resulted from elevated levels of SDF-1/CXCR4 axis induced by prolonged sorafenib treatment. We previously demonstrated metapristone (RU486 metabolite) as a cancer metastatic chemopreventive agent targeting SDF-1/CXCR4 axis. Therefore, we hypothesized that combining sorafenib with metapristone could synergistically suppress cell proliferation, enhance anti-cancer activity and repress potential drug resistance., Methods: Changes in cellular CXCR4 expression by metapristone were analyzed by RT-PCR and western blotting. Effect of combining sorafenib with metapristone on cell viability was examined by MTT assay; combination index value was calculated to evaluate the synergistic effect of combined therapy. To overcome poor pharmacokinetics and reduce off-target toxicity, CXCR4-targeted nanoparticles (NPs) were developed to co-deliver sorafenib and metapristone into CXCR4-expressing HCC in vitro and in vivo; cell proliferation, colony formation and apoptosis assays were conducted; nude mice bearing HCC xenograft were used to examine effects of this therapeutic approach on HCC progression., Results: Here we showed metapristone significantly reduced CXCR4 expression in HCC. Combinatory chemotherapy of sorafenib with metapristone synergistically suppressed HCC proliferation and resistance. CXCR4-targeted PEGylated poly (lactic-co-glycolic acid) NPs conjugated with LFC131 (a peptide inhibitor of CXCR4), could deliver more sorafenib and metapristone into HCC via specific recognition and binding with transmembrane CXCR4, and resulted in the enhanced cytotoxicity, colony inhibition and apoptosis by regulating more Akt/ERK/p38 MAPK/caspase signaling pathways. Co-delivery of sorafenib with metapristone by the LFC131-conjugated NPs showed prolonged circulation and target accumulation at tumor sites, and thus suppressed tumor growth in a tumor xenograft model., Conclusions: In conclusion, co-delivery of sorafenib and metapristone via the CXCR4-targeted NPs displays a synergistic therapy against HCC. Our results suggest combinational treatment of chemotherapeutics offer an effective strategy for enhancing the therapeutic efficacy on carcinoma, and highlight the potential application of ligand-modified tumor-targeting nanocarriers in delivering drugs as a promising cancer therapeutic approach.

Sorafenib (So) is a multi-target kinase inhibitor extensively used in clinic for hepatocellular carcinoma therapy. It demonstrated strong inhibition both in tumor proliferation and tumor angiogenesis, while hampered by associated cutaneous side-effect and drug resistance. The knockdown of miR-21 with antisense oligonucleotides (antimiRNA21) was regarded as an efficient strategy for increasing tumor sensibility to chemotherapy, which could be employed to appreciate the efficacy of So. Herein, we successfully formulated a dual-targeting delivery system for enhanced hepatocellular carcinoma therapy by encapsulating So and antimiRNA21 in RGD pentapeptide-modified reconstituted high-density lipoprotein (RGD-rHDL/So/antimiRNA21). The RGD and apolipoprotein A-I (ApoA-I) on nanoparticles (NPs) could drive the system simultaneously to tumor neovascular and parenchyma by binding to the overexpressed ανβ3-integrin and SR-B1 receptors, achieving precise delivery of therapeutics to maximize the efficacy. A series in vitro and in vivo experiments revealed that co-delivery of So and antimiRNA21 by RGD-rHDL significantly strengthened the anti-tumor and anti-angiogenic effect of So with negligible toxicity towards major organs, reversed drug-resistance and was capable of remodeling tumor environments. The constructed RGD-rHDL/So/antimiRNA21 with improved efficacy and excellent tumor targeting ability provided new idea for chemo-gene combined therapy in hepatocellular carcinoma., Statement of Significance: Sorafenib (So) is a multi-target kinase inhibitor which was approved by FDA as first-line drug for hepatocellular carcinoma (HCC) therapy. However, long term application of So in clinic was hampered by serious dermal toxicity and drug resistance. Although numerous researchers were devoted to finding alternatives or therapies as combination treatments with So to reach more desired therapeutic efficacy, the therapeutic options were still limited. The present study prepares RGD pentapeptide decorated biomimic reconstituted high-density lipoprotein (rHDL) loaded with So and antimiRNA21 (RGD-rHDL/So/antimiRNA21) for enhanced HCC therapy. The RGD-rHDL/So/antimiRNA21 NPs offer an effective platform for anti-tumor and anti-angiogenesis therapy in HCC and provide new approach to reverse drug-resistance of So for feasible clinical application., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Sorafenib is a first-line drug for hepatocellular carcinoma (HCC). Autophagy has been shown to facilitate sorafenib resistance. miR-375 has been shown to be an inhibitor of autophagy. In this study, miR-375 and sorafenib were co-loaded into calcium carbonate nanoparticles with lipid coating (miR-375/Sf-LCC NPs). The nanoparticles had high loading efficiency and were ∼50 nm in diameter. Besides, the NPs could increase the stability and residence time of both drugs. Moreover, we demonstrated that autophagy was activated in HCC cells by sorafenib but not by miR-375/Sf-LCC NPs. In vitro, miR-375/Sf-LCC NPs exhibited pH-dependent drug release and potent cytotoxicity. In vivo, miR-375/Sf-LCC NPs increased miR-375 and sorafenib uptake in tumor (2 folds compared with Lipofectamine 2000-miR-375 and 2-5 folds compared with free sorafenib). Furthermore, miR-375/Sf-LCC NPs showed greatly enhanced therapeutic efficacy in an HCC xenograft model. These findings suggest that miR-375/Sf-LCC NPs may be a promising agent for the HCC therapy., Statement of Significance: Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the third leading cause of cancer mortality globally. In this manuscript, miR-375 and sorafenib were co-loaded into calcium carbonate nanoparticles with lipid coating (miR-375/Sf-LCC NPs) to treat HCC. We demonstrated that miR-375/Sf-LCC NPs can deliver sorafenib and miR-375 into HCC cells and tumor tissues, increase drug retention time in tumor, significantly inhibit autophagy and produce enhanced anti-tumor effect., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: This multicentre, open-label, phase-I/randomised phase-II trial evaluated safety, pharmacokinetics, maximum-tolerated-dose (MTD) per dose-limiting toxicities (DLTs), and efficacy of nintedanib vs. sorafenib in European patients with unresectable advanced hepatocellular carcinoma (aHCC)., Methods: Phase I: Patients were stratified into two groups per baseline aminotransferase/alanine aminotransferase and Child-Pugh score; MTD was determined. Phase II: Patients were randomised 2:1 to nintedanib (MTD) or sorafenib (400-mg bid) in 28-day cycles until intolerance or disease progression. Time-to-progression (TTP, primary endpoint), overall survival (OS) and progression-free survival (PFS) were determined., Results: Phase-I: no DLTs observed; nintedanib MTD in both groups was 200 mg bid. Phase-II: patients (N = 93) were randomised to nintedanib (n = 62) or sorafenib (n = 31); TTP was 5.5 vs. 4.6 months (HR = 1.44 [95% CI, 0.81-2.57]), OS was 11.9 vs. 11.4 months (HR = 0.88 [95% CI, 0.52-1.47]), PFS was 5.3 vs. 3.9 months (HR = 1.35 [95% CI, 0.78-2.34]), respectively (all medians). Dose intensity and tolerability favoured nintedanib. Fewer patients on nintedanib (87.1%) vs. sorafenib (96.8%) had drug-related adverse events (AEs) or grade ≥ 3 AEs (67.7% vs. 90.3%), but more patients on nintedanib (28 [45.2%]) had AEs leading to drug discontinuation than did those on sorafenib (7 [22.6%])., Conclusions: Nintedanib may have similar efficacy to sorafenib in aHCC.

Hepatitis C is the most common health problem worldwide and is major cause of death due to proliferation of hepatocellular carcinoma. The medicines available for HCV treatment overcome up-to 95% complications of HCV. However, liver cancer needs some additional care. Normally Sorafenib tosylate 200 mg is recommended for liver cancer. There is no such trial in which this drug could effectively be used in combination of direct acting antivirals for HCV. The study was conducted for HCV patients (n=30) with liver cancer having decompensated stage. Combination of Sorafenib tosylate, Ribavirn and Sofosbuvir were used for the pharmacokinetics of these medicines. Child pugh score less then 7 (CP A) in adults during treatment phase (received 12 weeks of Sorafenib tosylate 200 mg, Ribavirn and Sofosbuvir 400 mg once daily) have no side effect while child pugh score 7-9 (CP B) have evidence of hypertension. The main efficiency end point sustained virology response with overcoming liver cancer as well in 12 weeks after end treatment (SVR-LLC 12). Mean pharmacokinetic exposure to Sorafenib tosylate 200 mg, Ribavirn and Sofosbuvir at week 8th was 2.1, 1.5,1.2 times greater in CP B than in CP A. Adverse effects (AEs) were observed in 12 out of 30 patients but not severe as lethal for life. Treatment with Sorafenib tosylate, Ribavirn and Sofosbuvir for twelve weeks was harmless and well accepted, 100 % patients achieve (SVR LLC 12) with 10-fold cure rate more than previous ones. The combination therapy of Sorafenib tosylate, Ribavirn and Sofosbuvir was found helpful for the management of decompensated liver cancer.