In vitro cytotoxicity of magnetic-fluorescent bioactive glasses on SaOS-2, MC3T3-E1, BJ fibroblast cells, their hemolytic activity, and sorafenib release behavior.

In the study, the fabrication of superparamagnetic-fluorescent bioactive glasses in the form of the particle, nanofiber, and 3D scaffolds was performed by including maghemite (γ-Fe2O3) nanoparticles and photoluminescent rare earth element ions (Eu3+, Gd3+, and Yb3+) using sol-gel, electrospinning, and robocasting techniques, respectively. The in vitro cytotoxicity of the magnetic-fluorescent bioactive glasses on osteosarcoma SaOS-2, pre-osteoblast MC3T3-E1, and BJ fibroblast cells, as well as their hemolytic activity and sorafenib tosylate loading and release behavior, were investigated. The cytotoxicity of the bioactive glass samples was tested using the MTT assay. Additionally, the alkaline phosphatase activity of the studied glasses was examined as a function of time. The mineralization behavior of the pre-osteoblast cell-seeded glass samples was analyzed using Alizarin red S staining. Results revealed that the in vitro cytotoxicity of the studied bioactive glasses in the form of particles and nanofibers depended on the sample concentration, whereas in the case of the 3D scaffolds, no cytotoxic response was observed on the osteosarcoma, pre-osteoblast, and fibroblast cells. Similarly, particle and nanofiber-based glass samples induced dose-dependent hemolysis on red blood cells. Drug loading rates were much lower for the 3D scaffolds compared to the particle and nanofiber-based samples. Drug release rates ranged from 25 % to 90 %, depending on the bioactive glass morphology and the pH of the release medium. It was concluded that the studied bioactive glasses have the potential to be used in tissue engineering applications and cancer therapy.

Sorafenib tosylate-loaded nanosuspension: preparation, optimization, and in vitro cytotoxicity study against human HepG2 carcinoma cells.

This study aimed to optimize nanosuspension of sorafenib tosylate (an anticancer hydrophobic drug molecule) using a central composite design. Nanosuspension was prepared using a nanoprecipitation-ultrasonication approach. FTIR and DSC analyses demonstrated that the drug and excipients were physicochemically compatible. X-ray powder diffraction analysis confirmed amorphous form of the payload in the formulation. The optimized formulation (batch NSS6) had a zeta potential of -18.1 mV, a polydispersity of 0.302, and a particle size of 97.11 nm. SEM analysis confirmed formation of rod-shaped particles. After 24 h, about 64.45% and 86.37% of the sorafenib tosylate was released in pH 6.8 and pH 1.2, respectively. The MTT assay was performed on HepG2 cell lines. IC50 value of the optimized batch was 39.4 µg/mL. The study concluded that sorafenib tosylate nanosuspension could be a promising approach in the treatment of hepatocellular cancer.

CD44 targeted delivery of hyaluronic acid-coated polymeric nanoparticles against colorectal cancer.

Aim: To develop hyaluronic acid (HA)-coated poly-lactic-co-glycolic acid (PLGA)-polysarcosine (PSAR) coupled sorafenib tosylate (SF) polymeric nanoparticles for targeted colon cancer therapy. Materials & methods: PLGA-PSAR shells were encapsulated with SF via nanoprecipitation. Interactions were examined with transmission electron microscopy, revealing formulation component interactions. Results: The optimized HA-coated polymeric nanoparticles (238.8 nm, -6.1 mV, 68.361% entrapment) displayed enhanced controlled release of SF. These formulations showed superior cytotoxicity against HCT116 cell lines compared with free drug (p < 0.05). In vivo tests on male albino Wistar rats demonstrated improved pharmacokinetics, targeting and biocompatibility. HA-coated PLGA-PSAR-coupled SF polymeric nanoparticles hold potential for effective colorectal therapy. Conclusion: Colon cancer may be precisely targeted by HA-coated PLGA-PSA-coupled SF polymeric nanoparticles.

Subconjunctival Delivery of Sorafenib-Tosylate-Loaded Cubosomes for Facilitated Diabetic Retinopathy Treatment: Formulation Development, Evaluation, Pharmacokinetic and Pharmacodynamic (PKPD) Studies.

Diabetic retinopathy (DR) is a microvascular complication associated with vascular endothelial growth factor (VEGF) overexpression. Therapeutic delivery to the retina is a challenging phenomenon due to ocular biological barriers. Sorafenib tosylate (ST) is a lipophilic drug with low molecular weight, making it ineffective at bypassing the blood-retinal barrier (BRB) to reach the target site. Cubosomes are potential nanocarriers for encapsulating and releasing such drugs in a sustained manner. The present research aimed to compare the effects of sorafenib-tosylate-loaded cubosome nanocarriers (ST-CUBs) and a sorafenib tosylate suspension (ST-Suspension) via subconjunctival route in an experimental DR model. In this research, ST-CUBs were prepared using the melt dispersion emulsification technique. The distribution of prepared nanoparticles into the posterior eye segments was studied with confocal microscopy. The ST-CUBs were introduced into rats' left eye via subconjunctival injection (SCJ) and compared with ST-Suspension to estimate the single-dose pharmacokinetic profile. Streptozotocin (STZ)-induced diabetic albino rats were treated with ST-CUBs and ST-Suspension through the SCJ route once a week for 28 days to measure the inhibitory effect of ST on the diabetic retina using histopathology and immunohistochemistry (IHC) examinations. Confocal microscopy and pharmacokinetic studies showed an improved concentration of ST from ST-CUBs in the retina. In the DR model, ST-CUB treatment using the SCJ route exhibited decreased expression levels of VEGF, pro-inflammatory cytokines, and adhesion molecules compared to ST-Suspension. From the noted research findings, it was concluded that the CUBs potentially enhanced the ST bioavailability. The study outcomes established that the developed nanocarriers were ideal for delivering the ST-CUBs via the SCJ route to target the retina for facilitated DR management.

Inhalable spray-dried polycaprolactone-based microparticles of Sorafenib Tosylate with promising efficacy on A549 cells.

The study developed and evaluated Sorafenib Tosylate (SRT)-loaded polymeric microparticles (MPs) using biodegradable polymer polycaprolactone (PCL) as a potential inhalable carrier for NSCLC. MPs were prepared by spray-drying an oil-in-water (o/w) emulsion. The optimized MPs demonstrated excellent flowability, particle size of 2.84 ± 0.5 µm, zeta potential of -14.0 ± 1.5 mV, and 85.08 ± 5.43% entrapment efficiency. ATR-FTIR/DSC studies revealed a lack of characteristic peaks of the crystalline drug signifying good entrapment of the drug. MPs were spherical and uniform in SEM pictures. The MPs showed a biphasic release pattern up to 72h. The Anderson cascade impactor (ACI) investigation demonstrated the highest drug deposition at stage 4, which revealed that the MPs can reach the lungs' secondary and terminal bronchi. Inhalable MPs had an efficient aerodynamic property with a mass median aerodynamic diameter (MMAD) of 2.63 ± 1.3 µm, a geometric standard deviation (GSD) of 1.93 ± 0.2 µm, and a fine particle fraction (FPF) of 87 ± 2.5%. Finally, in cytotoxicity studies on A549 cancer cells, MPs had an IC50 value of 0.6011 ± 0.8 µM, which was 85.68% lower than free drug. These findings suggest SRT-loaded inhalable PCL-based MPs as a novel NSCLC treatment.

Development of D-α-Tocopherol polyethylene glycol 1000 succinate fabricated nanostructural lipid carrier of sorafenib tosylate for metastatic colorectal targeting application: Stability, physical characterization, cytotoxicity, and apoptotic studies against SW48 cells PTEN.

The study aimed to create D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) nanostructured lipid carriers (NLC) of sorafenib tosylate (ST) as lymphatic delivery systems (LDDS) to fight Metastatic colorectal cancer. Initially, ST-SLN, ST-NLC, and ST-LNE were formulated considering oleic acid (OA), glycerol monolinoleate (GMO), glycerol monolinoleate (GML) as solid lipid and further characterised, and tested for stability. The most stable ST-NLC was fabricated with TPGS to produce ST-TPGS-NLC and evaluated by performing in vitro drug profiling, in vitro cytotoxicity, and apoptotic studies against human female colorectal adenocarcinoma cell lines (SW48 Cells PTEN). Stability studies on three lipidic nanoparticles (ST-SLN, ST-NLC, ST-LEN) showed particle size, polydispersity index, and zeta potential ranging from 165 nm to 298 nm, 0.125 to 0.288, and -31 mV to -16 mV. At 1600 minutes, more than 80% of ST-NLC1 was released, confirming the sustained release pattern of the formulation. ST-NLC and ST-TPGS-NLC have entrapment efficiencies above 50%. Pure ST's IC50 at 72 hr was 3.45 µg/mL, while 1.56 µg/mL was for ST-TPGS-NLC. The ST-TPGS-NLC reduced the number of livings SW48 Cells PTEN from 91% to 5%, compared to 75% to 8% of pure ST. The ST-TPGS-NLC is a promising LDDS for delivering ST for metastatic colorectal cancer.

Formulating Ternary Inclusion Complex of Sorafenib Tosylate Using ß-Cyclodextrin and Hydrophilic Polymers: Physicochemical Characterization and In Vitro Assessment.

Sorafenib tosylate (SFNT) is the first-line drug for hepatocellular carcinoma. It exhibits poor solubility leading to low oral bioavailability subsequently requiring intake of large quantities of drug to exhibit desired efficacy. The present investigation was aimed at enhancing the solubility and dissolution rate of SFNT using complexation method. The binary inclusion complex was prepared with ß-cyclodextrin (ß-CD). The molecular docking studies confirmed the hosting of SFNT into hydrophobic cavity of ß-CD, while the phase solubility studies revealed the stoichiometry of complexation with a stability constant of 735.8 M-1. The ternary complex was prepared by combining the SFNT-ß-CD complex with PEG-6000 and HPMC polymers. The results from ATR-IR studies revealed no interaction between drug and excipients. The decreased intensities in ATR-IR peaks and changes in chemical shifts from NMR of SFNT in complexes indicate the possibility of SFNT hosting into the hydrophobic cavity of ß-CD. The disappearance of SFNT peak in DSC and XRD studies revealed the amorphization upon complexation. The ternary complexes exhibited improved in vitro solubility (17.54 µg/mL) compared to pure SFNT (0.19 µg/mL) and binary inclusion complex (1.52 µg/mL). The dissolution profile of ternary inclusion complex in 0.1 N HCl was significantly higher compared to binary inclusion complex and pure drug. In cytotoxicity studies, the ternary inclusion complex has shown remarkable effect than the binary inclusion complex and pure drug on HepG2 cell lines.

Sorafenib tosylate incorporation into mesoporous starch xerogel for in-situ micronization and oral bioavailability enhancement.

Poorly water-soluble drugs like sorafenib tosylate (SFB) can be made more soluble and orally bioavailable using a biocompatible hydrophilic matrix yields amorphous or microcrystalline drugs with high stability and low recrystallization risk. Mesoporous starch (MPS) due to its edibility, biodegradability, high surface area, and confined pores. In this study, MPS, either alone or in combination with polyvinylpyrrolidone (PVP), was employed for improving SFB oral bioavailability. To this aim, MPS was prepared in three steps: gelatinization, solvent exchange, and vacuum drying, after which it was used to incorporate SFB at various ratios using the immersion/solvent evaporation technique. Nitrogen adsorption/desorption analysis, Fourier transform infrared spectrometry (FTIR), field emission scanning electron microscopy (FE-SEM), powder X-ray diffraction (XRD) crystallography, and differential scanning calorimetry (DSC) were used to characterize SFB-loaded and drug-free samples, which confirmed the successful preparation of mesoporous structures with desirable uniform porosity, small pore size (about 5.3 nm), and specific surface area of about 24 m2/g. In-vitro dissolution testing revealed that the SFB dissolution rate increased substantially for the loaded MPS or MPS-PVP samples. Furthermore, when SFB was loaded in MPS-PVP, single-dose pharmacokinetics in rats confirmed an enhanced oral absorption kinetic. Therefore, impregnation of poorly soluble drugs such as SFB in the PVP-modified MPS excipient, which is constructed from a combination of mesoporous materials and a drug recrystallization inhibitor such as hydrophilic polymers, is proposed as a promising strategy for desirable enhancements in drug solubility, oral bioavailability, and efficacy.

Polysaccharide and monosaccharide guided liver delivery of Sorafenib Tosylate - A nano-strategic approach and comparative assessment of hepatospecificity.

Hepatospecific delivery by ligand based receptor targeting is an established strategy to augment therapy associated with liver diseases and disorders. Previously, we have investigated the effect of ligand headgroup on cellular uptake mediated by the asialoglycoprotein receptor by in silico and in vitro approach. In this paper, we report the design of agarose based liposomes for delivery to liver cancer cells and provide a proof of concept of the targeting efficiency against galactose liposomes using an in vivo approach. Sorafenib Tosylate loaded targeting liposomes were developed and optimized using factorial design. Comparative evaluation including cell cytotoxicity, pharmacokinetics and biodistribution and hepatospecific uptake was performed for both the liposomal systems. The formulations possessed a particle size of 150 - 180 nm and a zeta potential of 30 - 60 mV depending on the amount of ligand and drug loading, with more than 90% entrapment efficiency. A two-fold increase in cytotoxicity was observed with agarose-based liposomes as compared to galactose based liposomes. In vivo PK evaluation indicated a reduction in half life of drug when loaded in agarose ligand loaded system, probably due to greater uptake in the liver as evidenced in biodistribution study. Intrahepatic disposition revealed a higher PC/NPC uptake ratio with the targeted systems as compared to conventional liposomes, although the agarose-based system resulted in highest uptake ratio. A biocompatible platform for specific delivery of drugs to hepatocytes was established validating a rational approach to design liver targeting systems.

Safety and efficacy of sorafenib in patients with advanced thyroid carcinoma: a phase II study (NCT02084732)

ABSTRACT Objective: Sorafenib significantly prolonged progression-free survival in patients with iodine-refractory advanced thyroid cancer. The present study was initiated before sorafenib was approved in Colombia and therefore represents an effort by an oncology institution to evaluate its efficacy and safety in this population. Subjects and methods: This phase II clinical trial had a single treatment arm. We included adult patients with progressive metastatic iodine-refractory thyroid cancer who received treatment with sorafenib 800 mg/day (400 mg every 12 hours) up to a maximum of 24 months or until the occurrence of limiting related toxicity, the progression of the disease, or voluntary withdrawal. Results: Nineteen patients received the treatment and were included in the safety analysis. However, for the efficacy analysis, 6 patients were excluded because they received only one month of therapy. Thirteen (68%) patients were women, and the mean age at diagnosis was 61.8 years. No complete responses were observed; 5 patients had a partial response (35.7%), 6 patients had stable disease, and 3 showed progression. Mean progression-free survival was calculated at 18 months (95% CI 10.7-20.3). Overall survival was estimated at 21.3 months (95% CI 17.8-24.8). Conclusion: For the first time in Colombia, the efficacy of sorafenib was evaluated in patients with advanced and progressive thyroid carcinoma refractory to radioactive iodine, with an efficacy and a safety profile similar to those previously reported.

Impact of Crystal Habit on the Dissolution Rate and In Vivo Pharmacokinetics of Sorafenib Tosylate.

The dissolution rate is the rate-limiting step for Biopharmaceutics Classification System (BCS) class II drugs to enhance their in vivo pharmacokinetic behaviors. There are some factors affecting the dissolution rate, such as polymorphism, particle size, and crystal habit. In this study, to improve the dissolution rate and enhance the in vivo pharmacokinetics of sorafenib tosylate (Sor-Tos), a BCS class II drug, two crystal habits of Sor-Tos were prepared. A plate-shaped crystal habit (ST-A) and a needle-shaped crystal habit (ST-B) were harvested by recrystallization from acetone (ACN) and n-butanol (BuOH), respectively. The surface chemistry of the two crystal habits was determined by powder X-ray diffraction (PXRD) data, molecular modeling, and face indexation analysis, and confirmed by X-ray photoelectron spectroscopy (XPS) data. The results showed that ST-B had a larger hydrophilic surface than ST-A, and subsequently a higher dissolution rate and a substantial enhancement of the in vivo pharmacokinetic performance of ST-B.

Structural Polymorphism of Sorafenib Tosylate as a Key Factor in Its Solubility Differentiation.

The presence of active pharmaceutical ingredients (APIs) in the forms of different polymorphic states can induce differences in their physicochemical properties. In the case of poorly soluble APIs, like the oncological drug sorafenib tosylate, small variations in solubility may result in large bioavailability differences. The control of its therapeutic dose is crucial from the effective pharmacotherapy point of view and the reduction of side effects. Therefore, this study aimed to assess the influence of sorafenib tosylate polymorphic forms on its solubility and, consequently, permeability, based on passive diffusion through membranes simulating the gastrointestinal tract (GIT) conditions. In the first part of the work, two crystalline forms of sorafenib tosylate were identified using the X-ray powder diffraction, FT-IR, and Raman spectroscopy. Subsequently, solubility studies were carried out. Both forms of sorafenib tosylate were insoluble in 0.1 N hydrochloric acid (HCl), in acetate buffer (pH 4.5), and in phosphate buffer (pH 6.8). Solubility (mg/mL) of form I and III of sorafenib tosylate in 0.1 N HCl + 1.0% SDS was 0.314 ± 0.006 and 1.103 ± 0.014, respectively, in acetate buffer pH 4.5 + 1.0% SDS it was 2.404 ± 0.012 and 2.355 ± 0.009, respectively, and in phosphate buffer pH 6.8 + 1.0% SDS it was 0.051 ± 0.005 and 1.805 ± 0.023, respectively. The permeability study was assessed using the parallel artificial membrane permeability assay (PAMPA) model. The apparent permeability coefficient (Papp-cm s-1) of form I and III in pH 1.2 was 3.01 × 10-5 ± 4.14 × 10-7 and 3.15 × 10-5 ± 1.89 × 10-6, respectively, while in pH 6.8 it was 2.72 × 10-5 ± 1.56 × 10-6 and 2.81 × 10-5 ± 9.0 × 10-7, respectively. Changes in sorafenib tosylate concentrations were determined by chromatography using the high-performance liquid chromatography (HPLC)-DAD technique. As a result of the research on the structural polymorphism of sorafenib tosylate, its full spectral characteristics and the possibility of using FT-IR and Raman spectroscopy for the study of polymorphic varieties were determined for the first time, and the HPLC method was developed, which is appropriate for the assessment of sorafenib solubility in various media. The consequences of various physicochemical properties resulting from differences in the solubility of sorafenib tosylate polymorphs are important for pre-formulation and formulation studies conducted with its participation and for the safety of oncological sorafenib therapy.

Safety and efficacy of sorafenib in patients with advanced thyroid carcinoma: a phase II study (NCT02084732).

OBJECTIVE: Sorafenib significantly prolonged progression-free survival in patients with iodine-refractory advanced thyroid cancer. The present study was initiated before sorafenib was approved in Colombia and therefore represents an effort by an oncology institution to evaluate its efficacy and safety in this population. METHODS: This phase II clinical trial had a single treatment arm. We included adult patients with progressive metastatic iodine-refractory thyroid cancer who received treatment with sorafenib 800 mg/day (400 mg every 12 hours) up to a maximum of 24 months or until the occurrence of limiting related toxicity, the progression of the disease, or voluntary withdrawal. RESULTS: Nineteen patients received the treatment and were included in the safety analysis. However, for the efficacy analysis, 6 patients were excluded because they received only one month of therapy. Thirteen (68%) patients were women, and the mean age at diagnosis was 61.8 years. No complete responses were observed; 5 patients had a partial response (35.7%), 6 patients had stable disease, and 3 showed progression. Mean progression-free survival was calculated at 18 months (95% CI 10.7-20.3). Overall survival was estimated at 21.3 months (95% CI 17.8-24.8). CONCLUSION: For the first time in Colombia, the efficacy of sorafenib was evaluated in patients with advanced and progressive thyroid carcinoma refractory to radioactive iodine, with an efficacy and a safety profile similar to those previously reported.

Self Nanoemulsifying Drug Delivery System of Sorafenib Tosylate: Development and In Vivo Studies.

BACKGROUND: Sorafenib tosylate (SFN) belongs to the BCS class II drug with low solubility and undergoes first-pass metabolism, which leads to reduced bioavailability of 38%. OBJECTIVE: The present study aimed at developing SFN SNEDDS to improve their solubility and bioavailability. METHODS: Preliminary solubility studies were performed to identify oil, surfactant, and co-surfactant ratios. Pseudo tertiary phase diagram was constructed to select the areas of nanoemulsion based on the monophasic region. A total of 15 formulations of SFN SNEDDS were prepared and screened for phase separation and temperature variation using thermodynamic stability studies. These SNEDDS further characterized for % transmission, content of the drug, and in vitro dissolution analysis. The optimized formulation was analyzed for particle size, Z average, entrapment efficiency, and SEM analysis. RESULTS: Based on the pseudo tertiary phase diagram, acrysol EL 135, kolliphor, and transcutol-P as oil, surfactant, and co-surfactant were selected, respectively. All the formulations were stable with no phase separation and maximum % transmittance of 98.92%. The formulation F15 was selected as an optimized one, based on maximum drug content of 99.89%, with 98.94% drug release within 1 hour and it will be stable for 6 months. From in vivo bioavailability studies, the Cmax of optimized SNEDDS (94.12±2.12ng/ml) is higher than pure SFN suspension (15.32±1.46 ng/ml) and the AUC0-∞ of optimized SNEDDS is also increased by 5 times (512.1±8.54 ng.h/ml) than pure drug (98.75±6.45ng.h/ml), which indicates improved bioavailability of the formulation. CONCLUSION: SFN loaded SNEDDS could potentially be exploited as a delivery system for improving oral bioavailability by minimizing first-pass metabolism and increased solubility. Lay Summary: Renal cell carcinoma accounts for 2% of global cancer diagnoses and deaths, it has more than doubled in incidence in the developed world over the past half-century, and today is the ninth most common neoplasm in the United States. Sorafenib is a protein kinase inhibitor indicated as a treatment for advanced renal cell carcinoma. The present study aimed at developing Sorafenib SNEDDS to improve their solubility and bioavailability. A total of 15 formulations of Sorafenib SNEDDS were prepared and screened for phase separation and temperature variation using thermodynamic stability studies. Sorafenib loaded SNEDDS could potentially be exploited as a delivery system for increased oral bioavailability by 5 times when comparing with pure drug by minimizing first-pass metabolism and increased solubility.

LC-ESI-QTOF-MS analysis utilizing gas-phase fragmentation reactions subjected to ESI-IS-CID and ESI-CID-MS/MS conditions to study the degradation behaviour of sorafenib tosylate: NMR and in vitro cytotoxicity and apoptosis detection studies of hydrolytic degradation products.

The present study was to investigate the degradation profile of sorafenib tosylate (SORA), a potent oral multi-kinase inhibitor under various stress conditions as per ICH (Q1A (R2)) guidelines. Separation of SORA and its degradation products (DP-1-DP-5) was achieved on Acquity UPLC BEH C18 (100 mm × 2.1 mm × 1.7 µm) column using a gradient elution of 0.1% formic acid and acetonitrile at a flow rate of 0.3 mL/min within 12 min. High resolution quadruple time-of-flight mass spectrometer (Q-TOF/MS) was utilized for characterization of all DPs. In ESI/CID-MS/MS experiments, the protonated DP-1 and DP-2 exhibited few interesting product ions which provide a compelling evidence for the compounds to undergo gas phase rearrangement reaction justified by its mechanistic explanation in support with density functional theory (DFT). In-source collision-induced dissociation (IS-CID) fragmentation using ESI/APCI-MS analysis exhibited the formation of N-deoxygenated product ion peak corresponds to pyridine N-oxide moiety as in DP-5. Further, major hydrolytic DPs (DP-2 and DP-3) were isolated on preparative HPLC and structural elucidation was done using ID NMR (1H, 13C and DEPT-135) experiments. In vitro cytotoxicity study for SORA and its isolated DPs were assessed by observing morphological changes in HepG2 cell lines under phase-contrast microscopy and MTT assay. Taken together, it was known that DP-2 and DP-3 were less potent with a cell viability of more than 90% and IC50 >50 µM in comparison with SORA (IC50 = 2.99 ±â€¯0.35 µM). The developed method was validated in terms of specificity, limit of detection, limit of quantification, linearity, accuracy, precision and robustness.

Transferrin-Modified Nanoliposome Codelivery Strategies for Enhancing the Cancer Therapy.

Chemotherapy remains one of the most effective treatments for many cancers in a clinic. At present, various targets have been used to modify the PEGylated liposomes for doxorubicin (Dox) delivery, but the antitumor effect of Dox is not satisfactory. Therefore, combination chemotherapeutics has been considered as a promising method to improve tumor treatment. These years, RAF/MEK/ERK-mediated cell signaling pathway has been discovered to inhibit the growth of tumors. Thus, Sorafenib tosylate (Sor) was used in this study, which directly inhibited tumor cell proliferation through blocking RAF/MEK/ERK-mediated cell signaling pathway and indirectly inhibited tumor cell growth through blocking angiogenesis by VEGFR and PDGF. In this article, we develop a "combination delivery system" to deliver the hydrophobic drug (Sor) in phospholipid bilayer and hydrophilic drug (Dox) in inner cores for enhancing the antitumor effect. Moreover, in vitro experiments verified whether the physicochemical properties of carriers were stable and transferrin-modified liposomes displayed the highest uptake. The results of in vivo experiments showed that the codelivery system inhibited the tumor growth more effectively than monotherapy. Overall, this combination delivery system for delivering the hydrophobic and hydrophilic drugs simultaneously may offer a novel strategy for breast cancer treatment and provide a reference for the possibility of clinical usage.

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

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.

Development of a validated liquid chromatographic method for quantification of sorafenib tosylate in the presence of stress-induced degradation products and in biological matrix employing analytical quality by design approach.

The current research work envisages an analytical quality by design-enabled development of a simple, rapid, sensitive, specific, robust and cost-effective stability-indicating reversed-phase high-performance liquid chromatographic method for determining stress-induced forced-degradation products of sorafenib tosylate (SFN). An Ishikawa fishbone diagram was constructed to embark upon analytical target profile and critical analytical attributes, i.e. peak area, theoretical plates, retention time and peak tailing. Factor screening using Taguchi orthogonal arrays and quality risk assessment studies carried out using failure mode effect analysis aided the selection of critical method parameters, i.e. mobile phase ratio and flow rate potentially affecting the chosen critical analytical attributes. Systematic optimization using response surface methodology of the chosen critical method parameters was carried out employing a two-factor-three-level-13-run, face-centered cubic design. A method operable design region was earmarked providing optimum method performance using numerical and graphical optimization. The optimum method employed a mobile phase composition consisting of acetonitrile and water (containing orthophosphoric acid, pH 4.1) at 65:35 v/v at a flow rate of 0.8 mL/min with UV detection at 265 nm using a C18 column. Response surface methodology validation studies confirmed good efficiency and sensitivity of the developed method for analysis of SFN in mobile phase as well as in human plasma matrix. The forced degradation studies were conducted under different recommended stress conditions as per ICH Q1A (R2). Mass spectroscopy studies showed that SFN degrades in strongly acidic, alkaline and oxidative hydrolytic conditions at elevated temperature, while the drug was per se found to be photostable. Oxidative hydrolysis using 30% H2 O2 showed maximum degradation with products at retention times of 3.35, 3.65, 4.20 and 5.67 min. The absence of any significant change in the retention time of SFN and degradation products, formed under different stress conditions, ratified selectivity and specificity of the systematically developed method.

Improving anti-tumor activity of sorafenib tosylate by lipid- and polymer-coated nanomatrix.

In the present study, we select the Sylysia 350 (Sylysia) as mesoporous material, distearoylphosphatidylethanolamine-poly(ethylene glycol)2000 (DSPE-PEG) as absorption enhancer and hydroxy propyl methyl cellulose (HPMC) as crystallization inhibitor to prepare sorafenib tosylate (SFN) nanomitrix (MSNM@SFN) for improving the anti-tumor activity of SFN. The MSNM@SFN was prepared by solvent evaporation method. The solubility, dissolution, and bioavailability of SFN in MSNM@SFN were also investigated. The anti-tumor activity of MSNM@SFN was evaluated in vitro and in vivo. Our results indicated that the solubility and dissolution of SFN in MSNM@SFN were significantly increased. The oral bioavailability of SFN in MSNM@SFN was greatly improved 7.7-fold compared with that in SFN suspension. The enhanced anti-tumor activity of MSNM@SFN was confirmed in vitro and in vivo experiments. This nanomatrix developed in this study could be a promising drug delivery platform for improving the therapeutic efficacy of poorly water-soluble drugs.

A large-scale prospective registration study of the safety and efficacy of sorafenib tosylate in unresectable or metastatic renal cell carcinoma in Japan: results of over 3200 consecutive cases in post-marketing all-patient surveillance.

OBJECTIVE: Real-life safety and efficacy of sorafenib in advanced renal cell carcinoma in a nationwide patient population were evaluated by post-marketing all-patient surveillance. METHODS: All patients with unresectable or metastatic renal cell carcinoma in Japan who started sorafenib therapy from February 2008 to September 2009 were registered and followed for up to 12 months. Baseline characteristics, treatment status, tumor response, survival and safety data were recorded by the prescribing physicians. RESULTS: Safety and efficacy were evaluated in 3255 and 3171 patients, respectively. The initial daily dose was 800 mg in 78.2% of patients. Median duration of treatment was 6.7 months and the mean relative dose intensity was 68.4%. Overall, 2227 patients (68.4%) discontinued the treatment by 12 months, half of which (52.0% of discontinued patients) were due to adverse events. The most common adverse drug reactions were hand-foot skin reaction (59%), hypertension (36%), rash (25%) and increase in lipase/amylase (23%). The median progression-free survival was 7.3 months (95% confidence intervals: 6.7-8.1), and the overall survival rate at 1 year was 75.4% (73.5-77.1). Prognostic factors for overall survival were mostly consistent with those in previous clinical trials in the univariate analysis and largely similar to those for progression-free survival and duration of treatment in the multivariate analysis. CONCLUSIONS: Sorafenib for the treatment of advanced renal cell carcinoma under the labeled dose was feasible in daily medical practice, for its acceptable toxicity profile and favorable clinical benefit that were consistent with those in clinical trials.