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

ABSTRACT: 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.

SUBMITTER: Monajati M

PROVIDER: S-EPMC6209830 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Monajati Maryam M Tavakoli Shirin S Abolmaali Samira Sadat SS Yousefi Gholamhossein G Tamaddon AliMohammad A

BioImpacts : BI 20180418 4

<i><b>Introduction:</b></i> 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 characte ...[more]

PMID: 30397579

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Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most malignant tumors and the fourth leading cause of cancer-related death worldwide. Sorafenib is currently acknowledged as a standard therapy for advanced HCC. However, acquired resistance substantially limits the clinical efficacy of sorafenib. Therefore, further investigations of the associated risk factors are highly warranted.MethodsWe analysed a group of 78 HCC patients who received sorafenib treatment after liver resection surgery. The expression of SCAP and its correlation with sorafenib resistance in HCC clinical samples were determined by immunohistochemical analyses. Overexpression and knockdown approaches in vitro were used to characterize the functional roles of SCAP in regulating sorafenib resistance. The effects of SCAP inhibition in HCC cell lines were analysed in proliferation, apoptosis, and colony formation assays. Autophagic regulation by SCAP was assessed by immunoblotting, immunofluorescence and immunoprecipitation assays. The combinatorial effect of a SCAP inhibitor and sorafenib was tested using nude mice.ResultsHypercholesterolemia was associated with sorafenib resistance in HCC treatment. The degree of sorafenib resistance was correlated with the expression of the cholesterol sensor SCAP and consequent deposition of cholesterol. SCAP is overexpressed in HCC tissues and hepatocellular carcinoma cell lines with sorafenib resistance, while SCAP inhibition could improve sorafenib sensitivity in sorafenib-resistant HCC cells. Furthermore, we found that SCAP-mediated sorafenib resistance was related to decreased autophagy, which was connected to decreased AMPK activity. A clinically significant finding was that lycorine, a specific SCAP inhibitor, could reverse acquired resistance to sorafenib in vitro and in vivo.ConclusionsSCAP contributes to sorafenib resistance through AMPK-mediated autophagic regulation. The combination of sorafenib and SCAP targeted therapy provides a novel personalized treatment to enhance sensitivity in sorafenib-resistant HCC.

Project description: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.

Project description:We reported recently that the addition of ester-functionalized, "charge-shifting" side chains to linear poly(ethyleneimine) (LPEI) can be used to design polyamines that promote both self-assembly and self-disassembly with DNA in aqueous environments. This investigation sought to characterize the influence of charge-shifting side chains on the ability of LPEI to mediate cell transfection and understand the extent to which increases (or decreases) in levels of transfection could be understood in terms of time-dependent changes in the net charges of these polymers. We report that the addition of "charge-shifting" side chains to LPEI leads to significant increases in levels of LPEI-mediated transfection. In particular, polymer 1e, functionalized with 20 mol % ester-functionalized side chains, mediates levels of transgene expression in vitro up to 8-fold higher than LPEI. Experiments using an amide-functionalized analog of polymer 1e demonstrated that the esters in polymer 1e play an important role in promoting increased levels of transfection. These results, in combination with the results of additional gel electrophoresis experiments, provide support for the view that increases in transfection result from time-dependent changes in the net charge of polymer 1e and the disruption of ionic interactions in polyplexes. Additional support for this view is provided by the results of confocal microscopy experiments and measurements of fluorescence resonance energy transfer, which suggest that polymer 1e promotes the disruption of polyplexes in intracellular environments effectively. The approach reported here provides a means of addressing one important "late-stage" obstacle to polyplex-mediated transfection (polyplex unpackaging). If integrated successfully with methods that have been developed to address other important barriers to transfection, this general approach could lead to the development of multifunctional polyplexes that mimic more effectively the range of functions of viruses as agents for the delivery of DNA.

Dataset Information

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

Publications

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

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