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.

Paclitaxel‐loaded polypeptide‐polyacrylamide nanomicelles overcome drug‐resistance by enhancing lysosomal membrane permeability and inducing apoptosis

“…C 6 ‐loaded NMs (100 μg/ml copolymer) were then added and incubation (37°C or 4°C) continued for 2 hr. Afterward, samples were washed (cold PBS) and stored in dark on ice before analysis (Monajati, Tavakoli, Abolmaali, Yousefi, & Tamaddon, 2018) using a FACS Calibur flow cytometer (BD) by measuring 10,000 events per sample. Data were analyzed using WinMDi software ver.…”

Construction of NIR Light Controlled Micelles with Photothermal Conversion Property: Poly(poly(ethylene glycol)methyl ether methacrylate) (PPEGMA) as Hydrophilic Block and Ketocyanine Dye as NIR Photothermal Conversion Agent

“…In aqueous solutions, pyrene is usually used as fluorescent probe to detect the CMC of the solutions [51]. Pyrene is nearly insoluble in water, and its I 1 /I 3 value in aqueous solution is about 1.8 [52].…”

“…After deprotection with TFA, the complete disappearance of the peak at 1.40 ppm was observed from 1 H NMR spectrum (Figure 3b), which proved the removal of the tert-butoxycarbonyl group (BOC) and deprotected block copolymer PBnMA-b-P(APMA-co-PEGMA) was obtained. In aqueous solutions, pyrene is usually used as fluorescent probe to detect the CMC of the solutions [51]. Pyrene is nearly insoluble in water, and its I1/I3 value in aqueous solution is about 1.8 [52].…”

Artificial metallonucleases

“…Modification of PEI by polymers and/or ligands has recently been investigated to overcome the increasing cytotoxicity with increasing molecular weight and aggregation in the case of high ionic strength [101,102]. Changing its physicochemical properties is aimed to enhance biocompatibility and transfection efficiency [103,104]. [108].…”

“…For the average molecular mass of PEI Mw ~ 139±1 kDa was obtained from DLS measurements (it can be found in the Appendix A.8), however, the same method was not suitable for the determination of the molecular mass of WSLP, because of the artefacts arising from the light scattering of some aggregates. The WSLPs obtained by cholesterylation of low molecular weight PEI are usually characterized by NMR and MALDI TOF MS in terms of the molecular weight and cholesterylation extent [104,133,[178][179][180][181][182][183][184]. These methods perform well with small and medium size molecules, but become of limited use for compounds with the molecular weight with several hundreds of kDa.…”