Abstract
The purpose of this study was to develop an oral proliposomal powder of protein using poly-l-arginine-conjugated 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG) (PLD) for enhancing cellular association upon reconstitution and to compare its effects with a non-grafted and PEGylated formulation. Cationic proliposome (CATL), PLD-grafted CATL (PLD-CATL), PEGylated CATL (PEG CATL), and PLD grafted-PEG CATL (PLD-PEG CATL) were prepared and compared. Successful conjugation between poly-l-arginine and DSPE-PEG was confirmed by 1H NMR and FT-IR. PLD was successfully grafted onto the proliposomal powder during the slurry process. Although reconstituted liposomal sizes of CATL and PLD-CATL were increased by agglomeration, PEGylation reduced the agglomeration and increased the encapsulation. The viabilities of cells treated with both CATL and PLD-CATL formulations were low but increased following PEGylation. With regard to cellular association, PLD-CATL enhanced cellular association/uptake more rapidly than did CATL. Upon PEGylation, PEG CATL showed a lower level of cellular association/uptake compared with CATL while PLD-PEG CATL did not exhibit the rapid cellular association/uptake as seen with PLD-CATL. However, PLD-PEG CATL still enhanced the higher cellular association/uptake than PEG CATL did without PLD. In conclusion, proliposomes with PLD could accelerate cellular association/uptake but also caused high cellular toxicity. PEGylation reduced cellular toxicity and also changed the cellular association pattern of the PLD formulation.
Highlights
There has been great progress in liposomal research with the development of innovative liposomal technologies, which can be used as specific drug delivery systems
Physicochemical properties, cellular toxicity, and cellular association/uptake of proliposomal powder grafted to PLD, DSPE-PEG, or both PLD and DSPE-PEG were characterized and compared with non-grafted and PEGylated proliposomal formulations
Poly-l-arginine hydrochloride (PLR), bovine serum albumin (BSA), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT), and Triton X-100 were purchased from Sigma–Aldrich Co
Summary
There has been great progress in liposomal research with the development of innovative liposomal technologies, which can be used as specific drug delivery systems. Beyond its main purpose as a specific drug delivery system, liposomes have been used to deliver multiple drugs synchronously [5], reduce drug cellular toxicity [6,7], and enhance drug bioavailability [8]. Liposomes have low stability in their aqueous dosage form. When used to prepare a proliposomal dosage form, these benefits help overcome the classical obstacles seen with the use of liposomes. Combination of cationic lipids, CPP, and PEG could increase the stability of proliposomes, reduce toxicity, and improve oral absorption. The aim of the present study was to develop an oral cationic proliposomal powder grafted to synthesized poly-l-arginine conjugated DSPE-PEG (PLD) to enhance the cellular association of a reconstituted liposome-encapsulated protein drug, and to investigate the feasibility of enhancement in oral absorption. Physicochemical properties, cellular toxicity, and cellular association/uptake of proliposomal powder grafted to PLD, DSPE-PEG, or both PLD and DSPE-PEG were characterized and compared with non-grafted and PEGylated proliposomal formulations
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