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Towards the Development of Long Circulating Phosphatidylserine (PS)- and Phosphatidylglycerol (PG)-Enriched Anti-Inflammatory Liposomes: Is PEGylation Effective?

ABSTRACT: The anionic phospholipids (PLs) phosphatidylserine (PS) and phosphatidylglycerol (PG) are endogenous phospholipids with anti-inflammatory and immunomodulatory activity. A potential clinical use requires well-defined systems and for several applications, a long circulation time is desirable. Therefore, we aimed the development of long circulating liposomes with intrinsic anti-inflammatory activity. Hence, PS- and PG-enriched liposomes were produced, whilst phosphatidylcholine (PC) liposomes served as control. Liposomes were either formulated as conventional or PEGylated formulations. They had diameters below 150 nm, narrow size distributions and composition-dependent surface charges. Pharmacokinetics were assessed non-invasively via in vivo fluorescence imaging (FI) and ex vivo in excised organs over 2 days. PC liposomes, conventionally formulated, were rapidly cleared from the circulation, while PEGylation resulted in prolongation of liposome circulation robustly distributing among most organs. In contrast, PS and PG liposomes, both as conventional or PEGylated formulations, were rapidly cleared. Non-PEGylated PS and PG liposomes did accumulate almost exclusively in the liver. In contrast, PEGylated PS and PG liposomes were observed mainly in liver and spleen. In summary, PEGylation of PS and PG liposomes was not effective to prolong the circulation time but caused a higher uptake in the spleen.

SUBMITTER: Klein ME

PROVIDER: S-EPMC7922817 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Towards the Development of Long Circulating Phosphatidylserine (PS)- and Phosphatidylglycerol (PG)-Enriched Anti-Inflammatory Liposomes: Is PEGylation Effective?

Klein Miriam E ME Rieckmann Max M Sedding Daniel D Hause Gerd G Meister Annette A Mäder Karsten K Lucas Henrike H

Pharmaceutics 20210219 2

The anionic phospholipids (PLs) phosphatidylserine (PS) and phosphatidylglycerol (PG) are endogenous phospholipids with anti-inflammatory and immunomodulatory activity. A potential clinical use requires well-defined systems and for several applications, a long circulation time is desirable. Therefore, we aimed the development of long circulating liposomes with intrinsic anti-inflammatory activity. Hence, PS- and PG-enriched liposomes were produced, whilst phosphatidylcholine (PC) liposomes serve ...[more]

PMID: 33669803

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Project description:IntroductionCancer is a big challenge of the 21 century, whose defeat requires efficient antitumor drugs.ObjectivesThe paper aims to investigate the synergistic effect of two structural building blocks, phenothiazine and poly(ethylene glycol), towards efficient antitumor drugs.MethodsTwo PEGylated phenothiazine derivatives were synthetized by attaching poly(ethylene glycol) of 550 Da to the nitrogen atom of phenothiazine by ether or ester linkage. Their antitumor activity has been investigated on five human tumour lines and a mouse tumor line as well, by determination of IC50. The in vivo toxicity was determined by measuring the LD50 in BALB/c mice by the sequential method and the in vivo antitumor potential was measured by the tumours growth test. The antitumor mechanism was investigated by complexation studies of zinc and magnesium ions characteristic to the farnesyltransferase enzyme, by studies of self-aggregation in the cells proximity and by investigation of the antitumor properties of the acid species resulted by enzymatic cleavage of the PEGylated derivatives.ResultsThe two compounds showed antitumor activity, with IC50 against mouse colon carcinoma cell line comparable with that of the traditional antitumor drugs 5-Fluorouracil and doxorubicin. The phenothiazine PEGylation resulted in a significant toxicity diminishing, the LD50 in BALB/c mice increasing from 952.38 up to 1450 mg/kg, in phenothiazine equivalents. Both compounds inflicted a 92% inhibition of the tumour growth for doses much smaller than LD50. The investigation of the possible tumour inhibition mechanism suggested the nanoaggregate formation and the cleavage of ester bonds as key factors for the inhibition of cancer cell proliferation and biocompatibility improvement.ConclusionPhenothiazine and PEG building blocks have a synergetic effect working for both tumour growth inhibition and biocompatibility improvement. All these findings recommend the PEGylated phenothiazine derivatives as a valuable workbench for a next generation of antitumor drugs.

Dataset Information

Towards the Development of Long Circulating Phosphatidylserine (PS)- and Phosphatidylglycerol (PG)-Enriched Anti-Inflammatory Liposomes: Is PEGylation Effective?

Publications

Towards the Development of Long Circulating Phosphatidylserine (PS)- and Phosphatidylglycerol (PG)-Enriched Anti-Inflammatory Liposomes: Is PEGylation Effective?

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