Oral Administration of Recombinant Human Erythropoietin in Liposomes in Rats: Influence of Lipid Composition and Size of Liposomes on Bioavailability

Maitani, Yoshie; Hazama, Megumi; Tojo, Yasuko; Shimoda, Naoto; Nagai, Tsuneji

doi:10.1021/js950477m

Cited by 40 publications

(11 citation statements)

References 33 publications

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“…This appearance is typical for discoid structures, because they are mainly adsorbed at their hydrophobic edges onto the copper grid (Gursky, 2002;Jayaraman et al, 2005;Mehta et al, 2003;Sevcsik et al, 2007Sevcsik et al, , 2008. Though rh-Epo containing vesicles were described as drug-delivery systems before, our observations showed, for the first time, that rh-Epo enables the transformation of liposomal membranes (Maitani et al, 1996(Maitani et al, , 1999Moriya et al, 1997). However, those drug-delivery experiments were performed with liposomes consisting of DPPC and various sterols.…”

Section: Resultssupporting

confidence: 51%

Topological transformation of liposomes by a membrane-affecting domain of recombinant human erythropoietin

Strobach¹,

Kunert²,

Stadlmann³

et al. 2009

Journal of Liposome Research

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Recombinant human erythropoietin (rh-Epo) is well accepted as a hematopoietic drug, but many other pleiotropic properties are currently under investigation. Rh-Epo-induced receptor-mediated signal transductions are accompanied with membrane dynamic processes, which facilitate the activation of individual pathways. However, its direct effect on membrane dynamics is still unknown. In the present study, we have proven the capability of rh-Epo to associate to and transform artificial lipid membranes. Association studies using neutral, negatively, and positively charged liposomes with the native as well as modified rh-Epo were performed and analyzed by transmission electron microscopy and differential scanning calorimetry. By these studies, we demonstrated that rh-Epo has the capability to transform negatively charged unilamellar vesicles into so-called disc-like micelles. Rh-Epo association to the negatively charged head groups via lysine and arginine initiates this transformation. At physiological temperatures, conformational changes within the rh-Epo structure expose a defined amino-acid sequence, which is able to induce the formation of discoid membrane structures. Enzymatic digestion, analysis, and isolation of related peptides by rp-HPLC and characterization by MS/MS enabled the identification of the membrane-affecting domain of rh-Epo (MAD-E) that represents the exposed helix B of rh-Epo. Finally, association studies performed with these peptides confirmed that the MAD-E is responsible for the formation of disc-like micelles. Since this helix B of rh-Epo has recently been supposed to be involved in the activation of neuroprotective pathways, we believe that the membrane-transforming capacity of rh-Epo participates in the proliferative activity of rh-Epo.

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Section: Resultssupporting

confidence: 51%

Topological transformation of liposomes by a membrane-affecting domain of recombinant human erythropoietin

Strobach¹,

Kunert²,

Stadlmann³

et al. 2009

Journal of Liposome Research

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“…Some studies have already demonstrated that liposomalization of therapeutic and cosmetic agents can enhance their activity by improving their stability and permeability as well as, giving targeting ability and controlling the release of entrapped agents. Some proteins, such as insulin, 14,15) calsitonin, 16,17) and erythropoietin, 18) which are can be digested and have low permeability through intestinal membrane, have been shown to improve their pharmacological effects through oral administration by various formulations of liposomes. We previously showed that oral administration of liposomal lactoferrin enhanced host immune ability and anti-inflammatory effects.…”

mentioning

confidence: 99%

Chemoprevention of Tumor Metastasis by Liposomal .BETA.-Sitosterol Intake

Imanaka

Koide

Shimizu

et al. 2008

Biological & Pharmaceutical Bulletin

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To investigate chemopreventive effect of liposomal b b-sitosterol on tumor metastasis, we prepared liposomal b b-sitosterol composed of egg yolk phosphatidylcholine for oral delivery. Although orally administered b b-sitosterol (4 m mmol as b b-sitosterol/mouse) was not absorbed into plasma, the amount of immune response cytokines such as IL-12 and IL-18 was increased in the small intestine after the liposome intake. Moreover, after daily oral administration of the liposome for 7 d, natural killer (NK) cell activity in the mice was increased, suggesting that the immune surveillance activity of mice was enhanced by the liposomal b b-sitosterol intake. Thus, we examined metastatic potential of B16BL6 melanoma cells, which were intravenously injected into mice after sequential administration of liposomal b b-sitosterol for 7 d. The number of metastatic colonies in the lungs was significantly less than that of control group two weeks after the injections of the cells. These results suggest that daily liposomal b b-sitosterol intake prevents tumor metastasis may be due to enhancement of gut immune surveillance systems.

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“…Some studies have already demonstrated that liposomalization of therapeutic and cosmetic agents can enhance their activity by improving their stability and permeability, and also giving a targeting ability and time release. Some protein agents such as insulin, 25,26) calcitonin, 27,28) parathyroid hormone 28) and erythropoietin, 29) which are susceptible to being digested and also have low permeability for the intestinal membrane, have been shown to improve their pharmacological effects through oral administration by various liposomal applications. In this study, bLF is encapsulated into liposome consisting of egg yolk phosphatidylcholine (EPC) and phytosterol in order to orally administer bLF more effectively.…”

mentioning

confidence: 99%

Liposomalization of Lactoferrin Enhanced It's Anti-inflammatory Effects via Oral Administration

Ishikado

Imanaka

Takeuchi

et al. 2005

Biological & Pharmaceutical Bulletin

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It is known that lactoferrin is one of the functional proteins contained in mammalian milk and that it plays an important role in the immune system. In this study, we prepared multi-lamellar liposomal bovine lactoferrin composed of egg yolk phosphatidylcholine and phytosterol for oral delivery, and examined any resulting anti-inflammatory effects. Oral pretreatment of liposomal lactoferrin exhibited more suppressive effects than did nonliposomal lactoferrin on CCl 4 -induced hepatic injury in rats as well as on lipopolysaccharide-induced TNF-alpha production from mouse peripheral blood mononuclear leukocytes. Further investigation revealed that the liposomalization did not exert influence on the absorbability of lactoferrin to the venous blood or lymph following an intraduodenal administration in rats. Furthermore, there was no significant difference exhibited between the antigenicity of liposomal and non-liposomal lactoferrin, which was measured using the passive cutaneous anaphylaxis reaction following oral sensitization to them in guinea pigs. These results suggest that liposomal lactoferrin might act more effectively than conventional lactoferrin in the intestinal site, which is regarded as an active site of orally administered lactoferrin, although the biological mechanism is not fully understood yet. Consequently we propose that liposomal lactoferrin could be a novel active constituent useful for preventive and therapeutic treatment of inflammatory diseases.

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Oral Administration of Recombinant Human Erythropoietin in Liposomes in Rats: Influence of Lipid Composition and Size of Liposomes on Bioavailability

Cited by 40 publications

References 33 publications

Topological transformation of liposomes by a membrane-affecting domain of recombinant human erythropoietin

Topological transformation of liposomes by a membrane-affecting domain of recombinant human erythropoietin

Chemoprevention of Tumor Metastasis by Liposomal .BETA.-Sitosterol Intake

Liposomalization of Lactoferrin Enhanced It's Anti-inflammatory Effects via Oral Administration

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