Accelerated blood clearance of PEGylated liposomes upon repeated injections: Effect of doxorubicin-encapsulation and high-dose first injection

For safe and effective therapy, drugs should be delivered selectively to their target tissues or cells at an optimal rate. Drug delivery system technology maximizes the therapeutic efficacy and minimizes unfavorable drug actions by controlling their distribution profiles. Ligand-receptor binding is a typical example of specific recognition mechanisms in the body; therefore, ligand-modified drug carriers have been developed for active targeting based on receptor-mediated endocytosis. Among the various ligands reported thus far, sugar recognition is a promising approach for active targeting because of their high affinity and expression. Glycosylation has been applied for both macromolecular and liposomal carriers for cell-selective drug targeting.Recently, the combination of ultrasound exposure and glycosylated bubble liposomes has been developed. In this review, recent advances of glycosylation-mediated targeted drug delivery systems are discussed.

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“…PEGylated liposomes [126]. This observation partly explains the observation by Laveman et al described above [119].…”

Section: Dams Et Al Reported That Repeated Injections Of Pegylated Lsupporting

confidence: 82%

Glycosylation-mediated targeting of carriers

Kawakami

Hashida

2014

Journal of Controlled Release

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“…With respect to PEGylated liposome, we showed that lipid dose for injection is one of crucial factors to determine the level of anti-PEG IgM induction; the higher the dose the smaller the anti-PEG IgM induction. 40) At low amounts of PEGylated protein in spleen the level of crosslinking with B cells might be sufficient to activate the cells specifically; at high amounts of PEGylated protein the cells might rather become anergic. Hence, it is presumed that the physicochemical properties of PEGylated proteins, such as PEG chain length, numbers of the PEG branch and the PEG modification ratio, strongly affect the pharmacokinetics and interactions with B cells and are crucial to determining the degree of anti-PEG IgM production elicited by PEGylated proteins (Fig.…”

Section: Discussionmentioning

confidence: 99%

Intravenous Administration of Polyethylene Glycol-Coated (PEGylated) Proteins and PEGylated Adenovirus Elicits an Anti-PEG Immunoglobulin M Response

Shimizu

Ichihara

Yoshioka

et al. 2012

Biological & Pharmaceutical Bulletin

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“…This is opposed to the subcutaneous space which is primarily filtered to the spleen via lymphatic circulation, and the large size of the liposomes may limit distribution via this system. It is surprising given the fact that PEG itself is generally believed to be immunologically inert, but Ishida and coworkers have reported the development of an IgM-based immune response to liposomes incorporating PEG 2000 -DSPE (58). Development of this response is T cell-independent, B cell-mediated, and the spleen plays a critical role (59,60).…”

Section: Discussionmentioning

confidence: 99%

“…Recognition of PEGylated liposomes by IgM could lead to compliment activation and further recruitment of APCs. If the development of an IgMbased response to the PEGylated liposomes is indeed the cause for this elevated immunogenicity, it is likely when extended to multiple dosing what little pharmacokinetic improvements we have observed will be lost due to the accelerated blood clearance phenomenon associated with this response (58). In these studies, we used PEG with a molecular weight of 2000.…”

Section: Discussionmentioning

confidence: 99%

PEGylation of a Factor VIII–Phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice

Peng

Kosloski

Nakamura

et al. 2011

AAPS J

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Abstract. Hemophilia A is an X-linked bleeding disorder caused by the deficiency of factor VIII (FVIII). Exogenous FVIII is administered therapeutically, and due to a short half-life, frequent infusions are often required. Fifteen to thirty-five percent of severe hemophilia A patients develop inhibitory antibodies toward FVIII that complicate clinical management of the disease. Previously, we used phosphatidylinositol (PI) containing lipidic nanoparticles to improve the therapeutic efficacy of recombinant FVIII by reducing immunogenicity and prolonging the circulating half-life. The objective of this study is to investigate further improvements in the FVIII-PI formulation resulting from the addition of polyethylene glycol (PEG) to the particle. PEGylation was achieved by passive transfer of PEG conjugated lipid into the FVIII-PI complex. PEGylated FVIII-PI (FVIII-PI/PEG) was generated with high association efficiency. Reduced activity in vitro and improved retention of activity in the presence of antibodies suggested strong shielding of FVIII by the particle; thus, in vivo studies were conducted in hemophilia A mice. Following intravenous administration, the apparent terminal half-life was improved versus both free FVIII and FVIII-PI, but exposure determined by area under the curve was reduced. The formation of inhibitory antibodies after subcutaneous immunization with FVIII-PI/PEG was lower than free FVIII but resulted in a significant increase in inhibitors following intravenous administration. Passive transfer of PEG onto the FVIII-PI complex does not provide any therapeutic benefit.

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Accelerated blood clearance of PEGylated liposomes upon repeated injections: Effect of doxorubicin-encapsulation and high-dose first injection

Cited by 255 publications

References 25 publications

Glycosylation-mediated targeting of carriers

Glycosylation-mediated targeting of carriers

Intravenous Administration of Polyethylene Glycol-Coated (PEGylated) Proteins and PEGylated Adenovirus Elicits an Anti-PEG Immunoglobulin M Response

PEGylation of a Factor VIII–Phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice

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