Accelerated blood clearance of PEGylated liposomes containing doxorubicin upon repeated administration to dogs

Suzuki, Takuya; Ichihara, Masako; Hyôdô, Kenji; Yamamoto, Eiichi; Ishida, Tatsuhiro; Kojima, Hiroshi; Ishiguro, Hiroshi; Kikuchi, Hiroshi

doi:10.1016/j.ijpharm.2012.07.049

Cited by 105 publications

(91 citation statements)

References 28 publications

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“…This study showed that mice, rabbits and guinea pigs could also produce an intense ABC phenomenon. Based on literature, the ABC phenomenon can also be induced in rhesus monkeys (Dams et al, 2000), beagles (Zhao et al, 2012;Suzuki et al, 2012;Li et al, 2012) and other animals. Thus, the ABC phenomenon is a ubiquitous immune phenomenon in life.…”

Section: Effect Of Different Animal Models On Abc Phenomenonmentioning

confidence: 99%

Influence of phospholipid types and animal models on the accelerated blood clearance phenomenon of PEGylated liposomes upon repeated injection

et al. 2014

Drug Delivery

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(2015) Influence of phospholipid types and animal models on the accelerated blood clearance phenomenon of PEGylated liposomes upon repeated injection, Drug Delivery, 22:5, 598-607, DOI: 10.3109/10717544.2014 AbstractWhen polyethylene glycol (PEG)ylated liposomes were repeatedly injected into the same animal, the second dose of liposomes would rapidly clear from the bloodstream and enhance accumulation in the liver and spleen, and this phenomenon is called ''accelerated blood clearance (ABC)''. There are many factors known to influence ABC phenomenon, in this study, we mainly focused on the effects of different phospholipids (PL) types and animal models. The effects of PL types on ABC phenomenon were examined by repeating injection of PEGylated liposomes prepared by five different types of PL (hydrogenated soy phosphatidylcholine, egg sphingomyelin, soybean phosphatidycholin, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and egg phosphatidycholin) in rats. Dramatically, repeated injection of different types of PL could induce ABC phenomenon altogether. Both t 1/2 and AUC of experimental group (EG) were lower significantly than those of control group (CG). Our results also showed that the liver accumulation of second dose increased significantly (p50.01) in all EG as compared that of CG. Interestingly, ABC phenomenon of liposomes prepared by unsaturated PL was more obvious than that of saturated PL. All the first dose could induce the antibody (anti-PEG IgM) level increasing significantly (p50.01). For different animal models, we found that after repeated injection of PEGylated liposomes, rats, mice, rabbits and guinea pigs could produce ABC phenomenon. Various PL types and animal models could all produce the ABC phenomenon. However, their extent of accelerated clearance differed. ABC phenomenon is possibly a ubiquitous immune phenomenon in life.

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Section: Effect Of Different Animal Models On Abc Phenomenonmentioning

confidence: 99%

Influence of phospholipid types and animal models on the accelerated blood clearance phenomenon of PEGylated liposomes upon repeated injection

et al. 2014

Drug Delivery

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“…However, we recently reported that doxil ® induces the ABc phenomenon in dogs when it is given with 2 mg dXR/m 2 or lower, which is much lower than the conventional dose. 34) It is likely that the lower dose of doxil ® rather activates the B cells and thereby enhances the secretion of anti-PEG IgM. This suggests that the suppression of ABc phenomenon by doxil ® is dose-dependent, and an increased doxil ® dose similar to the conventional treatment might inhibit the activation of B cells.…”

Section: Anti-peg Igm Response To Pegylated Nanoparticlesmentioning

confidence: 99%

Anti-polyethyleneglycol Antibody Response to PEGylated Substances

Ishida

Kojima

2013

Biological & Pharmaceutical Bulletin

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In contrast to the general assumption that polyethyleneglycol (PEG)-conjugated substances lack immunogenicity and antigenic, it has been reported that they can elicit antibodies against PEG (mainly anti-PEG immunoglobulin M (IgM)). In patients, the presence of anti-PEG antibodies may limit therapeutic efficacy of PEGylated substances as a consequence of inducing rapid clearance of and neutralizing biological activity of the substances. Here, we introduce specific examples of PEGylated substances including several PEGylated proteins and PEGylated particles (PEGylated nanocarriers) which induce anti-PEG antibody responses. Finally, we emphasize that the immunogenicity of PEGylated substances should be tested in the development stage and that the titer of anti-PEG antibodies in patients should be pre-screened and monitored prior to and throughout a course of treatment with a PEGylated substance.

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“…Some pharmacokinetic studies were conducted using DoXIL as model drug product and we have reported that DoXIL administered at a therapeutic dose (20 mg/m 2 ) did not cause the ABc phenomenon, but DoXIL administered at lower doses (<2 mg/m 2 ) caused anti-PEG IgM production and thereby a rapid clearance of the second and third administration of DoXIL in Beagle dogs. 33) our results indicate that the ABc phenomenon is not an issue with DoXIL in the therapeutic dose range and also may not be for the other PEG-modified liposomes encapsulating cytotoxic drug at therapeutic dose ranges. These results suggest that the pre-clinical study of PEG-modified liposomes containing anti-cancer agents must be carefully designed and performed with monitoring of the anti-PEG IgM level and the liposomal drug concentration in the blood.…”

Section: Pharmacology and Safety Studies To Initiate Clinical Trialsmentioning

confidence: 66%

Development of Liposomal Anticancer Drugs

Hyôdô

Yamamoto

Suzuki

et al. 2013

Biological & Pharmaceutical Bulletin

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Liposomes are drug delivery systems that can alter the pharmacokinetic properties of compounds. The adverse effects of anticancer agents are a limiting factor for cancer chemotherapy, therefore, liposomal formulations have the potential to improve the therapeutic efficacy of anticancer agents by enhancing their accumulation in tumors and reducing non-selective distribution to normal tissues, which is known as the enhanced permeability and retention effect. To develop a liposomal anticancer agent as a drug product, its formulation must be designed to ensure its quality until it is administered to patients and to exert maximum potency in clinical use rather than in animal experiments. The chemical stability and physicochemical stability of the ingredients are key factors in the design of liposomal formulations. Drug release rates are critical factors in the therapeutic efficacy of liposomal drug products because the encapsulated drug has no pharmacological activity, and only released drug can exert antitumor/toxic activities. Liposomes should maintain the drug in a stable state in the circulation and then promptly release it after accumulation in the target tissue in order to achieve a sufficient drug concentration. To understand the profile of the formulation and to guarantee the quality of drug product, a reliable analytical method that can determine the released and encapsulated drugs in biological fluids is required. Simple online solid phase extractions of the released and encapsulated drugs using a column-switching HPLC system meet the requirements and this system enables accurate in vitro release testing and in vivo pharmacokinetic evaluation. This review introduces the process of liposomal drug product development from various viewpoints.

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Accelerated blood clearance of PEGylated liposomes containing doxorubicin upon repeated administration to dogs

Cited by 105 publications

References 28 publications

Influence of phospholipid types and animal models on the accelerated blood clearance phenomenon of PEGylated liposomes upon repeated injection

Influence of phospholipid types and animal models on the accelerated blood clearance phenomenon of PEGylated liposomes upon repeated injection

Anti-polyethyleneglycol Antibody Response to PEGylated Substances

Development of Liposomal Anticancer Drugs

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