Accelerated drug release and clearance of PEGylated epirubicin liposomes following repeated injections: a new challenge for sequential low-dose chemotherapy

Qiang Yang,1 Yanling Ma,2 Yongxue Zhao,1 Zhennan She,1 Long Wang,1 Jie Li,1 Chunling Wang,1 Yihui Deng1 1College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 2Sichuan Kelun Pharmaceutical Co, Ltd, Chengdu, People’s Republic of China Backg...

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Autores principales:	Yang Q, Ma Y, Zhao Y, She Z, Wang L, Li J, Wang C, Deng Y
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2013
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/e20e30a5d58b4214b712e9645d339257
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spelling	oai:doaj.org-article:e20e30a5d58b4214b712e9645d3392572021-12-02T02:48:33ZAccelerated drug release and clearance of PEGylated epirubicin liposomes following repeated injections: a new challenge for sequential low-dose chemotherapy1176-91141178-2013https://doaj.org/article/e20e30a5d58b4214b712e9645d3392572013-03-01T00:00:00Zhttp://www.dovepress.com/accelerated-drug-release-and-clearance-of-pegylated-epirubicin-liposom-a12612https://doaj.org/toc/1176-9114https://doaj.org/toc/1178-2013Qiang Yang,1 Yanling Ma,2 Yongxue Zhao,1 Zhennan She,1 Long Wang,1 Jie Li,1 Chunling Wang,1 Yihui Deng1 1College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 2Sichuan Kelun Pharmaceutical Co, Ltd, Chengdu, People’s Republic of China Background: Sequential low-dose chemotherapy has received great attention for its unique advantages in attenuating multidrug resistance of tumor cells. Nevertheless, it runs the risk of producing new problems associated with the accelerated blood clearance phenomenon, especially with multiple injections of PEGylated liposomes. Methods: Liposomes were labeled with fluorescent phospholipids of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(7-nitro-2-1,3-benzoxadiazol-4-yl) and epirubicin (EPI). The pharmacokinetics profile and biodistribution of the drug and liposome carrier following multiple injections were determined. Meanwhile, the antitumor effect of sequential low-dose chemotherapy was tested. To clarify this unexpected phenomenon, the production of polyethylene glycol (PEG)-specific immunoglobulin M (IgM), drug release, and residual complement activity experiments were conducted in serum. Results: The first or sequential injections of PEGylated liposomes within a certain dose range induced the rapid clearance of subsequently injected PEGylated liposomal EPI. Of note, the clearance of EPI was two- to three-fold faster than the liposome itself, and a large amount of EPI was released from liposomes in the first 30 minutes in a complement-activation, direct-dependent manner. The therapeutic efficacy of liposomal EPI following 10 days of sequential injections in S180 tumor-bearing mice of 0.75 mg EPI/kg body weight was almost completely abolished between the sixth and tenth day of the sequential injections, even although the subsequently injected doses were doubled. The level of PEG-specific IgM in the blood increased rapidly, with a larger amount of complement being activated while the concentration of EPI in blood and tumor tissue was significantly reduced. Conclusion: Our investigation implied that the accelerated blood clearance phenomenon and its accompanying rapid leakage and clearance of drug following sequential low-dose injections may reverse the unique pharmacokinetic–toxicity profile of liposomes which deserved our attention. Therefore, a more reasonable treatment regime should be selected to lessen or even eliminate this phenomenon. Keywords: accelerated blood clearance (ABC) phenomenon, PEGylated liposomes, epirubicin, sequential low-dose injections, complementYang QMa YZhao YShe ZWang LLi JWang CDeng YDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2013, Iss default, Pp 1257-1268 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Yang Q Ma Y Zhao Y She Z Wang L Li J Wang C Deng Y Accelerated drug release and clearance of PEGylated epirubicin liposomes following repeated injections: a new challenge for sequential low-dose chemotherapy
description	Qiang Yang,1 Yanling Ma,2 Yongxue Zhao,1 Zhennan She,1 Long Wang,1 Jie Li,1 Chunling Wang,1 Yihui Deng1 1College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 2Sichuan Kelun Pharmaceutical Co, Ltd, Chengdu, People’s Republic of China Background: Sequential low-dose chemotherapy has received great attention for its unique advantages in attenuating multidrug resistance of tumor cells. Nevertheless, it runs the risk of producing new problems associated with the accelerated blood clearance phenomenon, especially with multiple injections of PEGylated liposomes. Methods: Liposomes were labeled with fluorescent phospholipids of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(7-nitro-2-1,3-benzoxadiazol-4-yl) and epirubicin (EPI). The pharmacokinetics profile and biodistribution of the drug and liposome carrier following multiple injections were determined. Meanwhile, the antitumor effect of sequential low-dose chemotherapy was tested. To clarify this unexpected phenomenon, the production of polyethylene glycol (PEG)-specific immunoglobulin M (IgM), drug release, and residual complement activity experiments were conducted in serum. Results: The first or sequential injections of PEGylated liposomes within a certain dose range induced the rapid clearance of subsequently injected PEGylated liposomal EPI. Of note, the clearance of EPI was two- to three-fold faster than the liposome itself, and a large amount of EPI was released from liposomes in the first 30 minutes in a complement-activation, direct-dependent manner. The therapeutic efficacy of liposomal EPI following 10 days of sequential injections in S180 tumor-bearing mice of 0.75 mg EPI/kg body weight was almost completely abolished between the sixth and tenth day of the sequential injections, even although the subsequently injected doses were doubled. The level of PEG-specific IgM in the blood increased rapidly, with a larger amount of complement being activated while the concentration of EPI in blood and tumor tissue was significantly reduced. Conclusion: Our investigation implied that the accelerated blood clearance phenomenon and its accompanying rapid leakage and clearance of drug following sequential low-dose injections may reverse the unique pharmacokinetic–toxicity profile of liposomes which deserved our attention. Therefore, a more reasonable treatment regime should be selected to lessen or even eliminate this phenomenon. Keywords: accelerated blood clearance (ABC) phenomenon, PEGylated liposomes, epirubicin, sequential low-dose injections, complement
format	article
author	Yang Q Ma Y Zhao Y She Z Wang L Li J Wang C Deng Y
author_facet	Yang Q Ma Y Zhao Y She Z Wang L Li J Wang C Deng Y
author_sort	Yang Q
title	Accelerated drug release and clearance of PEGylated epirubicin liposomes following repeated injections: a new challenge for sequential low-dose chemotherapy
title_short	Accelerated drug release and clearance of PEGylated epirubicin liposomes following repeated injections: a new challenge for sequential low-dose chemotherapy
title_full	Accelerated drug release and clearance of PEGylated epirubicin liposomes following repeated injections: a new challenge for sequential low-dose chemotherapy
title_fullStr	Accelerated drug release and clearance of PEGylated epirubicin liposomes following repeated injections: a new challenge for sequential low-dose chemotherapy
title_full_unstemmed	Accelerated drug release and clearance of PEGylated epirubicin liposomes following repeated injections: a new challenge for sequential low-dose chemotherapy
title_sort	accelerated drug release and clearance of pegylated epirubicin liposomes following repeated injections: a new challenge for sequential low-dose chemotherapy
publisher	Dove Medical Press
publishDate	2013
url	https://doaj.org/article/e20e30a5d58b4214b712e9645d339257
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Accelerated drug release and clearance of PEGylated epirubicin liposomes following repeated injections: a new challenge for sequential low-dose chemotherapy

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