Enhanced retention and anti-tumor efficacy of liposomes by changing their cellular uptake and pharmacokinetics behavior

doi:10.1016/j.biomaterials.2014.11.010

Biomaterials

Volume 41, February 2015, Pages 1-14

https://doi.org/10.1016/j.biomaterials.2014.11.010 Get rights and content

Abstract

Although PEGylated liposome-based drug delivery systems hold great promising applications for cancer therapy due to their prolonged blood circulation time, PEGylation significantly reduces their cellular uptake, which markedly impairs the in vivo tumor retention and antitumor efficiency of drug-loaded liposomes. Most importantly, it has been proved that repeated injections of PEGylated liposomes with cell cycle specific drug such as topotecan (TPT) in the same animal at certain time intervals will induce “accelerated blood clearance” (ABC) phenomenon, which decreases the tumor accumulation of drug-loaded liposomes and presents a tremendous challenge to the clinical use of liposome-based drug delivery systems. Herein, we developed a zwitterionic poly(carboxybetaine) (PCB) modified liposome-based drug delivery system. The presence of PCB could avoid protein adsorption and enhance the stability of liposomes as that for PEG. Quite different from the PEGylated liposomes, the pH-sensitive PCBylated liposomes were internalized into cells via endocytosis with excellent cellular uptake and drug release ability. Furthermore, the PCBylated liposomes would avoid ABC phenomenon, which promoted the tumor accumulation of drug-loaded liposomes in vivo. With higher tumor accumulation and cellular uptake, the PCBylated drug-loaded liposomes significantly inhibited tumor growth and provided a promising approach for cancer therapy.

Introduction

Widely recognized for their ability to produce a prolonged blood circulation time and facilitate tumor accumulation via the enhanced permeability and retention (EPR) effect, PEGylated liposome-based drug delivery systems hold great promising applications for cancer therapy [1], [2], [3], [4]. Unfortunately, PEGylation significantly reduces the cellular uptake and endosomal/lysosomal escape of the liposomes, and interferes with the tumor retention and antitumor efficacy of liposome-based drug delivery systems [5], [6]. Most importantly, it has been proved that repeated injections of PEGylated liposomes with cell cycle specific drugs such as topotecan (TPT) in the same animal at certain time intervals will induce “accelerated blood clearance” (ABC) phenomenon [7], [8]. PEGylated drug-loaded liposomes are intended to stimulate the spleen to produce anti-PEG IgM after the first administration, which selectively binds to PEG on the surface of the second administrated liposomes to cause rapid elimination and enhanced hepatic uptake [9], [10]. This immune response decreases the tumor accumulation of drug-loaded liposomes and presents a tremendous challenge to the clinical use of liposome-based drug delivery systems.

Advancement in nanotechnology has allowed for the development of delivery systems to avoid the induction of ABC phenomenon through changing the physicochemical properties of the PEGylated liposome-based drug delivery systems [11]. Unfortunately, most of these approaches were accompanied with sacrificing the therapeutic efficacy of PEGylated liposomes. It has been shown that liposomes modified with cleavable PEG-lipid derivatives could avoid the induction of ABC phenomenon. However, the effect on long circulation of the cleavable PEGylated liposomes was worse than that of non-cleavable PEGylated liposomes [12].

Another approach has focused on the use of alternative polymers to extend the circulation time of liposome-based drug delivery systems [13]. In our previous study, it has been proved that zwitterionic polymer poly(carboxybetaine) (PCB) has superior ability in extending the blood retention without interfering with the cellular uptake and endosomal/lysosomal escape of the liposomes, which is quite different from that of PEGylation [14]. However, whether liposome-based drug delivery systems modified with PCB would avoid ABC phenomenon in vivo has not been verified. Herein, to address the challenge, the performances of PCBylated liposome-based drug delivery systems in cellular uptake, pharmacokinetics and tumor therapy were investigated. Our findings demonstrated that PCBylation could change the cellular uptake behavior and avoid ABC phenomenon of drug-loaded liposomes, which facilitated the tumor accumulation and therefore enhanced the antitumor activity of liposome-based drug delivery systems (Scheme 1).

Section snippets

Materials

1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy (polyethylene glycol)-2000] (DSPE-PEG 2000), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), cholesterol were purchased from Advanced Vehicle Technology Ltd., Co. (Shanghai, China). Doxorubicin (DOX) and topotecan hydrochloride (TPT) were obtained from Melonepharma (Dalian, China). (5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), FITC-phalloidin and 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI) were

Preparation and characterization of empty and drug-loaded liposomes

We first developed PCBylated liposomes with distearoyl phosphoethanolamine-poly(carboxybetaine)₂₀ (DSPE-PCB₂₀), which has been shown comparable ability in prolonging the circulation time of liposomes with that of DSPE-PEG 2000 in our previous work [14]. In order to evaluate the pharmacokinetics and biodistribution of PCBylated liposome-based drug delivery systems reasonably, two model drugs were used as it has been proposed that drugs encapsulated in liposomes had influence on the ABC

Conclusion

In summary, we successfully developed zwitterionic PCB modified liposome-based drug delivery systems. Quite different from the DSPE-PEG liposomes, the pH-sensitive PCBylated liposomes changed the cellular uptake behavior of drug-loaded liposomes and were internalized into cells via endocytosis with excellent cellular uptake and drug release ability. Furthermore, the DSPE-PCB modified liposomes would avoid ABC phenomenon, which promoted the tumor accumulation of drug-loaded liposomes. With

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (21304099, 51203162, 51103159, 51373177), the National High Technology Research and Development Program (2014AA020708, 2012AA022703, 2012AA020804), the Instrument Developing Project of the Chinese Academy of Sciences (YZ201253, YZ201313), the Open Funding Project of the National Key Laboratory of Biochemical Engineering (Y22504A169) and the “Strategic Priority Research Program” of the Chinese Academy of

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¹: These authors contributed equally to this work.

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Enhanced retention and anti-tumor efficacy of liposomes by changing their cellular uptake and pharmacokinetics behavior

Abstract

Introduction

Section snippets

Materials

Preparation and characterization of empty and drug-loaded liposomes

Conclusion

Acknowledgments

Biomaterials

J Pharm Sci

J Control Release

Mol Ther

J Control Release

Biomaterials

J Control Release

J Control Release

J Control Release

Int J Pharm

Biomaterials

J Control Release

Biomaterials

Biomaterials

Biomaterials

J Control Release

Adv Drug Deliv Rev