Hepatosplenic phagocytic cells indirectly contribute to anti-PEG IgM production in the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes: Appearance of an unexplained mechanism in the ABC phenomenon

Sayed, Marwa M. El; Takata, Haruka; Shimizu, Taro; Kawaguchi, Y.; Lila, Amr S. Abu; Elsadek, Nehal E.; Alaaeldin, Eman; Ishima, Yu; Ando, Hidenori; Kamal, Amal; Sarhan, Hatem A.; Ishida, Tatsuhiro

doi:10.1016/j.jconrel.2020.04.011

Cited by 33 publications

(25 citation statements)

References 52 publications

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“…Clodronate-containing liposomes, composed of POPC/CHOL (45/8, molar ratio), were prepared by a thin film evaporation technique, as described previously [ 32 , 33 ]. Briefly, the lipids were dissolved in chloroform, and the organic solvent was removed by rotary evaporator under vacuum at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil®) in C26 Tumor-Bearing Immunocompetent Mice

et al. 2020

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Doxorubicin (DXR) has been reported to have direct cytotoxicity against cancer cells and indirect immunotoxicity by modulation of host antitumor immunity. Hence, it may prevent cancer progression by a dual mechanism. Doxil®, a formulation of DXR encapsulated in polyethylene glycol modified (PEGylated) liposomes, is the most widely used of the clinically approved liposomal anticancer drugs. However, the effect of Doxil® on host antitumor immunity is not well understood. In this study, Doxil® efficiently suppressed tumor growth in immunocompetent mice bearing C26 murine colorectal carcinomas, but not in T cell-deficient nude mice, indicating a contribution of T cells to the overall antitumor effect of Doxil®. In immunocompetent mice, Doxil® increased major histocompatibility complex (MHC-1) levels in C26 tumors, which may be an indicator of increased immunogenicity of tumor cells, and potentially amplified tumor immunogenicity by decreasing immunosuppressive cells such as regulatory T cells, tumor-associated microphages and myeloid-derived suppressor cells that collectively suppress T cell-mediated antitumor responses. This suggests that encapsulation of DXR into PEGylated liposomes increased the therapeutic efficacy of DXR though effects on host antitumor immunogenicity in addition to direct cytotoxic effects on tumor cells. This report describes the role of host antitumor immunity in the overall therapeutic effects of Doxil®. Manipulating pharmacokinetics and biodistribution of chemotherapeutic agents with immunomodulatory properties may increase their therapeutic efficacies by amplifying host antitumor immunity in addition to direct cytotoxic effects on tumor cells.

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Section: Methodsmentioning

confidence: 99%

Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil®) in C26 Tumor-Bearing Immunocompetent Mice

et al. 2020

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“…This phenomenon was initially found in PEGylated liposomes 156 , and it has been confirmed in many animals and a variety of PEGylated nanoparticles [157][158][159][160][161][162] . ABC is considered to the result of the occurrence of anti-PEG IgM in the spleen 163,164 . This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.…”

Section: Accelerate Blood Clearance Effectmentioning

confidence: 99%

Effects of polyethylene glycol on the surface of nanoparticles for targeted drug delivery

et al. 2021

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“…The ABC effect, which was initially described by the groups of Storm et al and Ishida et al , is characterized by the fast clearance of a first injection of a small lipid dose or by the fast clearance of a second injection of an average lipid dose of liposomes. Further investigations of the Ishida et al group with systemic administration of PEGylated liposomes in murine models revealed that the ABC effect is due to anti-PEG IgM binding to the vesicles, which then accounts for their rapid uptake by the mononuclear phagocyte system (MPS). , Triggering C activation by Ab liposome binding is likely to magnify this clearance effect further . These studies primarily used liposome doses that were lower than required for the therapeutic delivery of most drugs, and the authors did not report CARPA or any other form of HSR because mice and rats are insensitive to such reactions .…”

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confidence: 99%

Complement Activation: A Potential Threat on the Safety of Poly(ethylene glycol)-Coated Nanomedicines

Gabizón

Szebeni

2020

ACS Nano

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In this issue of ACS Nano, Chen et al. provide in vitro and in vivo evidence for monoclonal anti-poly(ethylene glycol) (anti-PEG) antibody-triggered, complement terminal complex-mediated damage to PEGylated liposomal doxorubicin, entailing the release of the encapsulated drug from the vesicles. These results reveal a new dimension of the potential damage of anti-PEG antibody-mediated complement activation on PEGylated nanomedicines in addition to previous observations on infusion hypersensitivity reactions and the accelerated blood clearance effect. The possibility of a destructive attack of the complement system on the liposome drug carrier may have safety implications in patients displaying high levels of preformed anti-PEG antibodies. In this Perspective, we summarize the experimental and clinical data highlighting the relationships among the above adverse immune phenomena and the options available for reducing the risk of immune damage caused by PEGylated nanomedicines.

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Hepatosplenic phagocytic cells indirectly contribute to anti-PEG IgM production in the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes: Appearance of an unexplained mechanism in the ABC phenomenon

Cited by 33 publications

References 52 publications

Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil®) in C26 Tumor-Bearing Immunocompetent Mice

Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil®) in C26 Tumor-Bearing Immunocompetent Mice

Effects of polyethylene glycol on the surface of nanoparticles for targeted drug delivery

Complement Activation: A Potential Threat on the Safety of Poly(ethylene glycol)-Coated Nanomedicines

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