Doxebo (doxorubicin-free Doxil-like liposomes) is safe to use as a pre-treatment to prevent infusion reactions to PEGylated nanodrugs

Yaelle Bavli, Ilan Winkler, Bing Mae Chen, Steve Roffler, Rivka Cohen, J. Szebeni, Yechezkel Barenholz

Research output: Article

Abstract

The increasing use in the last decade of PEGylated nanodrugs such as Doxil® has seen a rise in the number of associated occurrences of hypersensitivity reactions (HSRs). These reactions (also called infusion reactions or IR), can range from harmless symptoms to life-threatening reactions. Current means to prevent IR include the prophylactic use of antihistamines and steroids, but they cannot ensure total prevention. We previously showed that an intravenous injection of doxorubicin-free Doxil-like PEGylated nano-liposomes (Doxebo) prior to Doxil treatment suppresses Doxil-induced complement activation-related pseudoallergy (CARPA) in pigs, a model of human hypersensitivity reactions to Doxil. However, in order to use Doxebo to prevent Doxil-induced IR, we have to prove its safety and that it does not affect Doxil's performance. Here we show that Doxebo itself does not have toxic effects on the host or tumor, and it does not interfere with Doxil's antitumor activity in mice. Blood, microscopic and macroscopic organ evaluation of rats after repeated administration confirm the lack of intrinsic adverse effect of Doxebo. Likewise, the repeated injection of Doxebo before Doxil did not impact Doxil's pharmacokinetics in plasma and therefore does not cause accelerated blood clearance (ABC). Taken together with our previous publications, these data suggest that the injection of Doxebo prior to Doxil administration can help protect against Doxil-induced IR without adversely affecting treatment efficacy and safety.

Original languageEnglish
Pages (from-to)138-148
Number of pages11
JournalJournal of Controlled Release
Volume306
DOIs
Publication statusPublished - júl. 28 2019

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Liposomes
Doxorubicin
Therapeutics
liposomal doxorubicin
Hypersensitivity
Safety
Injections
Complement Activation
Poisons
Histamine Antagonists
Intravenous Injections
Swine
Pharmacokinetics
Steroids

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Doxebo (doxorubicin-free Doxil-like liposomes) is safe to use as a pre-treatment to prevent infusion reactions to PEGylated nanodrugs. / Bavli, Yaelle; Winkler, Ilan; Chen, Bing Mae; Roffler, Steve; Cohen, Rivka; Szebeni, J.; Barenholz, Yechezkel.

In: Journal of Controlled Release, Vol. 306, 28.07.2019, p. 138-148.

Research output: Article

Bavli, Yaelle ; Winkler, Ilan ; Chen, Bing Mae ; Roffler, Steve ; Cohen, Rivka ; Szebeni, J. ; Barenholz, Yechezkel. / Doxebo (doxorubicin-free Doxil-like liposomes) is safe to use as a pre-treatment to prevent infusion reactions to PEGylated nanodrugs. In: Journal of Controlled Release. 2019 ; Vol. 306. pp. 138-148.
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abstract = "The increasing use in the last decade of PEGylated nanodrugs such as Doxil{\circledR} has seen a rise in the number of associated occurrences of hypersensitivity reactions (HSRs). These reactions (also called infusion reactions or IR), can range from harmless symptoms to life-threatening reactions. Current means to prevent IR include the prophylactic use of antihistamines and steroids, but they cannot ensure total prevention. We previously showed that an intravenous injection of doxorubicin-free Doxil-like PEGylated nano-liposomes (Doxebo) prior to Doxil treatment suppresses Doxil-induced complement activation-related pseudoallergy (CARPA) in pigs, a model of human hypersensitivity reactions to Doxil. However, in order to use Doxebo to prevent Doxil-induced IR, we have to prove its safety and that it does not affect Doxil's performance. Here we show that Doxebo itself does not have toxic effects on the host or tumor, and it does not interfere with Doxil's antitumor activity in mice. Blood, microscopic and macroscopic organ evaluation of rats after repeated administration confirm the lack of intrinsic adverse effect of Doxebo. Likewise, the repeated injection of Doxebo before Doxil did not impact Doxil's pharmacokinetics in plasma and therefore does not cause accelerated blood clearance (ABC). Taken together with our previous publications, these data suggest that the injection of Doxebo prior to Doxil administration can help protect against Doxil-induced IR without adversely affecting treatment efficacy and safety.",
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AU - Chen, Bing Mae

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