Prevention of infusion reactions to PEGylated liposomal doxorubicin via tachyphylaxis induction by placebo vesicles: A porcine model

J. Szebeni, Péter Bedocs, Rudolf Urbanics, Rolf Bünger, L. Rosivall, Miklós Tóth, Yechezkel Barenholz

Research output: Article

51 Citations (Scopus)

Abstract

PEGylated liposomal doxorubicin (Doxil) has been used in cancer chemotherapy for 16 years. Clinical experience shows that it can cause mild-to-severe hypersensitivity (infusion) reactions, which are manifestations of complement (C) activation-related pseudoallergy (CARPA). Although in most cases CARPA is inconsequential, a main symptom, cardiopulmonary distress, may be life threatening in hypersensitive individuals. To date, the prevention of Doxil-induced CARPA is based on premedication and a slow infusion protocol. The present study suggests desensitization by Doxil-like empty liposomes, called placebo Doxil (Doxebo), as an alternative strategy, which is based on the tachyphylactic nature of Doxil reactions. Doxebo-induced tolerance to Doxil was shown to develop within minutes and to be specific to Doxil-like PEGylated liposomes. The procedure of desensitization involves slow, low-dose pre-infusion of Doxebo before Doxil treatment which minimizes the ensuing physiological changes or keeps them subclinical. Although the mechanism of tolerance induction is not yet clear, the effector arm of C response is unlikely to be affected, as the vascular reactivity of desensitized pigs to zymosan remains intact. Desensitization with empty vesicles represents a novel approach for reducing the risk of anaphylactic reactions to drug carrier liposomes. The underlying immediate, most likely passive silencing of an innate immune response may represent a novel mechanism of tolerance induction which may work for other reactogenic nanosystems as well.

Original languageEnglish
Pages (from-to)382-387
Number of pages6
JournalJournal of Controlled Release
Volume160
Issue number2
DOIs
Publication statusPublished - jún. 10 2012

Fingerprint

Tachyphylaxis
Swine
Placebos
Liposomes
liposomal doxorubicin
Drug Carriers
Zymosan
Premedication
Complement Activation
Anaphylaxis
Innate Immunity
Blood Vessels
Hypersensitivity
Drug Therapy

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Prevention of infusion reactions to PEGylated liposomal doxorubicin via tachyphylaxis induction by placebo vesicles : A porcine model. / Szebeni, J.; Bedocs, Péter; Urbanics, Rudolf; Bünger, Rolf; Rosivall, L.; Tóth, Miklós; Barenholz, Yechezkel.

In: Journal of Controlled Release, Vol. 160, No. 2, 10.06.2012, p. 382-387.

Research output: Article

Szebeni, J. ; Bedocs, Péter ; Urbanics, Rudolf ; Bünger, Rolf ; Rosivall, L. ; Tóth, Miklós ; Barenholz, Yechezkel. / Prevention of infusion reactions to PEGylated liposomal doxorubicin via tachyphylaxis induction by placebo vesicles : A porcine model. In: Journal of Controlled Release. 2012 ; Vol. 160, No. 2. pp. 382-387.
@article{fd6ef36e2cca42138401ef33cb9d6d43,
title = "Prevention of infusion reactions to PEGylated liposomal doxorubicin via tachyphylaxis induction by placebo vesicles: A porcine model",
abstract = "PEGylated liposomal doxorubicin (Doxil) has been used in cancer chemotherapy for 16 years. Clinical experience shows that it can cause mild-to-severe hypersensitivity (infusion) reactions, which are manifestations of complement (C) activation-related pseudoallergy (CARPA). Although in most cases CARPA is inconsequential, a main symptom, cardiopulmonary distress, may be life threatening in hypersensitive individuals. To date, the prevention of Doxil-induced CARPA is based on premedication and a slow infusion protocol. The present study suggests desensitization by Doxil-like empty liposomes, called placebo Doxil (Doxebo), as an alternative strategy, which is based on the tachyphylactic nature of Doxil reactions. Doxebo-induced tolerance to Doxil was shown to develop within minutes and to be specific to Doxil-like PEGylated liposomes. The procedure of desensitization involves slow, low-dose pre-infusion of Doxebo before Doxil treatment which minimizes the ensuing physiological changes or keeps them subclinical. Although the mechanism of tolerance induction is not yet clear, the effector arm of C response is unlikely to be affected, as the vascular reactivity of desensitized pigs to zymosan remains intact. Desensitization with empty vesicles represents a novel approach for reducing the risk of anaphylactic reactions to drug carrier liposomes. The underlying immediate, most likely passive silencing of an innate immune response may represent a novel mechanism of tolerance induction which may work for other reactogenic nanosystems as well.",
keywords = "CARPA, Drug targeting, Hypersensitivity reactions, Innate immunity, Nanomedicines, Tolerance induction",
author = "J. Szebeni and P{\'e}ter Bedocs and Rudolf Urbanics and Rolf B{\"u}nger and L. Rosivall and Mikl{\'o}s T{\'o}th and Yechezkel Barenholz",
year = "2012",
month = "6",
day = "10",
doi = "10.1016/j.jconrel.2012.02.029",
language = "English",
volume = "160",
pages = "382--387",
journal = "Journal of Controlled Release",
issn = "0168-3659",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - Prevention of infusion reactions to PEGylated liposomal doxorubicin via tachyphylaxis induction by placebo vesicles

T2 - A porcine model

AU - Szebeni, J.

AU - Bedocs, Péter

AU - Urbanics, Rudolf

AU - Bünger, Rolf

AU - Rosivall, L.

AU - Tóth, Miklós

AU - Barenholz, Yechezkel

PY - 2012/6/10

Y1 - 2012/6/10

N2 - PEGylated liposomal doxorubicin (Doxil) has been used in cancer chemotherapy for 16 years. Clinical experience shows that it can cause mild-to-severe hypersensitivity (infusion) reactions, which are manifestations of complement (C) activation-related pseudoallergy (CARPA). Although in most cases CARPA is inconsequential, a main symptom, cardiopulmonary distress, may be life threatening in hypersensitive individuals. To date, the prevention of Doxil-induced CARPA is based on premedication and a slow infusion protocol. The present study suggests desensitization by Doxil-like empty liposomes, called placebo Doxil (Doxebo), as an alternative strategy, which is based on the tachyphylactic nature of Doxil reactions. Doxebo-induced tolerance to Doxil was shown to develop within minutes and to be specific to Doxil-like PEGylated liposomes. The procedure of desensitization involves slow, low-dose pre-infusion of Doxebo before Doxil treatment which minimizes the ensuing physiological changes or keeps them subclinical. Although the mechanism of tolerance induction is not yet clear, the effector arm of C response is unlikely to be affected, as the vascular reactivity of desensitized pigs to zymosan remains intact. Desensitization with empty vesicles represents a novel approach for reducing the risk of anaphylactic reactions to drug carrier liposomes. The underlying immediate, most likely passive silencing of an innate immune response may represent a novel mechanism of tolerance induction which may work for other reactogenic nanosystems as well.

AB - PEGylated liposomal doxorubicin (Doxil) has been used in cancer chemotherapy for 16 years. Clinical experience shows that it can cause mild-to-severe hypersensitivity (infusion) reactions, which are manifestations of complement (C) activation-related pseudoallergy (CARPA). Although in most cases CARPA is inconsequential, a main symptom, cardiopulmonary distress, may be life threatening in hypersensitive individuals. To date, the prevention of Doxil-induced CARPA is based on premedication and a slow infusion protocol. The present study suggests desensitization by Doxil-like empty liposomes, called placebo Doxil (Doxebo), as an alternative strategy, which is based on the tachyphylactic nature of Doxil reactions. Doxebo-induced tolerance to Doxil was shown to develop within minutes and to be specific to Doxil-like PEGylated liposomes. The procedure of desensitization involves slow, low-dose pre-infusion of Doxebo before Doxil treatment which minimizes the ensuing physiological changes or keeps them subclinical. Although the mechanism of tolerance induction is not yet clear, the effector arm of C response is unlikely to be affected, as the vascular reactivity of desensitized pigs to zymosan remains intact. Desensitization with empty vesicles represents a novel approach for reducing the risk of anaphylactic reactions to drug carrier liposomes. The underlying immediate, most likely passive silencing of an innate immune response may represent a novel mechanism of tolerance induction which may work for other reactogenic nanosystems as well.

KW - CARPA

KW - Drug targeting

KW - Hypersensitivity reactions

KW - Innate immunity

KW - Nanomedicines

KW - Tolerance induction

UR - http://www.scopus.com/inward/record.url?scp=84861669650&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861669650&partnerID=8YFLogxK

U2 - 10.1016/j.jconrel.2012.02.029

DO - 10.1016/j.jconrel.2012.02.029

M3 - Article

C2 - 22421426

AN - SCOPUS:84861669650

VL - 160

SP - 382

EP - 387

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

IS - 2

ER -