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.
authors.affiliation: Nanomedicine Research and Education Center, Semmelweis University, Budapest, Hungary. jszebeni2@gmail.com
authors.forename: János
authors.initials: J
authors.lastname: Szebeni
authors.forename: Péter
authors.initials: P
authors.lastname: Bedőcs
authors.forename: Rudolf
authors.initials: R
authors.lastname: Urbanics
authors.forename: Rolf
authors.initials: R
authors.lastname: Bünger
authors.forename: László
authors.initials: L
authors.lastname: Rosivall
authors.forename: Miklós
authors.initials: M
authors.lastname: Tóth
authors.forename: Yechezkel
authors.initials: Y
authors.lastname: Barenholz
mesh_terms: D000818:Animals; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology; D003888:Desensitization, Immunologic / Q000379:methods; D004317:Doxorubicin / Q000008:administration & dosage* / Q000276:immunology; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D006967:Hypersensitivity / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D007262:Infusions, Intravenous / Q000009:adverse effects* / Q000379:methods; D008081:Liposomes; D008297:Male; D010919:Placebos / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D013552:Swine; D013618:Tachyphylaxis / Q000276:immunology*
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D010919:Placebos; D011092:Polyethylene Glycols; D004317:Doxorubicin