Journal
JOURNAL OF CONTROLLED RELEASE
Volume 160, Issue 2, Pages 382-387Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2012.02.029
Keywords
Drug targeting; Nanomedicines; Hypersensitivity reactions; CARPA; Tolerance induction; Innate immunity
Funding
- The Barenholz Fund
- National Office of Research and Technology of Hungary [Nanomedi, Carpa777]
- USUHS [RO70LO]
- TAMOP in the framework of the New Hungarian Development Plan [4-2-1 B-9/1/KMR, TAMOP-4.2.1.B-10/2/KONV-2010-0001]
- European Union
- European Social Fund
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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. (C) 2012 Elsevier B.V. All rights reserved.
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