Nanotoxicity of lipid-based nanomedicines

MORILLA, MARIA JOSE; ROMERO, EDER LILIA

Nanomaterials: Ecotoxicity, Safety and Public Perception

Springer International Publishing

Año: 2018; p. 133 - 165

The impact of lipid-based nanomedicines on living beings widely differs from that caused by nonintentional exposition of metallic, metallic oxides, or carbon-based inhaled nanomaterials. The scarce data gathered on nanotoxicity of lipid-based nanomedicines is mostly related to intravenous and inhalationroutes. This last is also the most important non-intentional exposition route. Intravenous nanomedicinesmostly consist of antitumoral and antimycotic agents, both responsible for the induction of potentially lethal acute hypersensitivity reactions. Their nanotoxicity is explained according to different mechanisms.The so called double hit theory states that the clinical symptoms arise from the sum of the complement activation (Complement Activation Related Pseudo Allergy, CARPA effect), where the anaphylatoxins C3a, C4a and C5a induce the release of allergomedins by mast cells, and from the direct activation by nanomedicines binding to pattern recognizing receptors on macrophages ; activation of bradykinin receptors B1 and B2 may contribute to the clinical picture. The rapid phagocytic response hypothesis instead, states that the complement activation would not be responsible for the clinical symptoms, whereas the hypersensitivity reaction occur by direct activation of IgG opsonized nanomedicines, of receptorsexpressed mostly in pulmonary intravascular macrophages (PIM). Activated PIMs thus, would release platelet activating factor (PAF), a highly active and very short-lived molecule, a mast cells activator responsible for the potentially lethal toxic effects. The nanotoxicity of inhaled liposomes , developed totreat bronchiectasis caused by bacterial infections on the other hand, was preclinically observed in rodents (species of unknown value as reliable predictors of the effects of inhaled medicines in humans), while in dogs was reported as transient, lymph node reactions (perivascular/peribronchiolar lymphoid cell infiltration) that are not readily reversible and lymphoid findings associated with foamy macrophages. In early clinical phase, the nanotoxicity manifested after repeated administrations along months, as higherairway reactogenicity, higher rates of treatment-related adverse events and higher rates of discontinuations due to adverse events. In case of liposomal amikacin?a per se irritant drug?, the nanotoxicity was related to the presence of free antibiotic; in case of liposomal ciprofloxacin, it was manifested as dyspnea, bronchospasm, hemoptysis, cough, taste disorders. Not surprisingly, the nanotoxicity of nanomedicines has not been properly anticipated by preclinical studies. More accurate disease models for example based on artificial three-dimensional human cell organs, may aid preclinical studies to acquire highersignificance.