title: A safety and tolerability study of differently-charged nanoparticles for local pulmonary drug delivery.
abstract: Nanoparticle (NP) based drug delivery systems provide promising opportunities in the treatment of lung diseases. Here we examined the safety and tolerability of pulmonary delivered NPs consisting of PEG-PLA as a function of particle surface charge. The rationale for such a comparison should be attributed to the differential pulmonary toxicity of positively and negatively charged PEG-PLA NP. Thus, the local and systemic effects of pulmonary administered NPs were investigated following 5days of daily endotracheal instillation to BALB/c mice that were euthanized on the eighth or nineteenth day of the experiment. We collected bronchoalveolar lavages and studied hematological as well as histochemistry parameters. Notably, the cationic stearylamine based PEG-PLA NPs elicited increased local and systemic toxic effects both on the eighth and nineteenth day. In contrast, anionic NPs of similar size were much better tolerated with local inflammatory effects observed only on the eighth experimental day after pulmonary instillation. No systemic toxicity effect was observed although a moderate change was noted in the platelet count that was not considered to be of clinical significance. No pathological observations were detected in the internal organs following instillation of anionic NPs. Overall these observations suggest that anionic PEG-PLA NPs are useful pulmonary drug carriers that should be considered as a promising therapeutic drug delivery system.
authors.affiliation: Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Oshrat
authors.initials: O
authors.lastname: Harush-Frenkel
authors.forename: Maytal
authors.initials: M
authors.lastname: Bivas-Benita
authors.forename: Taher
authors.initials: T
authors.lastname: Nassar
authors.forename: Chaim
authors.initials: C
authors.lastname: Springer
authors.forename: Yoav
authors.initials: Y
authors.lastname: Sherman
authors.forename: Avraham
authors.initials: A
authors.lastname: Avital
authors.forename: Yoram
authors.initials: Y
authors.lastname: Altschuler
authors.forename: Jurgen
authors.initials: J
authors.lastname: Borlak
authors.forename: Simon
authors.initials: S
authors.lastname: Benita
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000336:Aerosols; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols