ABSTRACT
Polymeric nanocarriers (NCs) are efficient vehicles to prevent drug unspecific biodistribution and increase the drug amounts delivered to tumor tissues. However, some toxicological aspects of NCs still lack a comprehensive assessment, such as their effects on cellular processes that lead to toxicity. We evaluate the interaction of poly(lactic-co-glycolic acid) (PLGA) NCs prepared using dextran (Dex) and Pluronic®-F127 as stabilizing agents with myocardial cells (H9C2), breast adenocarcinoma cells (MCF-7) and macrophages (RAW 264.7) to address the effect of Dex in PLGA NC formulations. By an emulsion diffusion method, doxorubicin-loaded NCs were prepared with no Dex (PLGA-DOX), 1% (w/v) Dex (Dex1/PLGA-DOX) and 5% (w/v) Dex (Dex5/PLGA-DOX). Uptake analyses revealed a significant reduction in Dex5/PLGA-DOX NC uptake by H9C2 and MCF-7, as in the case of Dex1/PLGA-DOX NCs in the absence of in vitro protein corona, revealing an effect of dextran concentration on the formation of protein corona. RAW 264.7 cells presented a greater uptake of Dex5/PLGA-DOX NCs than the other NCs likely because of receptor mediated endocytosis, since C-type lectins like SIGN-R1, mannose receptors and scavenger receptor type 1 that are expressed in RAW 264.7 can mediate Dex uptake. Despite the lower uptake, Dex5/PLGA-DOX NCs promote the generation of reactive oxygen species and oxidative membrane damage in MCF-7 and H9C2 even though cellular metabolic activity assessed by MTT was comparable among all the NCs. Our results highlight the importance of an in-depth investigation of the NC-cell interaction considering additional mechanisms of damage apart from metabolic variations, as nanoparticle-induced damage is not limited to imbalance in metabolic processes, but also associated with other mechanisms, e.g., membrane and DNA damage.
Subject(s)
Antineoplastic Agents , Protein Corona , Humans , Polylactic Acid-Polyglycolic Acid Copolymer/metabolism , Dextrans , Drug Carriers/metabolism , Antineoplastic Agents/pharmacology , Tissue Distribution , Poloxamer/metabolism , Emulsions/metabolism , Excipients/metabolism , Reactive Oxygen Species/metabolism , Doxorubicin/pharmacology , Doxorubicin/metabolism , Cell Membrane/metabolism , Lectins, C-Type/metabolismABSTRACT
Nanotechnology is a very promising technological tool to combat health problems associated with the loss of effectiveness of currently used antibiotics. Previously, we developed a formulation consisting of a chitosan and tween 80-decorated alginate nanocarrier that encapsulates rifampicin and the antioxidant ascorbic acid (RIF/ASC), intended for the treatment of respiratory intracellular infections. Here, we investigated the effects of RIF/ASC-loaded NPs on the respiratory mucus and the pulmonary surfactant. In addition, we evaluated their cytotoxicity for lung cells in vitro, and their biodistribution on rat lungs in vivo after their intratracheal administration. Findings herein demonstrated that RIF/ASC-loaded NPs display a favorable lung biocompatibility profile and a uniform distribution throughout lung lobules. RIF/ASC-loaded NPs were mainly uptaken by lung macrophages, their primary target. In summary, findings show that our novel designed RIF/ASC NPs could be a suitable system for antibiotic lung administration with promising perspectives for the treatment of pulmonary intracellular infections.
Subject(s)
Alginates/chemistry , Ascorbic Acid/chemistry , Lung Diseases/drug therapy , Lung Diseases/metabolism , Nanoparticles/chemistry , Rifampin/metabolism , Rifampin/toxicity , A549 Cells , Alginates/metabolism , Alginates/toxicity , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Antioxidants/toxicity , Ascorbic Acid/metabolism , Ascorbic Acid/toxicity , Biological Transport/drug effects , Biological Transport/physiology , Cell Line , Cell Line, Tumor , Chitosan/metabolism , Chitosan/toxicity , Drug Carriers/chemistry , Drug Carriers/metabolism , Drug Carriers/toxicity , Drug Delivery Systems/methods , Female , Humans , Lung/drug effects , Lung/metabolism , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/metabolism , Male , Nanoparticles/metabolism , Nanoparticles/toxicity , Particle Size , Polylactic Acid-Polyglycolic Acid Copolymer/metabolism , Polylactic Acid-Polyglycolic Acid Copolymer/toxicity , Polymers/metabolism , Polymers/toxicity , Rats , Rats, Wistar , Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , Rifampin/pharmacology , Swine , Tissue DistributionABSTRACT
This paper describes the development and in vitro evaluation of poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with chitosan (CS) for oral delivery of ferulic acid (FA). Nanoparticles were obtained by an emulsion evaporation technique and characterized. Furthermore, we evaluated the scavenging activity over hypochlorous acid (HOCl), the cytotoxicity over tumour cells and the in vitro intestinal permeability. Nanoparticles were spherical with a mean diameter of 242 nm, positive zeta potential and 50% of encapsulation efficiency. The in vitro release in phosphate buffered saline (PBS) (pH 7.4) demonstrated a prolonged and biphasic profile diffusion-controlled. In simulated gastrointestinal fluids, about 15% of FA was released in gastric fluid and a negligible release was observed in the intestinal fluid. In the HOCl scavenging activity and cytotoxicity over B16-F10 and HeLa cells, FA-loaded nanoparticles presented the same efficacy of the free drug. Besides, in the antioxidant and cytotoxic assay, CS contributed to FA effects. In the intestinal permeability study, FA-loaded nanoparticles exhibited a permeation of 6% through the Caco-2 monolayer and 20% through the Caco-2/HT29-MTX/Raji B co-culture. CS-coated PLGA nanoparticles are promising carriers for oral delivery of FA.