Macrophage apoptosis using alendronate in targeted nanoarchaeosomes

JEREZ, HORACIO EMANUEL; ALTUBE, MARÍA JULIA; GÁNDOLA, YAMILA B.; GONZÁLEZ, LORENA; GONZÁLEZ, MARINA CECILIA; MORILLA, MARÍA JOSÉ; ROMERO, EDER LILIA

EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS

ELSEVIER SCIENCE BV

Año: 2021 vol. 160 p. 42 - 54

0939-6411

Nanoarchaeosomes are non-hydrolysable nanovesicles made of archaeolipids, naturally functionalised withligand for scavenger receptor class 1. We hypothesized that nitrogenate bisphosphonate alendronate (ALN)loaded nanoarchaeosomes (nanoarchaeosomes(ALN)) may constitute more efficient macrophage targetedapoptotic inducers than ALN loaded nanoliposomes (nanoliposomes (ALN)). To that aim, ALN was loaded incholesterol containing (nanoARC-chol(ALN)) or not (nanoARC(ALN)) nanoarchaeosomes. Nanoarchaeosomes(ALN) (220?320 nm sized, ~ 􀀀 40 mV ξ potential, 38?50 μg ALN/mg lipid ratio) displayed higher structuralstability than nanoliposomes(ALN) of matching size and ξ potential, retaining most of ALN against a 1/200 foldsdilution. The cytotoxicity of nanoARC(ALN) on J774A.1 cells, resulted > 30 folds higher than free ALN andnanoliposomes(ALN) and was reduced by cholesterol in nanoARC-chol(ALN). Devoid of ALN, nanoARC-chol wasnon-cytotoxic, exhibited pronounced anti-inflammatory activity on J774.1 cells, strongly reducing reactive oxygenspecies (ROS) and IL-6 induced by LPS. Nanoarchaeosomes bilayer extensively interacted with serumproteins but resulted refractory to phospholipases. Upon J774A.1 cells uptake, nanoarchaeosomes inducedcytoplasmic acid vesicles, reduced the mitochondrial membrane potential by 20?40 % without consuming ATPneither damaging lysosomes and increasing pERK. Refractory to chemoenzymatic attacks, either void or drugloaded, nanoarchaeosomes induced either anti-inflammation or macrophages apoptosis, constituting promisingtargeted nanovesicles for multiple therapeutic purposes.