title: Encapsulation and covalent binding of molecular payload in enzymatically activated micellar nanocarriers.
abstract: The high selectivity and often-observed overexpression of specific disease-associated enzymes make them extremely attractive for triggering the release of hydrophobic drug or probe molecules from stimuli-responsive micellar nanocarriers. Here we utilized highly modular amphiphilic polymeric hybrids, composed of a linear hydrophilic polyethylene glycol (PEG) and an esterase-responsive hydrophobic dendron, to prepare and study two diverse strategies for loading of enzyme-responsive micelles. In the first type of micelles, hydrophobic coumarin-derived dyes were encapsulated noncovalently inside the hydrophobic core of the micelle, which was composed of lipophilic enzyme-responsive dendrons. In the second type of micellar nanocarrier the hydrophobic molecular cargo was covalently linked to the end-groups of the dendron through enzyme-cleavable bonds. These amphiphilic hybrids self-assembled into micellar nanocarriers with their cargo covalently encapsulated within the hydrophobic core. Both types of micelles were highly responsive toward the activating enzyme and released their molecular cargo upon enzymatic stimulus. Importantly, while faster release was observed with noncovalent encapsulation, higher loading capacity and slower release rate were achieved with covalent encapsulation. Our results clearly indicate the great potential of enzyme-responsive micellar delivery platforms due to the ability to tune their payload capacities and release rates by adjusting the loading strategy.
authors.affiliation: Department of Organic Chemistry, School of Chemistry, Faculty of Exact Sciences, ‡Department of Physical Chemistry, School of Chemistry, Faculty of Exact Sciences, §Tel Aviv University Center for Nanoscience and Nanotechnology, and ∥School of Physics and Astronomy, Faculty of Exact Sciences, Tel-Aviv University , Tel-Aviv 69978, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Rosenbaum
authors.forename: Assaf J
authors.initials: AJ
authors.lastname: Harnoy
authors.forename: Einat
authors.initials: E
authors.lastname: Tirosh
authors.forename: Marina
authors.initials: M
authors.lastname: Buzhor
authors.forename: Merav
authors.initials: M
authors.lastname: Segal
authors.forename: Liat
authors.initials: L
authors.lastname: Frid
authors.forename: Rona
authors.initials: R
authors.lastname: Shaharabani
authors.forename: Ram
authors.initials: R
authors.lastname: Avinery
authors.forename: Roy
authors.initials: R
authors.lastname: Beck
authors.forename: Roey J
authors.initials: RJ
authors.lastname: Amir
mesh_terms: D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D004798:Enzymes / Q000378:metabolism*; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D013050:Spectrometry, Fluorescence
chemical_list: D004337:Drug Carriers; D004798:Enzymes; D008823:Micelles