title: Solubilization of therapeutic agents in micellar nanomedicines.
abstract: We use atomistic molecular dynamics simulations to reveal the binding mechanisms of therapeutic agents in PEG-ylated micellar nanocarriers (SSM). In our experiments, SSM in buffer solutions can solubilize either ≈11 small bexarotene molecules or ≈6 (2 in low ionic strength buffer) human vasoactive intestinal peptide (VIP) molecules. Free energy calculations reveal that molecules of the poorly water-soluble drug bexarotene can reside at the micellar ionic interface of the PEG corona, with their polar ends pointing out. Alternatively, they can reside in the alkane core center, where several bexarotene molecules can self-stabilize by forming a cluster held together by a network of hydrogen bonds. We also show that highly charged molecules, such as VIP, can be stabilized at the SSM ionic interface by Coulombic coupling between their positively charged residues and the negatively charged phosphate headgroups of the lipids. The obtained results illustrate that atomistic simulations can reveal drug solubilization character in nanocarriers and be used in efficient optimization of novel nanomedicines.
authors.affiliation: Department of Chemistry, University of Illinois at Chicago , Chicago, Illinois 60607, United States.
authors.forename: Lela
authors.initials: L
authors.lastname: Vuković
authors.forename: Antonett
authors.initials: A
authors.lastname: Madriaga
authors.forename: Antonina
authors.initials: A
authors.lastname: Kuzmis
authors.forename: Amrita
authors.initials: A
authors.lastname: Banerjee
authors.forename: Alan
authors.initials: A
authors.lastname: Tang
authors.forename: Kevin
authors.initials: K
authors.lastname: Tao
authors.forename: Neil
authors.initials: N
authors.lastname: Shah
authors.forename: Petr
authors.initials: P
authors.lastname: Král
authors.forename: Hayat
authors.initials: H
authors.lastname: Onyuksel
mesh_terms: D000595:Amino Acid Sequence; D000077610:Bexarotene; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D008823:Micelles; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D050997:Nanomedicine; D049329:Nanostructures / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011487:Protein Conformation; D012995:Solubility; D013764:Tetrahydronaphthalenes / Q000737:chemistry*; D013816:Thermodynamics; D014660:Vasoactive Intestinal Peptide / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D008823:Micelles; D013764:Tetrahydronaphthalenes; D014660:Vasoactive Intestinal Peptide; D011092:Polyethylene Glycols; D000077610:Bexarotene