title: Mitochondrial routing of glucose and sucrose polymers after pinocytotic uptake: avenues for drug delivery.
abstract: Mitochondria are key organelles organizing cellular metabolic flux. Therefore, a targeted drug delivery to mitochondria promises the advancement of medicine in fields that are associated with mitochondrial dysfunction. However, successful mitochondrial drug delivery is limited by complex transport steps across organelle membranes and fast drug efflux in cases of multidrug resistance. Strategies to deliver small-molecular-weight drugs to mitochondria are very limited, while the use of complex polymeric carriers is limited by a lack of clinical feasibility. We show here that clinically established macromolecules such as a sucrose copolymer (Ficoll 70/400 kDa) and polyglucose (dextran 70/500 kDa) are micropinocytosed swiftly by mesenchymal stem cells and subsequently routed to mitochondria. The intracellular level of Ficoll appears to decrease over time, suggesting that it does not persist within cells. After coupling to polysucrose, the low-molecular-weight photodynamic drug Rose Bengal reached mitochondria and thus exhibited an increased destructive potential after laser excitation. These findings support new opportunities to deliver already clinically approved drugs to mitochondria.
authors.affiliation: NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore , 117456 Singapore.
authors.forename: Rafi
authors.initials: R
authors.lastname: Rashid
authors.forename: Sebastian
authors.initials: S
authors.lastname: Beyer
authors.forename: Anna
authors.initials: A
authors.lastname: Blocki
authors.forename: Catherine
authors.initials: C
authors.lastname: Le Visage
authors.forename: Dieter
authors.initials: D
authors.lastname: Trau
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wohland
authors.forename: Michael
authors.initials: M
authors.lastname: Raghunath
mesh_terms: D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods*; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010873:Pinocytosis / Q000187:drug effects / Q000502:physiology*; D011108:Polymers / Q000008:administration & dosage / Q000378:metabolism*; D013395:Sucrose / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D011108:Polymers; D013395:Sucrose; D005947:Glucose