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.

Improving cell distribution on 3D additive manufactured scaffolds through engineered seeding media density and viscosity

“…The fact that after the 4h seeding the macroMs were found to colocalize with the cell cytoplasm and that the amount of macroMs was drastically reduced after 24h culture in CM, suggests that the macroMs were internalized by cells during the seeding period, followed by their exocytosis towards the cell culture media after 24 h. Fluorescently labeled dextran and Ficoll have been shown to enter different cell types, including hMSCs, by macropinocytosis [62 , 63] and micropinocytosis [64] , respectively. Within the first 24 h after uptake, they have seen to accumulate in lysosomal compartments [64][65][66] , were they degrade into glucose and fructose moieties. Moreover, since the cell culture media was renewed after 24h culture and every 2 days from then on, the effect of the macroMs as crowders influencing ECM deposition can be ruled out.…”

Enhanced Photodynamic Efficiency Achieved via a Dual-Targeted Strategy Based on Photosensitizer/Micelle Structure

“…So far two major apoptotic pathways have been characterized: the death receptor-mediated, or extrinsic pathway, and the mitochondria-mediated apoptosis or intrinsic pathway. The role played by mitochondria in apoptosis makes these cellular organelles desired targets for therapeutic drugs. − Currently, several strategies for the delivery of biologically active molecules to the mitochondria of live mammalian cells are widely used: (1) tethering a mitochondrial localization peptide sequence, which utilizes protein import pathway; (2) attaching a lipophilic cation group, which utilizes the high membrane potential (180 mV) across the inner mitochondrial membrane; and (3) using lyposome-based carrier (e.g., vesicle) for transporting large or vulnerable cargo. , As for the lipophilic cation approach, Murphy, Chang, and so on have designed a series of triphenylphosphonium-based bioactive molecules with excellent mitochondria targeting capability. ,, The delocalized positive charge in these lipophilic cations enables them to permeate lipid bilayers easily and to accumulate several hundred-fold within mitochondria because of the large mitochondrial membrane potential (∼180 mV, negative inside). In addition to triphenylphosphonium, some other lipophilic cations, like ammonium-containing cations were also found to be able to target mitochondria.…”