Moreover, deletion of SQR, complex I, or AMPK abolishes therapeutic effects of H2S following intracerebral hemorrhage. 1C; SI Appendix, Fig. The versatility of this platform was demonstrated by studying various mitochondria-acting therapeutics for different applications, including the mitochondria-targeting chemotherapeutics lonidamine and α-tocopheryl succinate for cancer, the mitochondrial antioxidant curcumin for Alzheimer’s disease, and the mitochondrial uncoupler 2,4-dinitrophenol for obesity. 4B and SI Appendix, Table S4). An in vitro survival evaluation of human neuroblastoma IMR-32 cells treated with 20 μM Aβ using the MTT [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide] assay demonstrated enhanced neuroprotection with the targeted curcumin NPs compared with the nontargeted curcumin NPs or free curcumin (Fig. These targeted NPs can be used in various mitochondrial dysfunction-related disorders, including AD, obesity, and cancer. NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. NPs with a high positive charge are expected to be imported at a lower ΔΨm than NPs with a lower positive charge; thus, using a HeLa model cell line, we performed a comparative evaluation of the effect of NP size and charge in crossing the mitochondrial inner membrane (Fig.
1B), and obtained targeted and nontargeted blended NPs with reproducible diameter and surface charges in more than three independent nanoprecipitation experiments (SI Appendix, Table S2).
(B) Confocal images of time-dependent uptake of targeted PLGA-b-PEG-TPP/PLGA-b-PEG-QD blended NPs and nontargeted PLGA-b-PEG-OH/PLGA-b-PEG-QD blended NPs in HeLa cells.
(C) (Upper) Size and zeta potential variation in blended NPs from PLGA-b-PEG-TPP and PLGA-COOH. With the nontargeted NPs, the red signals of the NPs and the mitochondrial staining differed in position, as demonstrated by a lower ρ value (ρ = 0.03).
SQR-induced mitochondrial uncoupling is separated from the inhibition of mitochondrial complex IV by H2S. A greater cytotoxic effect also was observed with targeted α-TOS NPs compared with nontargeted α-TOS NPs and free α-TOS (IC50 75 ± 2 nM, 230 ± 4 nM, and 381 ± 5 nM, respectively) (Fig. S7). We performed a time-dependent uptake study using the early endosome marker EAA-1 to investigate the fusogenic character necessary for efficient endosomal escape of the targeted NPs. Proton absorbance by buffering of positively charged PEG prevents acidification of endosomal vesicles, thereby increasing the ATPase-mediated influx of protons and counter ions, which in turn leads to osmotic swelling, endosomal membrane rupture, and eventual leakage of the NPs into the cytosol, making them accessible for mitochondrial uptake. A 3-D electron microscopy reconstruction of mitochondria in the hippocampus of a mouse model of Alzheimer's disease. and S.D.
P < 0.05 was considered to indicate statistical significance.
Intracellular lipids were stained with AdipoRed (Lonza), and percent lipid accumulation was calculated.
Mitochondrial trafficking of nanoparticles. Not all types of NPs have the ability to enter mitochondria, because they cannot cross the complex double membrane owing to restrictions in programming surface charge and size.
We found another jump in cellular uptake as the surface charge increased to ∼34 mV and reached saturation. 1 A and B).
5 and SI Appendix, Fig S14) during the differentiation period for 7 d, and evaluated cell viability and intracellular lipid accumulation.
One of the most challenging problems in the development of drug therapy to treat mitochondrial dysfunction is not the creation of the drugs themselves, but rather the distribution of these drugs to the mitochondria of cells (2). However, 2,4-DNP’s narrow therapeutic window led to the abandonment of its use. Mitochondria-acting LND and α-TOS were selected to demonstrate the applicability of our system in cancer. Image credit: Norbert Kirchgessner (ETH Zürich, Zürich, Switzerland).
After 6 d of treatment, cells were analyzed for triglyceride accumulation using the AdipoRed (Lonza) assay following the manufacturer’s instructions. The authors declare no conflict of interest.
Currently, only a handful of metal oxide- or liposomal-based carriers are known to deliver payloads to the mitochondria of cells (SI Appendix, Table S1) (9⇓⇓⇓⇓⇓⇓⇓–17), none of which has demonstrated optimization and application of the FDA-approved biodegradable PLGA-based NP system in delivering known mitochondria-acting therapeutics to their precise destination. About the lab. Preferential localization in the target organelle accounts for the enhanced cytotoxicity of both LND and α-TOS encapsulated in the targeted NPs. Optimizing the application of PLGA-based NPs as mitochondrial-targeted delivery vehicles requires a representative and comprehensive study addressing the effect of size and surface charge on the mitochondrial uptake.
1H-NMR (CHCl3-d) (SI Appendix, Fig. PLGA-COOH (0.4 g; 80 μmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) (12.4 mg; 80 μmol), and NHS (9 mg; 80 μmol) were dissolved in 3 mL of dimethylformamide (DMF), and a 250-μL solution of 8 μM QD-PEG-NH2 was added. Author contributions: S.M. We evaluated immune responses from size- and charge-varied NPs in terms of the production of proinflammatory cytokines IL-6 and TNF-α in RAW 264.7 macrophages by ELISA, with LPS used as a control. In brief, PLGA-b-PEG-OH or PLGA-b-PEG-TPP in acetonitrile to a final polymer concentration of 5 mg/mL was added dropwise to nanopure water with constant stirring. Immune cells in the bloodstream and in tissues have a propensity to engulf and eliminate positively charged NPs.
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