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Effects of arginine on coenzyme-Q10 micelle uptake for mitochondria-targeted nanotherapy in phenylketonuria

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Abstract

Phenylketonuria (PKU) is a rare inherited metabolic disease characterized by phenylalanine hydroxylase enzyme deficiency. In PKU patients, coenzyme Q10 (CoQ10) levels were found low. Therefore, we focused on the modification of CoQ10 to load the micelles and increase entry of micelles into the cell and mitochondria, and it is taking a part in ATP turnover. Micelles had produced by comparing two different production methods (thin-film layer and direct-dissolution), and characterization studies were performed (zeta potential, size, and encapsulation efficiency). Then, l-arginine (LARG) and poly-arginine (PARG) were incorporated with the micelles for subsequential release and PKU cell studies. The effects of these components on intracellular uptake and their use in the cellular cycle were analyzed by ELISA, Western blot, membrane potential measurement, and flow cytometry methods. In addition, both effects of LARG and PARG micelles on pharmacokinetics at the cellular level and their cell binding rate were determined. The thin-film method was found superior in micelle preparation. PARG/LARG-modified micelles showed sustained release. In the cellular and mitochondrial uptake of CoQ10, CoQ10-micelle + PARG > CoQ10-micelle + LARG > CoQ10-micelle > CoQ10 was found. This increased localization caused lowering of oxygen consumption rates, but maintaining mitochondrial membrane potential. The study results had showed that besides micelle formulation, PARG and LARG are effective in cellular and mitochondrial targeting.

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The datasets of the current study are available from the corresponding author on reasonable request.

References

  1. Zhao X, Poon Z, Engler AC, Bonner DK, Hammond PT. Enhanced stability of polymeric micelles based on postfunctionalized poly(ethylene glycol)-b-poly(gamma-propargyl L-glutamate): the substituent effect. Biomacromol. 2012;13(5):1315–22.

    Article  CAS  Google Scholar 

  2. Bodratti AM, Alexandridis P. Formulation of poloxamers for drug delivery. J Funct Biomater. 2018;9(1).

  3. Russo E, Villa C. Poloxamer hydrogels for biomedical applications. Pharmaceutics. 2019;11(12).

  4. Sotoudegan F, Amini M, Faizi M, Aboofazeli R. Nimodipine-loaded Pluronic(®) block copolymer micelles: preparation, characterization, in-vitro and in-vivo studies. Iran J Pharm Res. 2016;15(4):641–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Sezgin Z, Yuksel N, Baykara T. Preparation and characterization of polymeric micelles for solubilization of poorly soluble anticancer drugs. Eur J Pharm Biopharm. 2006;64(3):261–8.

    Article  CAS  PubMed  Google Scholar 

  6. Thapa RK, Cazzador F, Gronlien KG, Tonnesen HH. Effect of curcumin and cosolvents on the micellization of Pluronic F127 in aqueous solution. Colloids Surf B Biointerfaces. 2020;195.

  7. Ozturk K, Arslan FB, Ozturk SC, Calis S. Mixed micelles formulation for carvedilol delivery: In-vitro characterization and in-vivo evaluation. Int J Pharm. 2022;611:121294.

  8. Sezgin-Bayindir Z, Antep MN, Yuksel N. Development and characterization of mixed niosomes for oral delivery using candesartan cilexetil as a model poorly water-soluble drug. AAPS PharmSciTech. 2015;16(1):108–17.

    Article  CAS  PubMed  Google Scholar 

  9. Sun K, Raghavan SR. Thermogelling aqueous fluids containing low concentrations of Pluronic F127 and laponite nanoparticles. Langmuir. 2010;26(11):8015–20.

    Article  CAS  PubMed  Google Scholar 

  10. Yurtdaş-Kırımlıoğlu G. A promising approach to design thermosensitive in situ gel based on solid dispersions of desloratadine with Kolliphor® 188 and Pluronic® F127. J Therm Anal Calorim. 2021;147(2):1307–27.

    Article  Google Scholar 

  11. Patil S, Ujalambkar V, Rathore A, Rojatkar S, Pokharkar V. Galangin loaded galactosylated pluronic F68 polymeric micelles for liver targeting. Biomed Pharmacother. 2019;112:108691.

  12. Zhang Y, Huang Y, Li S. Polymeric micelles: nanocarriers for cancer-targeted drug delivery. AAPS PharmSciTech. 2014;15(4):862–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang S, Liu Y, Gan Y, Qiu N, Gu Y, Zhu H. Conjugates of TAT and folate with DOX-loaded chitosan micelles offer effective intracellular delivery ability. Pharm Dev Technol. 2019;24(2):253–61.

    Article  CAS  PubMed  Google Scholar 

  14. Sezgin-bayindir Z, Ergin AD, Parmaksiz M, Elcin AE, Elcin YM, Yuksel N. Evaluation of various block copolymers for micelle formation and brain drug delivery: in vitro characterization and cellular uptake studies. J Drug Deliv Sci Technol. 2016;36:120–9.

    Article  CAS  Google Scholar 

  15. Mallick A, More P, Ghosh S, Chippalkatti R, Chopade BA, Lahiri M, et al. Dual drug conjugated nanoparticle for simultaneous targeting of mitochondria and nucleus in cancer cells. ACS Appl Mater Interfaces. 2015;7(14):7584–98.

    Article  CAS  PubMed  Google Scholar 

  16. Mallick S, Song SJ, Bae Y, Choi JS. Self-assembled nanoparticles composed of glycol chitosan-dequalinium for mitochondria-targeted drug delivery. Int J Biol Macromol. 2019;132:451–60.

    Article  CAS  PubMed  Google Scholar 

  17. Wei Z, Yuan S, Hao J, Fang X. Mechanism of inhibition of P-glycoprotein mediated efflux by Pluronic P123/F127 block copolymers: relationship between copolymer concentration and inhibitory activity. Eur J Pharm Biopharm. 2013;83(2):266–74.

    Article  CAS  PubMed  Google Scholar 

  18. van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12(1):162.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hernandez-Camacho JD, Bernier M, Lopez-Lluch G, Navas P. Coenzyme Q(10) supplementation in aging and disease. Front Physiol. 2018;9:44.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hargreaves I, Heaton RA, Mantle D. Disorders of human coenzyme Q10 metabolism: an overview. Int J Mol Sci. 2020;21(6695).

  21. Çelik F, Ayaz A. Fenilketonüri ve B Grubu Vitaminler. Beslenme ve Diyet Dergisi. 2012;40(1):50–8.

    Google Scholar 

  22. Montero R, Yubero D, Salgado MC, González MJ, Campistol J, O’Callaghan MDM, et al. Plasma coenzyme Q(10) status is impaired in selected genetic conditions. Sci Rep. 2019;9(1):793.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Artuch R, Vilaseca MA, Moreno J, Lambruschini N, Cambra FJ, Campistol J. Decreased serum ubiquinone-10 concentrations in phenylketonuria. Am J Clin Nutr. 1999;70(5):892–5.

    Article  CAS  PubMed  Google Scholar 

  24. Artuch R, Colomé C, Vilaseca MA, Sierra C, Cambra FJ, Lambruschini N, et al. Plasma phenylalanine is associated with decreased serum ubiquinone-10 concentrations in phenylketonuria. J Inherit Metab Dis. 2001;24(3):359–66.

    Article  CAS  PubMed  Google Scholar 

  25. Stepien KM, Heaton R, Rankin S, Murphy A, Bentley J, Sexton D, et al. Evidence of oxidative stress and secondary mitochondrial dysfunction in metabolic and non-metabolic disorders. J Clin Med. 2017;6(7).

  26. Baschiera E, Sorrentino U, Calderan C, Desbats MA, Salviati L. The multiple roles of coenzyme Q in cellular homeostasis and their relevance for the pathogenesis of coenzyme Q deficiency. Free Radical Biol Med. 2021;166:277–86.

    Article  CAS  Google Scholar 

  27. Rondanelli M, Porta F, Gasparri C, Barrile GC, Cavioni A, Mansueto F, et al. A food pyramid for adult patients with phenylketonuria and a systematic review on the current evidences regarding the optimal dietary treatment of adult patients with PKU. Clin Nutr. 2023;42:732–63.

    Article  CAS  PubMed  Google Scholar 

  28. Matalon R, Michals-Matalon K, Bhatia G, Grechanina E, Novikov P, McDonald JD, et al. Large neutral amino acids in the treatment of phenylketonuria (PKU). 2006;29(6):732–8.

  29. Karpińska J, Mikołuć B, Motkowski R, Piotrowska-Jastrzębska J. HPLC method for simultaneous determination of retinol, α-tocopherol and coenzyme Q10 in human plasma. J Pharm Biomed Anal. 2006;42(2):232–6.

    Article  PubMed  Google Scholar 

  30. Banun VJ, Rewatkar P, Chaudhary Z, Qu Z, Janjua T, Patil A, et al. Protein nanoparticles for enhanced oral delivery of coenzyme-Q10: in vitro and in silico studies. ACS Biomater Sci Eng. 2021.

  31. Perkins R, Vaida V. Phenylalanine increases membrane permeability. J Am Chem Soc. 2017;139(41):14388–91.

    Article  CAS  PubMed  Google Scholar 

  32. Miranda-Perez ME, Ortega-Camarillo C, Escobar-Villanueva MDC, Blancas-Flores G, Alarcon-Aguilar FJ. Cucurbita ficifolia Bouché increases insulin secretion in RINm5F cells through an influx of Ca2+ from the endoplasmic reticulum. J Ethnopharmacol. 2016;188:159–66.

    Article  PubMed  Google Scholar 

  33. Uranishi K, Akagi T, Koide H, Yokota T. Esrrb directly binds to Gata6 promoter and regulates its expression with Dax1 and Ncoa3. Biochem Biophys Res Commun. 2016;478(4):1720–5.

    Article  CAS  PubMed  Google Scholar 

  34. Brown M, Wittwer C. Flow cytometry: principles and clinical applications in hematology. Clin Chem. 2000;46(8 Pt 2):1221–9.

    Article  CAS  PubMed  Google Scholar 

  35. Lang A, Grether-Beck S, Singh M, Kuck F, Jakob S, Kefalas A, et al. MicroRNA-15b regulates mitochondrial ROS production and the senescence-associated secretory phenotype through sirtuin 4/SIRT4. Aging (Albany NY). 2016;8(3):484–505.

    Article  CAS  PubMed  Google Scholar 

  36. Lee SY, Cho H-J. Mitochondria targeting and destabilizing hyaluronic acid derivative-based nanoparticles for the delivery of lapatinib to triple-negative breast cancer. Biomacromol. 2019;20(2):835–45.

    Article  CAS  Google Scholar 

  37. Zorova LD, Popkov VA, Plotnikov EY, Silachev DN, Pevzner IB, Jankauskas SS, et al. Mitochondrial membrane potential. Anal Biochem. 2018;552:50–9.

    Article  CAS  PubMed  Google Scholar 

  38. Jin S, Zhang QY, Kang XM, Wang JX, Zhao WH. Daidzein induces MCF-7 breast cancer cell apoptosis via the mitochondrial pathway. Ann Oncol. 2010;21(2):263–8.

    Article  CAS  PubMed  Google Scholar 

  39. Cevik O, Acidereli H, Turut FA, Yildirim S, Acilan C. Cabazitaxel exhibits more favorable molecular changes compared to other taxanes in androgen-independent prostate cancer cells. J Biochem Mol Toxicol. 2020;34(9):e22542.

  40. Li Z, Graham BH. Measurement of mitochondrial oxygen consumption using a Clark electrode. Methods Mol Biol. 2012;837:63–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pike Winer SL, Min W. Rapid analysis of glycolytic and oxidative substrate flux of cancer cells in a microplate. PLoS ONE. 2014;9(10):e109916.

  42. Magnoni R, Palmfeldt J, Christensen JH, Sand M, Maltecca F, Corydon TJ, et al. Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in mice. Neurobiol Dis. 2013;54:12–23.

    Article  CAS  PubMed  Google Scholar 

  43. Yang G, Zhou D, Li J, Wang W, Zhong W, Fan W, et al. VDAC1 is regulated by BRD4 and contributes to JQ1 resistance in breast cancer. Oncol Lett. 2019;18(3):2340–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Cader MZ, Boroviak K, Zhang Q, Assadi G, Kempster SL, Sewell GW, et al. C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nat Immunol. 2016;17(9):1046–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Atanase LI, Desbrieres J, Riess G. Micellization of synthetic and polysaccharides-based graft copolymers in aqueous media. Prog Polym Sci. 2017;73:32–60.

    Article  CAS  Google Scholar 

  46. Varona S, Martín Á, Cocero MJ. Liposomal incorporation of lavandin essential oil by a thin-film hydration method and by particles from gas-saturated solutions. Ind Eng Chem Res. 2011;50(4):2088–97.

    Article  CAS  Google Scholar 

  47. Hwang D, Ramsey JD, Kabanov AV. Polymeric micelles for the delivery of poorly soluble drugs: from nanoformulation to clinical approval. Adv Drug Deliv Rev. 2020;156:80–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dang LH, Vu MT, Chen J, Nguyen CK, Bach LG, Tran NQ, et al. Effect of ultrasonication on self-assembled nanostructures formed by amphiphilic positive-charged copolymers and negative-charged drug. ACS Omega. 2019;4(3):4540–52.

    Article  CAS  Google Scholar 

  49. Forgács E. Study of the binding of sodium dodecylsulfate to dibasic amino acids by reversed-phase chromatography. Fresenius J Anal Chem. 1994;349(10):743–5.

    Article  Google Scholar 

  50. Siepmann J, Siepmann F. Mathematical modeling of drug dissolution. Int J Pharm. 2013;453(1):12–24.

    Article  CAS  PubMed  Google Scholar 

  51. Hafezi Moghaddam R, Dadfarnia S, Shabani AMH, Moghaddam ZH, Tavakol M. Electron beam irradiation synthesis of porous and non-porous pectin based hydrogels for a tetracycline drug delivery system. Mater Sci Eng, C. 2019;102:391–404.

    Article  CAS  Google Scholar 

  52. Ilgin P, Ozay H, Ozay O. A new dual stimuli responsive hydrogel: modeling approaches for the prediction of drug loading and release profile. Eur Polym J. 2019.

  53. Guideline: Validation of Analytical Procedures: Textand Methodology Q2 (R1). (2005).

  54. Behera SK, Mohanty ME, Mohapatra M. A fluorescence study of the interaction of anticancer drug molecule doxorubicin hydrochloride in Pluronic P123 and F127 micelles. J Fluoresc. 2021;31(1):17–27.

    Article  CAS  PubMed  Google Scholar 

  55. Ganguly R, Kumar S, Kunwar A, Nath S, Sarma HD, Tripathi A, et al. Structural and therapeutic properties of curcumin solubilized pluronic F127 micellar solutions and hydrogels. J Mol Liq. 2020;314:113591.

  56. Gao S, Tian B, Han J, Zhang J, Shi Y, Lv Q, et al. Enhanced transdermal delivery of lornoxicam by nanostructured lipid carrier gels modified with polyarginine peptide for treatment of carrageenan-induced rat paw edema. Int J Nanomedicine. 2019;14:6135–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Deng ZJ, Morton SW, Ben-Akiva E, Dreaden EC, Shopsowitz KE, Hammond PT. Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment. ACS Nano. 2013;7(11):9571–84.

    Article  CAS  PubMed  Google Scholar 

  58. Rondelli V, Koutsioubas A, Di Cola E, Fragneto G, Grillo I, Del Favero E, et al. Dysmyelination and glycolipid interference caused by phenylalanine in phenylketonuria. Int J Biol Macromol. 2022;221:784–95.

    Article  CAS  PubMed  Google Scholar 

  59. Kanzelmeyer N, Tsikas D, Chobanyan-Jurgens K, Beckmann B, Vaske B, Illsinger S, et al. Asymmetric dimethylarginine in children with homocystinuria or phenylketonuria. Amino Acids. 2012;42(5):1765–72.

    Article  CAS  PubMed  Google Scholar 

  60. Gallivan JP, Dougherty DA. Cation-pi interactions in structural biology. Proc Natl Acad Sci USA. 1999;96(17):9459–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Flocco MM, Mowbray SL. Planar stacking interactions of arginine and aromatic side-chains in proteins. J Mol Biol. 1994;235(2):709–17.

    Article  CAS  PubMed  Google Scholar 

  62. Kumar K, Woo SM, Siu T, Cortopassi WA, Duarte F, Paton RS. Cation-pi interactions in protein-ligand binding: theory and data-mining reveal different roles for lysine and arginine. Chem Sci. 2018;9(10):2655–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Armstrong CT, Mason PE, Anderson JL, Dempsey CE. Arginine side chain interactions and the role of arginine as a gating charge carrier in voltage sensitive ion channels. Sci Rep. 2016;6:21759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kabanov AV, Batrakova EV, Alakhov VY. Pluronic® block copolymers for overcoming drug resistance in cancer. Adv Drug Deliv Rev. 2002;54(5):759–79.

    Article  CAS  PubMed  Google Scholar 

  65. Melik-Nubarov NS, Pomaz OO, Dorodnych T, Badun GA, Ksenofontov AL, Schemchukova OB, et al. Interaction of tumor and normal blood cells with ethylene oxide and propylene oxide block copolymers. FEBS Lett. 1999;446(1):194–8.

    Article  CAS  PubMed  Google Scholar 

  66. Varkouhi AK, Scholte M, Storm G, Haisma HJ. Endosomal escape pathways for delivery of biologicals. J Control Release. 2011;151(3):220–8.

    Article  CAS  PubMed  Google Scholar 

  67. Li Y-Y, Li L, Dong H-Q, Cai X-J, Ren T-B. Pluronic F127 nanomicelles engineered with nuclear localized functionality for targeted drug delivery. Mater Sci Eng, C. 2013;33(5):2698–707.

    Article  CAS  Google Scholar 

  68. Khan S, Boateng J. Effects of cyclodextrins (β and γ) and l-arginine on stability and functional properties of mucoadhesive buccal films loaded with omeprazole for pediatric patients. Polymers. 2018;10(2):157.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Ohtake K, Maeno T, Ueda H, Natsume H, Morimoto Y. Poly-L-arginine predominantly increases the paracellular permeability of hydrophilic macromolecules across rabbit nasal epithelium in vitro. Pharm Res. 2003;20:153–60.

    Article  CAS  PubMed  Google Scholar 

  70. Walrant A, Bauza A, Girardet C, Alves ID, Lecomte S, Illien F, et al. Ionpair-pi interactions favor cell penetration of arginine/tryptophan-rich cell-penetrating peptides. Biochim Biophys Acta Biomembr. 2020;1862(2):183098.

  71. Maiolo JR, Ferrer M, Ottinger EA. Effects of cargo molecules on the cellular uptake of arginine-rich cell-penetrating peptides. Biochim Biophys Acta. 2005;1712(2):161–72.

    Article  CAS  PubMed  Google Scholar 

  72. Slastnikova TA, Ulasov AV, Rosenkranz AA, Sobolev AS. Targeted intracellular delivery of antibodies: the state of the art. Front Pharmacol. 2018;9:1208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wu D, Zhang Y, Xu X, Guo T, Xie D, Zhu R, et al. RGD/TAT-functionalized chitosan-graft-PEI-PEG gene nanovector for sustained delivery of NT-3 for potential application in neural regeneration. Acta Biomater. 2018;72:266–77.

    Article  CAS  PubMed  Google Scholar 

  74. Balhorn R, Hok S, DeNardo S, Natarajan A, Mirick G, Corzett M, et al. Hexa-arginine enhanced uptake and residualization of selective high affinity ligands by Raji lymphoma cells. Mol Cancer. 2009;8:25.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Samadi Moghaddam M, Heiny M, Shastri VP. Enhanced cellular uptake of nanoparticles by increasing the hydrophobicity of poly(lactic acid) through copolymerization with cell-membrane-lipid components. Chem Commun. 2015;51(78):14605–8.

    Article  CAS  Google Scholar 

  76. Teskač K, Kristl J. The evidence for solid lipid nanoparticles mediated cell uptake of resveratrol. Int J Pharm. 2010;390(1):61–9.

    Article  PubMed  Google Scholar 

  77. Lee JS, Tung CH. Enhanced cellular uptake and metabolic stability of lipo-oligoarginine peptides. Biopolymers. 2011;96(6):772–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Farkhani SM, Johari-Ahar M, Zakeri-Milani P, Shahbazi Mojarrad J, Valizadeh H. Enhanced cellular internalization of CdTe quantum dots mediated by arginine- and tryptophan-rich cell-penetrating peptides as efficient carriers. Artif Cells Nanomed Biotechnol. 2016;44(6):1424–8.

    Article  CAS  PubMed  Google Scholar 

  79. Zhang H, Zhu D, Song L, Liu L, Dong X, Liu Z, et al. Arginine conjugation affects the endocytic pathways of chitosan/DNA nanoparticles. J Biomed Mater Res A. 2011;98(2):296–302.

    Article  PubMed  Google Scholar 

  80. Cardarelli F, Serresi M, Bizzarri R, Giacca M, Beltram F. In vivo study of HIV-1 Tat arginine-rich motif unveils its transport properties. Mol Ther. 2007;15(7):1313–22.

    Article  CAS  PubMed  Google Scholar 

  81. Du W, Fan Y, He B, Zheng N, Yuan L, Dai W, et al. Bionano interactions of mcf-7 breast tumor cells with a transferrin receptor targeted nanoparticle. Mol Pharm. 2015;12(5):1467–76.

    Article  CAS  PubMed  Google Scholar 

  82. Walrant A, Correia I, Jiao CY, Lequin O, Bent EH, Goasdoue N, et al. Different membrane behaviour and cellular uptake of three basic arginine-rich peptides. Biochim Biophys Acta. 2011;1808(1):382–93.

    Article  CAS  PubMed  Google Scholar 

  83. Zhang R, Qin X, Kong F, Chen P, Pan G. Improving cellular uptake of therapeutic entities through interaction with components of cell membrane. Drug Deliv. 2019;26(1):328–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Herrera C, Harman S, Aldon Y, Rogers P, Armanasco N, Ziprin P, et al. The entry inhibitor DS003 (BMS-599793): a BMS-806 analogue, provides superior activity as a pre-exposure prophylaxis candidate. AIDS. 2021;35(12):1907–17.

    Article  CAS  PubMed  Google Scholar 

  85. Zhao T, Chen S, Li C, Han S, Jia Y, Liu L, et al. Metabolites from the mucus of Volutharpa ampullacea perryi: a prospective marine resource for bioactive molecules. Waste and Biomass Valorization. 2021;12:4287–98.

    Article  CAS  Google Scholar 

  86. Rijt SHv, Kostrhunova H, Brabec V, Sadler PJ. Functionalization of osmium arene anticancer complexes with (poly) arginine: effect on cellular uptake, internalization, and cytotoxicity. Bioconjug Chem. 2011;22(2):218–26.

  87. Sun M, Gao Y, Zhu Z, Wang H, Han C, Yang X, et al. A systematic in vitro investigation on poly-arginine modified nanostructured lipid carrier: Pharmaceutical characteristics, cellular uptake, mechanisms and cytotoxicity. Asian J Pharm Sci. 2017;12(1):51–8.

  88. Lee B-J, Huang Y-C, Chen S-J, Lin P-T. Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with coronary artery disease. Nutrition. 2012;28(3):250–5.

    Article  CAS  PubMed  Google Scholar 

  89. Takahashi E, Yamaoka Y. Simple and inexpensive technique for measuring oxygen consumption rate in adherent cultured cells. J Physiol Sci. 2017;67(6):731–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ozbek M, Erdogan M, Karadeniz M, Cetinkalp S, Ozgen A, Saygili F, et al. Evaluation of beta cell dysfunction by mixed meal tolerance test and oral L-arginine in patients with newly diagnosed type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2009;117(10):573–6.

    Article  CAS  PubMed  Google Scholar 

  91. Dadali T, Diers AR, Kazerounian S, Muthuswamy SK, Awate P, Ng R, et al. Elevated levels of mitochondrial CoQ(10) induce ROS-mediated apoptosis in pancreatic cancer. Sci Rep. 2021;11(1):5749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Jing L, He MT, Chang Y, Mehta SL, He QP, Zhang JZ, et al. Coenzyme Q10 protects astrocytes from ROS-induced damage through inhibition of mitochondria-mediated cell death pathway. Int J Biol Sci. 2015;11(1):59–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Shoshan-Barmatz V, Keinan N, Zaid H. Uncovering the role of VDAC in the regulation of cell life and death. J Bioenerg Biomembr. 2008;40(3):183–91.

    Article  CAS  PubMed  Google Scholar 

  94. Crane FL, Low H, Sun IL. Evidence for a relation between plasma membrane coenzyme Q and autism. Front Biosci (Elite Ed). 2013;5(3):1011–6.

    Article  PubMed  Google Scholar 

  95. Gvozdjakova A, Kucharska J, Ostatnikova D, Babinska K, Nakladal D, Crane FL. Ubiquinol improves symptoms in children with autism. Oxid Med Cell Longev. 2014;2014:798957.

  96. Na HS, Woo JS, Kim JH, Lee JS, Um IG, Cho K-H, et al. Coenzyme Q10 encapsulated in micelles ameliorates osteoarthritis by inhibiting inflammatory cell death. PLoS ONE. 2022;17(6):e0270351.

  97. Hendershot LM. The ER function BiP is a master regulator of ER function. Mt Sinai J Med. 2004;71(5):289–97.

    PubMed  Google Scholar 

  98. Yang G, Zhou D, Li J, Wang W, Zhong W, Fan W, et al. VDAC1 is regulated by BRD4 and contributes to JQ1 resistance in breast cancer. Oncol Lett. 2019.

  99. Camara AKS, Zhou Y, Wen P-C, Tajkhorshid E, Kwok W-M. Mitochondrial VDAC1: a key gatekeeper as potential therapeutic target. Front Physiol. 2017;8.

  100. Arif T, Vasilkovsky L, Refaely Y, Konson A, Shoshan-Barmatz V. Silencing VDAC1 expression by sirna inhibits cancer cell proliferation and tumor growth in vivo. Mol Ther Nucleic Acids. 2014;3.

  101. Teng R, Liu Z, Tang H, Zhang W, Chen Y, Xu R, et al. HSP60 silencing promotes Warburg-like phenotypes and switches the mitochondrial function from ATP production to biosynthesis in ccRCC cells. Redox Biol. 2019;24.

  102. Meng Q, Li BX, Xiao X. Toward developing chemical modulators of Hsp60 as potential therapeutics. Front Mol Biosci. 2018;5.

  103. Liyanagamage DSNK, Martinus RD. Role of mitochondrial stress protein HSP60 in diabetes-induced neuroinflammation. Mediators Inflamm. 2020;2020:1–8.

    Article  Google Scholar 

  104. Kumar R, Chaudhary AK, Woytash J, Inigo JR, Gokhale AA, Bshara W, et al. A mitochondrial unfolded protein response inhibitor suppresses prostate cancer growth in mice via HSP60. J Clin Invest. 2022;132(13).

  105. Pala R, Beyaz F, Tuzcu M, Er B, Sahin N, Cinar V, et al. The effects of coenzyme Q10 on oxidative stress and heat shock proteins in rats subjected to acute and chronic exercise. J Exerc Nutr Biochem. 2018;22(3):14–20.

    Article  Google Scholar 

  106. Cottrell DA, Turnbull DM. Mitochondria and ageing. Curr Opin Clin Nutr Metab Care. 2000;3(6):473–8.

    Article  CAS  PubMed  Google Scholar 

  107. Roelofs BA, Ge SX, Studlack PE, Polster BM. Low micromolar concentrations of the superoxide probe MitoSOX uncouple neural mitochondria and inhibit complex IV. Free Radical Biol Med. 2015;86:250–8.

    Article  CAS  Google Scholar 

  108. Broniarek I, Dominiak K, Galganski L, Jarmuszkiewicz W. The influence of statins on the aerobic metabolism of endothelial cells. Int J Mol Sci. 2020;21(4).

Download references

Acknowledgements

We would like to thank the St. Louis College of Pharmacy, Department of Pharmaceutical Technology, for providing facility for our work.

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Authors and Affiliations

  1. Department of Pharmaceutical and Administrative Sciences, University of Health Science and Pharmacy in St. Louis, St. Louis, USA

    Burcu Uner & Pankaj Dwivedi

  2. Department of Pharmaceutical Technology, Faculty of Pharmacy, Trakya University, Edirne, Turkey

    Ahmet Doğan Ergin

  3. Department of Neuroscience, University of Turin, Turin, Italy

    Ahmet Doğan Ergin

Authors
  1. Burcu Uner
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  2. Pankaj Dwivedi
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  3. Ahmet Doğan Ergin
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Contributions

Burcu ÜNER: conceptualization, methodology, data curation, writing–reviewing and editing. Pankaj DWIVEDI: conceptualization, methodology, data curation, writing–reviewing and editing, supervision. Ahmet Doğan ERGİN: conceptualization, methodology, data collection, writing–reviewing and editing, supervision.

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Correspondence to Burcu Uner.

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Uner, B., Dwivedi, P. & Ergin, A.D. Effects of arginine on coenzyme-Q10 micelle uptake for mitochondria-targeted nanotherapy in phenylketonuria. Drug Deliv. and Transl. Res. 14, 191–207 (2024). https://doi.org/10.1007/s13346-023-01392-x

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