Sirolimus-loaded exosomes as a promising vascular delivery system for the prevention of post-angioplasty restenosis

Liu Y, Yang F, Zou S, Qu L. Rapamycin: a bacteria-derived immunosuppressant that has anti-atherosclerotic effects and its clinical application. Front Pharmacol. 2019;9:1520. https://doi.org/10.3389/fphar.2018.01520. Onnis C, Cadeddu Dessalvi C, Cademartiri F, Muscogiuri G, Angius S, Contini F, et al. Quantitative and qualitative features of carotid and coronary atherosclerotic plaque among men and women. Front Cardiovasc Med. 2022;9:970438. https://doi.org/10.3389/fcvm.2022.970438. Nestelberger T, Jeger R. Drug-coated balloons for small coronary vessel interventions: a literature review. Interv Cardiol (London, England). 2019;14(3):131–6. https://doi.org/10.15420/icr.2019.06.R3. Andreou I, Stone PH, Ikonomidis I, Alexopoulos D, Sabate M. Recurrent atherosclerosis complications as a mechanism for stent failure. Hellenic J Cardiol. 2020;61(1):9–14. https://doi.org/10.1016/j.hjc.2019.04.007. Cheng Y, Shibuya M, McGregor J, Conditt GB, Yi GH, Kaluza GL, et al. Biological effect on restenosis and vascular healing of encapsulated paclitaxel nanocrystals delivered via coated balloon technology in the familial hypercholesterolaemic swine model of in-stent restenosis. EuroIntervention. 2016;12(9):1164–73. https://doi.org/10.4244/eijv12i9a188. Megaly M, Rofael M, Saad M, Shishehbor M, Brilakis ES. Outcomes with drug-coated balloons for treating the side branch of coronary bifurcation lesions. J Invasive Cardiol. 2018;30(11):393–9. Haeri A, Sadeghian S, Rabbani S, Anvari MS, Ghassemi S, Radfar F, et al. Effective attenuation of vascular restenosis following local delivery of chitosan decorated sirolimus liposomes. Carbohyd Polym. 2017;157:1461–9. https://doi.org/10.1016/j.carbpol.2016.11.021. Trepanier CM, Burke-Kleinman J, Strauss BH, Santerre JP, Bendeck MP. Less is more: developments in nanotechnology for antirestenosis therapies. Arterioscler Thromb Vasc Biol. 2023;43(7):1096–110. https://doi.org/10.1161/atvbaha.123.318450. Haeri A, Sadeghian S, Rabbani S, Anvari MS, Lavasanifar A, Amini M, et al. Sirolimus-loaded stealth colloidal systems attenuate neointimal hyperplasia after balloon injury: a comparison of phospholipid micelles and liposomes. Int J Pharm. 2013;455(1–2):320–30. https://doi.org/10.1016/j.ijpharm.2013.07.003. Akhlaghi S, Rabbani S, Alavi S, Alinaghi A, Radfar F, Dadashzadeh S, et al. Green formulation of curcumin loaded lipid-based nanoparticles as a novel carrier for inhibition of post-angioplasty restenosis. Mater Sci Eng: C. 2019;105:110037. https://doi.org/10.1016/j.msec.2019.110037. Wang Y, Zhao D, Wei X, Ma L, Sheng J, Lu P. PEGylated polyethylenimine derivative-mediated local delivery of the shSmad3 inhibits intimal thickening after vascular injury. Biomed Res Int. 2019;2019:8483765. https://doi.org/10.1155/2019/8483765. Sun Z, Yang J, Li H, Wang C, Fletcher C, Li J, et al. Progress in the research of nanomaterial-based exosome bioanalysis and exosome-based nanomaterials tumor therapy. Biomaterials. 2021;274:120873. https://doi.org/10.1016/j.biomaterials.2021.120873. Bell BM, Kirk ID, Hiltbrunner S, Gabrielsson S, Bultema JJ. Designer exosomes as next-generation cancer immunotherapy. Nanomedicine: Nanotechnol Biol Med. 2016;12(1):163–9. https://doi.org/10.1016/j.nano.2015.09.011. Montis C, Salvatore A, Valle F, Paolini L, Carlà F, Bergese P, et al. Biogenic supported lipid bilayers as a tool to investigate nano-bio interfaces. J Colloid Interface Sci. 2020;570:340–9. https://doi.org/10.1016/j.jcis.2020.03.014. Thakur A, Parra DC, Motallebnejad P, Brocchi M, Chen HJ. Exosomes: Small vesicles with big roles in cancer, vaccine development, and therapeutics. Bioact Mater. 2022;10:281–94. https://doi.org/10.1016/j.bioactmat.2021.08.029. Yang Z, Li Y, Wang Z. Recent advances in the application of mesenchymal stem cell-derived exosomes for cardiovascular and neurodegenerative disease therapies. Pharmaceutics. 2022;14(3):618. Mehryab F, Taghizadeh F, Goshtasbi N, Merati F, Rabbani S, Haeri A. Exosomes as cutting-edge therapeutics in various biomedical applications: an update on engineering, delivery, and preclinical studies. Biochimie. 2023;213:139–67. https://doi.org/10.1016/j.biochi.2023.05.010. Janockova J, Slovinska L, Harvanova D, Spakova T, Rosocha J. New therapeutic approaches of mesenchymal stem cells-derived exosomes. J Biomed Sci. 2021;28(1):39. https://doi.org/10.1186/s12929-021-00736-4. Liao W, Du Y, Zhang C, Pan F, Yao Y, Zhang T, et al. Exosomes: the next generation of endogenous nanomaterials for advanced drug delivery and therapy. Acta Biomater. 2019;86:1–14. https://doi.org/10.1016/j.actbio.2018.12.045. Mehryab F, Rabbani S, Shahhosseini S, Shekari F, Fatahi Y, Baharvand H, et al. Exosomes as a next-generation drug delivery system: an update on drug loading approaches, characterization, and clinical application challenges. Acta Biomater. 2020;113:42–62. https://doi.org/10.1016/j.actbio.2020.06.036. Kamerkar S, LeBleu VS, Sugimoto H, Yang S, Ruivo CF, Melo SA, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature. 2017;546(7659):498–503. https://doi.org/10.1038/nature22341. Ichim TE, O’Heeron P, Kesari S. Fibroblasts as a practical alternative to mesenchymal stem cells. J Transl Med. 2018;16(1):212. https://doi.org/10.1186/s12967-018-1536-1. Roskoski R Jr. Properties of FDA-approved small molecule protein kinase inhibitors: a 2020 update. Pharmacol Res. 2020;152:104609. https://doi.org/10.1016/j.phrs.2019.104609. Freixo C, Ferreira V, Martins J, Almeida R, Caldeira D, Rosa M, et al. Efficacy and safety of sirolimus in the treatment of vascular anomalies: a systematic review. J Vasc Surg. 2020;71(1):318–27. https://doi.org/10.1016/j.jvs.2019.06.217. Talimi R, Rabbani S, Mehryab F, Haeri A. Perivascular application of sirolimus multilayer nanofibrous mat for prevention of vascular stenosis: preparation, in vitro characterization, and in vivo efficacy evaluation. J Drug Deliv Sci Technol. 2022;77:103816. https://doi.org/10.1016/j.jddst.2022.103816. Vahdat S, Pahlavan S, Mahmoudi E, Barekat M, Ansari H, Bakhshandeh B, et al. Expansion of human pluripotent stem cell-derived early cardiovascular progenitor cells by a cocktail of signaling factors. Sci Rep. 2019;9(1):16006. https://doi.org/10.1038/s41598-019-52516-8. Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Current protocols in cell biology. 2006; Chapter 3:Unit 3.22. https://doi.org/10.1002/0471143030.cb0322s30. Mardpour S, Ghanian MH, Sadeghi-abandansari H, Mardpour S, Nazari A, Shekari F, et al. Hydrogel-mediated sustained systemic delivery of mesenchymal stem cell-derived extracellular vesicles improves hepatic regeneration in chronic liver failure. ACS Appl Mater Interfaces. 2019;11(41):37421–33. https://doi.org/10.1021/acsami.9b10126. Jain A, Jain SK. In vitro release kinetics model fitting of liposomes: an insight. Chem Phys Lipid. 2016;201:28-40. https://doi.org/10.1016/j.chemphyslip.2016.10.005. Javidi J, Haeri A, Shirazi FH, Kobarfard F, Dadashzadeh S. Synthesis, Characterization, in vivo imaging, hemolysis, and toxicity of hydrophilic Ag2S near-infrared quantum dots. J Cluster Sci. 2017;28(1):165–78. https://doi.org/10.1007/s10876-016-1060-5. Hinz B, Celetta G, Tomasek JJ, Gabbiani G, Chaponnier C. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell. 2001;12(9):2730–41. https://doi.org/10.1091/mbc.12.9.2730. Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol (Baltimore, Md : 1950). 1984;133(4):1710–5. Chen Q, Jin M, Yang F, Zhu J, Xiao Q, Zhang L. Matrix metalloproteinases: inflammatory regulators of cell behaviors in vascular formation and remodeling. Mediator Inflamm. 2013;2013:928315. https://doi.org/10.1155/2013/928315. Gallo G, Pierelli G, Forte M, Coluccia R, Volpe M, Rubattu S. Role of oxidative stress in the process of vascular remodeling following coronary revascularization. Int J Cardiol. 2018;268:27–33. https://doi.org/10.1016/j.ijcard.2018.05.046. McDonald AI, Iruela-Arispe ML. Healing arterial ulcers: endothelial lining regeneration upon vascular denudation injury. Vascul Pharmacol. 2015;72:9–15. https://doi.org/10.1016/j.vph.2015.06.007. Aqil F, Kausar H, Agrawal AK, Jeyabalan J, Kyakulaga AH, Munagala R, et al. Exosomal formulation enhances therapeutic response of celastrol against lung cancer. Exp Mol Pathol. 2016;101(1):12–21. https://doi.org/10.1016/j.yexmp.2016.05.013. Granada JF, Tellez A, Baumbach WR, Bingham B, Keng YF, Wessler J, et al. In vivo delivery and long-term tissue retention of nano-encapsulated sirolimus using a novel porous balloon angioplasty system. EuroIntervention. 2016;12(6):740–7. https://doi.org/10.4244/eijy15m10_01. Agrawal AA, Raval AJ, Velhal SM, Patel VV, Patravale VB. Nanoparticle-eluting stents for coronary intervention: formulation, characterization, and in vitro evaluation. Can J Physiol Pharmacol. 2022;100(3):220–33. https://doi.org/10.1139/cjpp-2021-0245. Kim MS, Haney MJ, Zhao Y, Mahajan V, Deygen I, Klyachko NL, et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomed Nanotechnol Biol Med. 2016;12(3):655–64. https://doi.org/10.1016/j.nano.2015.10.012. Kim MS, Haney MJ, Zhao Y, Yuan D, Deygen I, Klyachko NL, et al. Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: in vitro and in vivo evaluations. Nanomed Nanotechnol Biol Med. 2018;14(1):195–204. https://doi.org/10.1016/j.nano.2017.09.011. Mendt M, Kamerkar S, Sugimoto H, McAndrews KM, Wu CC, Gagea M et al. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI insight. 2018;3(8):e99263. https://doi.org/10.1172/jci.insight.99263. You Y, Tian Y, Yang Z, Shi J, Kwak KJ, Tong Y, et al. Intradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy. Nat Biomed Eng. 2023;7(7):887-900. https://doi.org/10.1038/s41551-022-00989-w. Gangadaran P, Oh EJ, Rajendran RL, Kim HM, Oh JM, Kwak S et al. Identification of angiogenic cargoes in human fibroblasts-derived extracellular vesicles and induction of wound healing. Pharmaceuticals (Basel). 2022;15(6):702. https://doi.org/10.3390/ph15060702. Salazar-Puerta AI, Rincon-Benavides MA, Cuellar-Gaviria TZ, Aldana J, Vasquez Martinez G, Ortega-Pineda L et al. Engineered extracellular vesicles derived from dermal fibroblasts attenuate inflammation in a murine model of acute lung injury. Adv Mater. 2023;35(28):e2210579. https://doi.org/10.1002/adma.202210579. Kalimuthu S, Gangadaran P, Rajendran RL, Zhu L, Oh JM, Lee HW, et al. A new approach for loading anticancer drugs into mesenchymal stem cell-derived exosome mimetics for cancer therapy. Front Pharmacol. 2018;9:1116. https://doi.org/10.3389/fphar.2018.01116. Familtseva A, Jeremic N, Tyagi SC. Exosomes: cell-created drug delivery systems. Mol Cell Biochem. 2019;459(1–2):1–6. https://doi.org/10.1007/s11010-019-03545-4. Fuhrmann G, Serio A, Mazo M, Nair R, Stevens MM. Active loading into extracellular vesicles significantly improves the cellular uptake and photodynamic effect of porphyrins. J Control Release. 2015;205:35–44. https://doi.org/10.1016/j.jconrel.2014.11.029. Eloy JO, Petrilli R, Topan JF, Antonio HMR, Barcellos JPA, Chesca DL, et al. Co-loaded paclitaxel/rapamycin liposomes: development, characterization and in vitro and in vivo evaluation for breast cancer therapy. Colloids surf B biointerfaces. 2016;141:74–82. https://doi.org/10.1016/j.colsurfb.2016.01.032. Onyesom I, Lamprou DA, Sygellou L, Owusu-Ware SK, Antonijevic M, Chowdhry BZ, et al. Sirolimus encapsulated liposomes for cancer therapy: physicochemical and mechanical characterization of sirolimus distribution within liposome bilayers. Mol Pharm. 2013;10(11):4281–93. https://doi.org/10.1021/mp400362v. Haeri A, Sadeghian S, Rabbani S, Anvari MS, Boroumand MA, Dadashzadeh S. Use of remote film loading methodology to entrap sirolimus into liposomes: preparation, characterization and in vivo efficacy for treatment of restenosis. Int J Pharm. 2011;414(1–2):16–27. https://doi.org/10.1016/j.ijpharm.2011.04.055. Schorn I, Malinoff H, Anderson S, Lecy C, Wang J, Giorgianni J, et al. The Lutonix® drug-coated balloon: a novel drug delivery technology for the treatment of vascular disease. Adv Drug Deliv Rev. 2017;112:78–87. https://doi.org/10.1016/j.addr.2017.05.015. Ma J, Zhuang H, Zhuang Z, Lu Y, Xia R, Gan L, et al. Development of docetaxel liposome surface modified with CD133 aptamers for lung cancer targeting. Artif Cells Nanomed Biotechnol. 2018;46(8):1864–71. https://doi.org/10.1080/21691401.2017.1394874. Stead SO, McInnes SJP, Kireta S, Rose PD, Jesudason S, Rojas-Canales D, et al. Manipulating human dendritic cell phenotype and function with targeted porous silicon nanoparticles. Biomaterials. 2018;155:92–102. https://doi.org/10.1016/j.biomaterials.2017.11.017. Zlotogorski-Hurvitz A, Dekel BZ, Malonek D, Yahalom R, Vered M. FTIR-based spectrum of salivary exosomes coupled with computational-aided discriminating analysis in the diagnosis of oral cancer. J Cancer Res Clin Oncol. 2019;145(3):685–94. https://doi.org/10.1007/s00432-018-02827-6. Baddela VS, Nayan V, Rani P, Onteru SK, Singh D. Physicochemical biomolecular insights into buffalo milk-derived nanovesicles. Appl Biochem Biotechnol. 2016;178(3):544–57. https://doi.org/10.1007/s12010-015-1893-7. Bruno S, Collino F, Iavello A, Camussi G. Effects of mesenchymal stromal cell-derived extracellular vesicles on tumor growth. Front Immunol. 2014;5:382. https://doi.org/10.3389/fimmu.2014.00382. Kong J, Wang F, Zhang J, Cui Y, Pan L, Zhang W, et al. Exosomes of endothelial progenitor cells inhibit neointima formation after carotid artery injury. J Surg Res. 2018;232:398–407. https://doi.org/10.1016/j.jss.2018.06.066. Hu H, Jiang C, Li R, Zhao J. Comparison of endothelial cell- and endothelial progenitor cell-derived exosomes in promoting vascular endothelial cell repair. Int J Clin Exp Pathol. 2019;12(7):2793–800. Hou YC, Li JA, Zhu SJ, Cao C, Tang JN, Zhang JY, et al. Tailoring of cardiovascular stent material surface by immobilizing exosomes for better pro-endothelialization function. Colloids surf B Biointerfaces. 2020;189:110831. https://doi.org/10.1016/j.colsurfb.2020.110831. Gu J, Zhang H, Ji B, Jiang H, Zhao T, Jiang R, et al. Vesicle miR-195 derived from endothelial cells inhibits expression of serotonin transporter in vessel smooth muscle cells. Sci Rep. 2017;7:43546. https://doi.org/10.1038/srep43546. Liu R, Shen H, Ma J, Sun L, Wei M. Extracellular vesicles derived from adipose mesenchymal stem cells regulate the phenotype of smooth muscle cells to limit intimal hyperplasia. Cardiovasc Drugs Ther. 2016;30(2):111–8. https://doi.org/10.1007/s10557-015-6630-5. Li B, Zang G, Zhong W, Chen R, Zhang Y, Yang P, et al. Activation of CD137 signaling promotes neointimal formation by attenuating TET2 and transferrring from endothelial cell-derived exosomes to vascular smooth muscle cells. Biomed Pharmacother. 2020;121:109593. https://doi.org/10.1016/j.biopha.2019.109593. Schiener M, Hossann M, Viola JR, Ortega-Gomez A, Weber C, Lauber K, et al. Nanomedicine-based strategies for treatment of atherosclerosis. Trends Mol Med. 2014;20(5):271–81. https://doi.org/10.1016/j.molmed.2013.12.001. Bobiński M, Okła K, Łuszczki J, Bednarek W, Wawruszak A, Moreno-Bueno G, et al. Gemcitabine and selected mTOR inhibitors in uterine sarcomas and carcinosarcoma cells- an isobolographic analysis. Int J Med Sci. 2020;17(18):2987–97. https://doi.org/10.7150/ijms.48187. Asani B, Siedlecki J, Wertheimer C, Liegl R, Wolf A, Ohlmann A, et al. Anti-angiogenic properties of rapamycin on human retinal pericytes in an in vitro model of neovascular AMD via inhibition of the mTOR pathway. BMC Ophthalmol. 2022;22(1):138. https://doi.org/10.1186/s12886-022-02334-w. Zha Y, Yang Y, Zhou Y, Ye B, Li H, Liang J. Dietary evodiamine inhibits atherosclerosis-associated changes in vascular smooth muscle cells. Int J Mol Sci. 2023;24(7):6653. https://doi.org/10.3390/ijms24076653. Westedt U, Barbu-Tudoran L, Schaper AK, Kalinowski M, Alfke H, Kissel T. Deposition of nanoparticles in the arterial vessel by porous balloon catheters: localization by confocal laser scanning microscopy and transmission electron microscopy. AAPS PharmSci. 2002;4(4):E41. https://doi.org/10.1208/ps040441.