Generic placeholder image

Current Drug Delivery


ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

Research Article

Evaluation of Doxorubicin-loaded Echogenic Macroemulsion for Targeted Drug Delivery

Author(s): Jong-Ryul Park, Gayoung Kim, Jongho Won, Chul-Woo Kim and Donghee Park*

Volume 21, Issue 5, 2024

Published on: 14 April, 2023

Page: [785 - 793] Pages: 9

DOI: 10.2174/1567201820666230403111118

Price: $65


Background: The latest technology trend in targeted drug delivery highlights stimuliresponsive particles that can release an anticancer drug in a solid tumor by responding to external stimuli.

Objective: This study aims to design, fabricate, and evaluate an ultrasound-responsive drug delivery vehicle for an ultrasound-mediated drug delivery system.

Methods: The drug-containing echogenic macroemulsion (eME) was fabricated by an emulsification method using the three phases (aqueous lipid solution as a shell, doxorubicin (DOX) contained oil, and perfluorohexane (PFH) as an ultrasound-responsive agent). The morphological structure of eMEs was investigated using fluorescence microscopy, and the size distribution was analyzed by using DLS. The echogenicity of eME was measured using a contrast-enhanced ultrasound device. The cytotoxicity was evaluated using a breast cancer cell (MDA-MB-231) via an in vitro cell experiment.

Results: The obtained eME showed an ideal morphological structure that contained both DOX and PFH in a single particle and indicated a suitable size for enhancing ultrasound response and avoiding complications in the blood vessel. The echogenicity of eME was demonstrated via an in vitro experiment, with results showcasing the potential for targeted drug delivery. Compared to free DOX, enhanced cytotoxicity and improved drug delivery efficiency in a cancer cell were proven by using DOX-loaded eMEs and ultrasound.

Conclusion: This study established a platform technology to fabricate the ultrasound-responsive vehicle. The designed drug-loaded eME could be a promising platform with ultrasound technology for targeted drug delivery.

Keywords: Cancer therapy, drug delivery systems, emulsion, macroemulsion, sonoporation, ultrasound, targeted drug delivery.

« Previous
Graphical Abstract
Sharma, A.; Garg, T.; Aman, A.; Panchal, K.; Sharma, R.; Kumar, S.; Markandeywar, T. Nanogel—an advanced drug delivery tool: Current and future. Artif. Cells Nanomed. Biotechnol., 2016, 44(1), 165-177.
[] [PMID: 25053442]
Demetzos, C.; Pippa, N. Advanced drug delivery nanosystems (aDDnSs): A mini-review. Drug Deliv., 2014, 21(4), 250-257.
[] [PMID: 24134707]
Couvreur, P. Nanoparticles in drug delivery: Past, present and future. Adv. Drug Deliv. Rev., 2013, 65(1), 21-23.
[] [PMID: 22580334]
Vargason, A.M.; Anselmo, A.C.; Mitragotri, S. The evolution of commercial drug delivery technologies. Nat. Biomed. Eng., 2021, 5(9), 951-967.
[] [PMID: 33795852]
Tiwari, G.; Tiwari, R.; Bannerjee, S.K.; Bhati, L.; Pandey, S.; Pandey, P.; Sriwastawa, B. Drug delivery systems: An updated review. Int. J. Pharm. Investig., 2012, 2(1), 2-11.
[] [PMID: 23071954]
Khan, I.; Khan, M.; Umar, M.N.; Oh, D.H. Nanobiotechnology and its applications in drug delivery system: A review. IET Nanobiotechnol., 2015, 9(6), 396-400.
[] [PMID: 26647817]
Wilczewska, A.Z.; Niemirowicz, K.; Markiewicz, K.H.; Car, H. Nanoparticles as drug delivery systems. Pharmacol. Rep., 2012, 64(5), 1020-1037.
[] [PMID: 23238461]
Yih, T.C.; Al-Fandi, M. Engineered nanoparticles as precise drug delivery systems. J. Cell. Biochem., 2006, 97(6), 1184-1190.
[] [PMID: 16440317]
Ajazuddin; Alexander, A.; Khichariya, A.; Gupta, S.; Patel, R.J.; Giri, T.K.; Tripathi, D.K. Recent expansions in an emergent novel drug delivery technology. Emulgel. J. Control. Release, 2013, 171(2), 122-132.
[] [PMID: 23831051]
Fenaroli, F.; Repnik, U.; Xu, Y.; Johann, K.; Van Herck, S.; Dey, P.; Skjeldal, F.M.; Frei, D.M.; Bagherifam, S.; Kocere, A.; Haag, R.; De Geest, B.G.; Barz, M.; Russell, D.G.; Griffiths, G. Enhanced permeability and retention-like extravasation of nanoparticles from the vasculature into tuberculosis granulomas in zebrafish and mouse models. ACS Nano, 2018, 12(8), 8646-8661.
[] [PMID: 30081622]
Suk, J.S.; Xu, Q.; Kim, N.; Hanes, J.; Ensign, L.M. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv. Drug Deliv. Rev., 2016, 99(Pt A), 28-51.
[] [PMID: 26456916]
Attia, M.F.; Anton, N.; Wallyn, J.; Omran, Z.; Vandamme, T.F. An overview of active and passive targeting strategies to improve the nanocarriers efficiency to tumour sites. J. Pharm. Pharmacol., 2019, 71(8), 1185-1198.
[] [PMID: 31049986]
Chen, W.C.; Zhang, A.X.; Li, S.D. Limitations and niches of the active targeting approach for nanoparticle drug delivery. Eur. J. Nanomed., 2012, 4(2-4), 89-93.
Lee, K.J.; Shin, S.H.; Lee, J.H.; Ju, E.J.; Park, Y.Y.; Hwang, J.J.; Suh, Y.A.; Hong, S.M.; Jang, S.J.; Lee, J.S.; Song, S.Y.; Jeong, S.Y.; Choi, E.K. A strategy for actualization of active targeting nanomedicine practically functioning in a living body. Biomaterials, 2017, 141, 136-148.
[] [PMID: 28688285]
Thomas-Moore, B.A.; del Valle, C.A.; Field, R.A.; Marín, M.J. Recent advances in nanoparticle-based targeting tactics for antibacterial photodynamic therapy. Photochem. Photobiol. Sci., 2022, 21(6), 1111-1131.
[] [PMID: 35384638]
Lu, H.; Zhou, Q.; He, J.; Jiang, Z.; Peng, C.; Tong, R.; Shi, J. Recent advances in the development of protein–protein interactions modulators: Mechanisms and clinical trials. Signal Transduct. Target. Ther., 2020, 5(1), 213.
[] [PMID: 32968059]
Gao, X.; Yu, Z.; Liu, B.; Yang, J.; Yang, X.; Yu, Y. A smart drug delivery system responsive to pH/enzyme stimuli based on hydrophobic modified sodium alginate. Eur. Polym. J., 2020, 133, 109779.
Park, J.R.; Verderosa, A.D.; Totsika, M.; Hoogenboom, R.; Dargaville, T.R. Thermoresponsive polymer–antibiotic conjugates based on gradient copolymers of 2-Oxazoline and 2-Oxazine. Biomacromolecules, 2021, 22(12), 5185-5194.
[] [PMID: 34726387]
Duc, N.M.; Keserci, B. Emerging clinical applications of high-intensity focused ultrasound. Diagn. Interv. Radiol., 2019, 25(5), 398-409.
[] [PMID: 31287428]
De Luca, R.; Forzoni, L.; Gelli, F.; Bamber, J. An educational overview of ultrasound probe types and their fields of application. Arch. Acoust., 2021, 46, 3-15.
Darrow, D.P. Focused ultrasound for neuromodulation. Neurotherapeutics, 2019, 16(1), 88-99.
[] [PMID: 30488340]
Pitt, W.G.; Husseini, G.A.; Staples, B.J. Ultrasonic drug delivery-a general review. Expert Opin. Drug Deliv., 2004, 1(1), 37-56.
[] [PMID: 16296719]
Kim, Y.S.; Ko, M.J.; Moon, H.; Sim, W.; Cho, A.S.; Gil, G.; Kim, H.R. Ultrasound-responsive liposomes for targeted drug delivery combined with focused ultrasound. Pharmaceutics, 2022, 14(7), 1314.
[] [PMID: 35890210]
Yu, Z.; Wang, Y.; Xu, D.; Zhu, L.; Hu, M.; Liu, Q.; Lan, W.; Jiang, J.; Wang, L. G250 antigen-targeting drug-loaded nanobubbles combined with ultrasound targeted nanobubble destruction: a potential novel treatment for renal cell carcinoma. Int. J. Nanomedicine, 2020, 15, 81-95.
[] [PMID: 32021166]
Shin Low, S.; Nong Lim, C.; Yew, M.; Siong Chai, W.; Low, L.E.; Manickam, S.; Ti Tey, B.; Show, P.L. Recent ultrasound advancements for the manipulation of nanobiomaterials and nanoformulations for drug delivery. Ultrason. Sonochem., 2021, 80, 105805.
[] [PMID: 34706321]
Wu, J.; Nyborg, W.L. Ultrasound, cavitation bubbles and their interaction with cells. Adv. Drug Deliv. Rev., 2008, 60(10), 1103-1116.
[] [PMID: 18468716]
Wolloch, L.; Kost, J. The importance of microjet vs shock wave formation in sonophoresis. J. Control. Release, 2010, 148(2), 204-211.
[] [PMID: 20655341]
Stride, E.P.; Coussios, C.C. Cavitation and contrast: The use of bubbles in ultrasound imaging and therapy. Proc. Inst. Mech. Eng. H, 2010, 224(2), 171-191.
[] [PMID: 20349814]
Treat, L.H.; McDannold, N.; Zhang, Y.; Vykhodtseva, N.; Hynynen, K. Improved anti-tumor effect of liposomal doxorubicin after targeted blood-brain barrier disruption by MRI-guided focused ultrasound in rat glioma. Ultrasound Med. Biol., 2012, 38(10), 1716-1725.
[] [PMID: 22818878]
Liu, H.L.; Hua, M.Y.; Chen, P.Y.; Chu, P.C.; Pan, C.H.; Yang, H.W.; Huang, C.Y.; Wang, J.J.; Yen, T.C.; Wei, K.C. Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment. Radiology, 2010, 255(2), 415-425.
[] [PMID: 20413754]
Browning, R.; Thomas, N.; Marsh, L.K.; Tear, L.R.; Owen, J.; Stride, E.; Farrer, N. J. Ultrasound‐triggered delivery of iproplatin from microbubble‐conjugated liposomes. ChemistryOpen, 2021, 10(12), 1170-1176.
[] [PMID: 34708552]
Lentacker, I.; Geers, B.; Demeester, J.; De Smedt, S.C.; Sanders, N.N. Design and evaluation of doxorubicin-containing microbubbles for ultrasound-triggered doxorubicin delivery: cytotoxicity and mechanisms involved. Mol. Ther., 2010, 18(1), 101-108.
[] [PMID: 19623162]
Ting, C.Y.; Fan, C.H.; Liu, H.L.; Huang, C.Y.; Hsieh, H.Y.; Yen, T.C.; Wei, K.C.; Yeh, C.K. Concurrent blood–brain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment. Biomaterials, 2012, 33(2), 704-712.
[] [PMID: 22019122]
Zhou, L.; Liu, J.; Meng, W.; Zhang, H.; Chen, B. Evaluation of silibinin-loaded microbubbles combined with ultrasound in ovarian cancer cells: Cytotoxicity and mechanisms. Anticancer. Agents Med. Chem., 2022, 22(7), 1320-1327.
[] [PMID: 34102993]
Escoffre, J.; Mannaris, C.; Geers, B.; Novell, A.; Lentacker, I.; Averkiou, M.; Bouakaz, A. Doxorubicin liposome-loaded microbubbles for contrast imaging and ultrasound-triggered drug delivery. IEEE Trans. Ultrason. Ferroelectr. Freq. Control, 2013, 60(1), 78-87.
[] [PMID: 23287915]
Abou-Saleh, R.H.; Peyman, S.A.; Johnson, B.R.G.; Marston, G.; Ingram, N.; Bushby, R.; Coletta, P.L.; Markham, A.F.; Evans, S.D. The influence of intercalating perfluorohexane into lipid shells on nano and microbubble stability. Soft Matter, 2016, 12(34), 7223-7230.
[] [PMID: 27501364]
Zhou, Y.; Wang, Z.; Chen, Y.; Shen, H.; Luo, Z.; Li, A.; Wang, Q.; Ran, H.; Li, P.; Song, W.; Yang, Z.; Chen, H.; Wang, Z.; Lu, G.; Zheng, Y. Microbubbles from gas-generating perfluorohexane nanoemulsions for targeted temperature-sensitive ultrasonography and synergistic HIFU ablation of tumors. Adv. Mater., 2013, 25(30), 4123-4130.
[] [PMID: 23788403]
Zhong, J.; Yang, S.; Wen, L.; Xing, D. Imaging-guided photoacoustic drug release and synergistic chemo-photoacoustic therapy with paclitaxel-containing nanoparticles. J. Control. Release, 2016, 226, 77-87.
[] [PMID: 26860283]
Zhang, X.; Sun, X.; Li, J.; Zhang, X.; Gong, T.; Zhang, Z. Lipid nanoemulsions loaded with doxorubicin-oleic acid ionic complex: Characterization, in vitro and in vivo studies. Pharmazie, 2011, 66(7), 496-505.
[PMID: 21812324]
Zhao, S.; Minh, L.V.; Li, N.; Garamus, V.M.; Handge, U.A.; Liu, J.; Zhang, R.; Willumeit-Römer, R.; Zou, A. Doxorubicin hydrochloride-oleic acid conjugate loaded nanostructured lipid carriers for tumor specific drug release. Colloids Surf. B Biointerfaces, 2016, 145, 95-103.
[] [PMID: 27137808]
Lages, E.B.; Fernandes, R.S.; Silva, J.O.; de Souza, Â.M.; Cassali, G.D.; de Barros, A.L.B.; Miranda Ferreira, L.A. Co-delivery of doxorubicin, docosahexaenoic acid, and α-tocopherol succinate by nanostructured lipid carriers has a synergistic effect to enhance antitumor activity and reduce toxicity. Biomed. Pharmacother., 2020, 132, 110876.
[] [PMID: 33113428]
Benjanuwattra, J.; Siri-Angkul, N.; Chattipakorn, S.C.; Chattipakorn, N. Doxorubicin and its proarrhythmic effects: A comprehensive review of the evidence from experimental and clinical studies. Pharmacol. Res., 2020, 151, 104542.
[] [PMID: 31730804]
Choi, J.J.; Feshitan, J.A.; Baseri, B.; Wang, S.; Tung, Y-S.; Borden, M.A.; Konofagou, E.E. Microbubble-size dependence of focused ultrasound-induced blood–brain barrier opening in mice in vivo. IEEE Trans. Biomed. Eng., 2009, 57(1), 145-154.
Samiotaki, G.; Vlachos, F.; Tung, Y.S.; Konofagou, E.E. A quantitative pressure and microbubble-size dependence study of focused ultrasound-induced blood-brain barrier opening reversibility in vivo using MRI. Magn. Reson. Med., 2012, 67(3), 769-777.
[] [PMID: 21858862]
Jangjou, A.; Meisami, A.H.; Jamali, K.; Niakan, M.H.; Abbasi, M.; Shafiee, M.; Salehi, M.; Hosseinzadeh, A.; Amani, A.M.; Vaez, A. The promising shadow of microbubble over medical sciences: From fighting wide scope of prevalence disease to cancer eradication. J. Biomed. Sci., 2021, 28(1), 49.
[] [PMID: 34154581]
Seki, M.; Otsuka, T.; Oitate, R.; Masuda, K.; Unga, J.; Suzuki, R.; Maruyama, K. Viability validation of therapeutic cells according to surrounded amount of microbubbles and ultrasound exposure condition. Jpn. J. Appl. Phys., 2019, 58(SG), SGGE13.
Escoffre, J.M.; Piron, J.; Novell, A.; Bouakaz, A. Doxorubicin delivery into tumor cells with ultrasound and microbubbles. Mol. Pharm., 2011, 8(3), 799-806.
[] [PMID: 21495672]
Wang, M.; Zhang, Y.; Cai, C.; Tu, J.; Guo, X.; Zhang, D. Sonoporation-induced cell membrane permeabilization and cytoskeleton disassembly at varied acoustic and microbubble-cell parameters. Sci. Rep., 2018, 8(1), 3885.
[] [PMID: 29497082]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy