Among external stimuli used to trigger release of a drug from a polymeric carrier, ultrasound has gained increasing attention due to its non-invasive nature, safety and low cost. Despite this attention, there is only limited knowledge about how materials available for the preparation of drug carriers respond to ultrasound. This study investigates the effect of ultrasound on the release of a hydrophobic drug, dexamethasone, from poly(2-oxazoline)-based micelles. Spontaneous and ultrasound-mediated release of dexamethasone from five types of micelles made of poly(2-oxazoline) block copolymers, composed of hydrophilic poly(2-methyl-2-oxazoline) and hydrophobic poly(2-n-propyl-2-oxazoline) or poly(2-butyl-2-oxazoline-co-2-(3-butenyl)-2-oxazoline), was studied. The release profiles were fitted by zero-order and Ritger-Peppas models. The ultrasound increased the amount of released dexamethasone by 6% to 105% depending on the type of copolymer, the amount of loaded dexamethasone, and the stimulation time point. This study investigates for the first time the interaction between different poly(2-oxazoline)-based micelle formulations and ultrasound waves, quantifying the efficacy of such stimulation in modulating dexamethasone release from these nanocarriers.

Department for Biomaterials Research Polymer Institute of the Slovak Academy of Sciences Dúbravská cesta 9 845 41 Bratislava Slovakia

Functional Polymer Materials Chair for Chemical Technology of Materials Synthesis University of Würzburg Röntgenring 11 97070 Würzburg Germany

Institute of Macromolecular Chemistry Academy of Sciences of the Czech Republic Heyrovského nám 2 162 06 Prague 6 Czech Republic

Institute of Natural and Synthetic Polymers Faculty of Chemical and Food Technology Slovak University of Technology Radlinského 9 812 37 Bratislava Slovakia

The BioRobotics Institute Scuola Superiore Sant'Anna Viale R Piaggio 34 56025 Pontedera Italy

See more in PubMed

Timko BP, Dvir T, Kohane DS. Remotely triggerable drug delivery systems. Adv. Mater. 2010;22:4925–4943. doi: 10.1002/adma.201002072. PubMed DOI

Ganta S, Devalapally H, Shahiwala A, Amiji M. A review of stimuli-responsive nanocarriers for drug and gene delivery. J. Control. Release. 2008;126:187–204. doi: 10.1016/j.jconrel.2007.12.017. PubMed DOI

Tokarev I, Minko S. Stimuli-responsive hydrogel thin films. Soft Matter. 2009;5:511–524. doi: 10.1039/B813827C. DOI

Zha L, Banik B, Alexis F. Stimulus responsive nanogels for drug delivery. Soft Matter. 2011;7:5908–5916. doi: 10.1039/c0sm01307b. DOI

Karimi M, et al. Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems. Chem. Soc. Rev. 2016;45:1457–1501. doi: 10.1039/C5CS00798D. PubMed DOI PMC

Wang, Y. & Kohane, D. S. External triggering and triggered targeting strategies for drug delivery. Nat. Rev. Mater. 2 (2017).

Ricotti L, Cafarelli A, Iacovacci V, Vannozzi L, Menciassi A. Advanced Micro-Nano-Bio Systems for Future Targeted Therapies. Curr. Nanosci. 2015;11:144–160. doi: 10.2174/1573413710666141114221246. DOI

Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 2013;12:991–1003. doi: 10.1038/nmat3776. PubMed DOI

Deckers R, Moonen CTW. Ultrasound triggered, image guided, local drug delivery. J. Control. Release. 2010;148:25–33. doi: 10.1016/j.jconrel.2010.07.117. PubMed DOI

Sirsi SR, Borden MA. State-of-the-art materials for ultrasound-triggered drug delivery. Adv. Drug Deliv. Rev. 2014;72:3–14. doi: 10.1016/j.addr.2013.12.010. PubMed DOI PMC

Mitragotri S. Healing sound: the use of ultrasound in drug delivery and other therapeutic applications. Nat. Rev. Drug Discov. 2005;4:255–260. doi: 10.1038/nrd1662. PubMed DOI

Ahmed SE, Martins AM, Husseini GA. The use of ultrasound to release chemotherapeutic drugs from micelles and liposomes. J. Drug Target. 2015;23:16–42. doi: 10.3109/1061186X.2014.954119. PubMed DOI

Husseini GA, Pitt WG. Micelles and Nanoparticles for Ultrasonic Drug and gene Delivery. Adv. Drug Deliv. Rev. 2008;60:1137–1152. doi: 10.1016/j.addr.2008.03.008. PubMed DOI PMC

Rapoport N. Ultrasound-mediated micellar drug delivery. Int. J. Hyperth. 2012;28:374–85. doi: 10.3109/02656736.2012.665567. PubMed DOI

Xia, H., Zhao, Y. & Tong, R. In Therapeutic Ultrasound (eds Escoffre, J.-M. & Bouakaz, A.) 880, 365–384 (Springer US, 2016).

Xuan J, Pelletier M, Xia H, Zhao Y. Ultrasound-induced disruption of amphiphilic block copolymer micelles. Macromol. Chem. Phys. 2011;212:498–506. doi: 10.1002/macp.201000624. DOI

Li Y, Tong R, Xia H, Zhang H, Xuan J. High intensity focused ultrasound and redox dual responsive polymer micelles. Chem. Commun. 2010;46:7739–7741. doi: 10.1039/c0cc02628j. PubMed DOI

Husseini Ga, Pitt WG, Martins AM. Ultrasonically triggered drug delivery: Breaking the barrier. Colloids Surfaces B Biointerfaces. 2014;123:364–386. doi: 10.1016/j.colsurfb.2014.07.051. PubMed DOI

Husseini GA, Myrup GD, Pitt WG, Christensen DA, Rapoport NY. Factors affecting acoustically triggered release of drugs from polymeric micelles. J. Control. Release. 2000;69:43–52. doi: 10.1016/S0168-3659(00)00278-9. PubMed DOI

Tanbour, R., M. Martins, A., G. Pitt, W. & A. Husseini, G. Drug Delivery Systems Based on Polymeric Micelles andUltrasound: A Review. Curr. Pharm. Des. 22, 2796–2807 (2016). PubMed

Hoogenboom R, Schlaad H. Bioinspired Poly(2-oxazoline)s. Polymers (Basel). 2011;3:467–488. doi: 10.3390/polym3010467. DOI

Guillerm B, Monge S, Lapinte V, Robin JJ. How to modulate the chemical structure of polyoxazolines by appropriate functionalization. Macromol. Rapid Commun. 2012;33:1600–1612. doi: 10.1002/marc.201200266. PubMed DOI

Wyffels L, et al. μpET imaging of the pharmacokinetic behavior of medium and high molar mass 89Zr-labeled poly(2-ethyl-2-oxazoline) in comparison to poly(ethylene glycol) J. Control. Release. 2016;235:63–71. doi: 10.1016/j.jconrel.2016.05.048. PubMed DOI

Kronek J, et al. In vitro bio-immunological and cytotoxicity studies of poly(2-oxazolines) J. Mater. Sci. Mater. Med. 2011;22:1725–1734. doi: 10.1007/s10856-011-4346-z. PubMed DOI

Luxenhofer R, et al. Structure-property relationship in cytotoxicity and cell uptake of poly(2-oxazoline) amphiphiles. J. Control. Release. 2011;153:73–82. doi: 10.1016/j.jconrel.2011.04.010. PubMed DOI PMC

He Z, et al. A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity. Biomaterials. 2016;101:296–309. doi: 10.1016/j.biomaterials.2016.06.002. PubMed DOI PMC

Moreadith RW, et al. Clinical development of a poly(2-oxazoline) (POZ) polymer therapeutic for the treatment of Parkinson’s disease – Proof of concept of POZ as a versatile polymer platform for drug development in multiple therapeutic indications. Eur. Polym. J. 2017;88:524–552. doi: 10.1016/j.eurpolymj.2016.09.052. DOI

Farkas P, Korcova J, Kronek J, Bystricky S. Preparation of synthetic polyoxazoline based carrier and Vibrio cholerae O-specific polysaccharide conjugate vaccine. Eur. J. Med. Chem. 2010;45:795–9. doi: 10.1016/j.ejmech.2009.11.002. PubMed DOI

Tong J, et al. Conjugates of Superoxide Dismutase 1 with Amphiphilic Poly(2-oxazoline) Block Copolymers for Enhanced Brain Delivery: Synthesis, Characterization and Evaluation in Vitro and in Vivo. Mol. Pharm. 2013;10:360–377. doi: 10.1021/mp300496x. PubMed DOI PMC

Konradi R, Acikgoz C, Textor M. Polyoxazolines for nonfouling surface coatings - a direct comparison to the gold standard PEG. Macromol. Rapid Commun. 2012;33:1663–1676. doi: 10.1002/marc.201200422. PubMed DOI

Dworak A, et al. Poly(2-substituted-2-oxazoline) surfaces for dermal fibroblasts adhesion and detachment. J. Mater. Sci. Mater. Med. 2014;25:1149–1163. doi: 10.1007/s10856-013-5135-7. PubMed DOI

Zahoranova A, et al. Poly(2-oxazoline) Hydrogels Crosslinked with Aliphatic bis(2-oxazoline)s: Properties, Cytotoxicity, and Cell Cultivation. J. Polym. Sci. Part A Polym. Chem. 2016;54:1548–1559. doi: 10.1002/pola.28009. DOI

Lorson T, et al. A Thermogelling Supramolecular Hydrogel with Sponge-Like Morphology as a Cytocompatible Bioink. Biomacromolecules. 2017;18:2161–2171. doi: 10.1021/acs.biomac.7b00481. PubMed DOI

Hsiue G, Chiang H, Wang C, Juang T. Nonviral Gene Carriers Based on Diblock Copolymers of Poly(2-ethyl-2-oxazoline) and Linear Polyethylenimine. Bioconjug. Chem. 2006;35:781–786. doi: 10.1021/bc050317u. PubMed DOI

He Z, et al. A Low Protein Binding Cationic Poly(2-oxazoline) as Non-Viral Vector. Macromol. Biosci. 2015;15:1004–1020. doi: 10.1002/mabi.201500021. PubMed DOI PMC

Hruby M, et al. Polyoxazoline Thermoresponsive Micelles as Radionuclide Delivery Systems. Macromol. Biosci. 2010;10:916–924. doi: 10.1002/mabi.201000034. PubMed DOI

Bonné TB, Lüdtke K, Jurdan R, Štěpánek P, Papadakis CM. Aggregation behavior of amphiphilic poly(2-alkyl-2-oxazoline) diblock copolymers in aqueous solution studied by fluorescence correlation spectroscopy. Colloid Polym. Sci. 2004;282:833–843. doi: 10.1007/s00396-004-1131-2. DOI

Trzebicka B, Koseva N, Mitova V, Dworak A. Organization of poly(2-ethyl-2-oxazoline)-block-poly(2-phenyl-2-oxazoline) copolymers in water solution. Polymer (Guildf). 2010;51:2486–2493. doi: 10.1016/j.polymer.2010.03.043. DOI

Krumm C, Konieczny S, Dropalla GJ, Milbradt M, Tiller JC. Amphiphilic Polymer Conetworks Based on End Group Cross-Linked Poly(2-oxazoline) Homo- and Triblock Copolymers. Macromolecules. 2013;46:3234–3245. doi: 10.1021/ma4004665. DOI

Stoenescu R, Meier W. Asymmetric membranes from amphiphilic ABC triblock copolymers. Mol. Cryst. Liq. Cryst. 2004;417:3016–3017. doi: 10.1080/15421400490478812. PubMed DOI

Seo Y, et al. Poly(2-oxazoline) block copolymer based formulations of taxanes: Effect of copolymer and drug structure, concentration, and environmental factors. Polym. Adv. Technol. 2015;26:837–850. doi: 10.1002/pat.3556. DOI

He Z, et al. Poly(2-oxazoline) based micelles with high capacity for 3rd generation taxoids: Preparation, in vitro and in vivo evaluation. J. Control. Release. 2015;208:67–75. doi: 10.1016/j.jconrel.2015.02.024. PubMed DOI PMC

Luxenhofer R, et al. Doubly amphiphilic poly(2-oxazoline)s as high-capacity delivery systems for hydrophobic drugs. Biomaterials. 2010;31:4972–4979. doi: 10.1016/j.biomaterials.2010.02.057. PubMed DOI PMC

Milonaki Y, Kaditi E, Pispas S, Demetzos C. Amphiphilic gradient copolymers of 2-methyl- and 2-phenyl-2-oxazoline: Self-organization in aqueous media and drug encapsulation. J. Polym. Sci. Part A Polym. Chem. 2012;50:1226–1237. doi: 10.1002/pola.25888. DOI

Lübtow MM, Hahn L, Haider MS, Luxenhofer R. Drug Specificity, Synergy and Antagonism in Ultrahigh Capacity Poly(2-oxazoline)/Poly(2-oxazine) based Formulations. J. Am. Chem. Soc. 2017;139:10980–10983. doi: 10.1021/jacs.7b05376. PubMed DOI

Schulz A, et al. Drug-Induced Morphology Switch in Drug Delivery Systems Based on Poly(2-oxazoline)s. ACS Nano. 2014;8:2686–2696. doi: 10.1021/nn406388t. PubMed DOI PMC

Kempe K, et al. Multifunctional Poly(2-oxazoline) Nanoparticles for Biological Applications. Macromol. Rapid Commun. 2010;31:1869–1873. doi: 10.1002/marc.201000283. PubMed DOI

Schubert, U. S., Hartlieb, M. & Kempe, K. Covalently cross-linked poly(2-oxazoline) materials for biomedical applications - from hydrogels to self-assembled and templated structures. J. Mater. Chem. B3, 526–538 (2015). PubMed

Marin A, et al. Drug delivery in pluronic micelles: Effect of high-frequency ultrasound on drug release from micelles and intracellular uptake. J. Control. Release. 2002;84:39–47. doi: 10.1016/S0168-3659(02)00262-6. PubMed DOI

Zahoranová A, Mrlík M, Tomanová K, Kronek J, Luxenhofer R. ABA and BAB Triblock Copolymers Based on 2-Methyl-2-oxazoline and 2-n-Propyl-2-oxazoline: Synthesis and Thermoresponsive Behavior in Water. Macromol. Chem. Phys. 2017;218:1–12. doi: 10.1002/macp.201700031. DOI

Grube M, Leiske MN, Schubert US, Nischang I. POx as an Alternative to PEG? A Hydrodynamic and Light Scattering Study. Macromolecules. 2018;51:1905–1916. doi: 10.1021/acs.macromol.7b02665. DOI

Yalkowsky, S. H., He, Y. & Jain, P. Handbook of Aqueous Solubility Data (2010).

Janas C, Mostaphaoui Z, Schmiederer L, Bauer J, Wacker MG. Novel polymeric micelles for drug delivery: Material characterization and formulation screening. Int. J. Pharm. 2016;509:197–207. doi: 10.1016/j.ijpharm.2016.05.029. PubMed DOI

Yang J, Yan J, Zhou Z, Amsden BG. Dithiol-PEG-PDLLA micelles: Preparation and evaluation as potential topical ocular delivery vehicle. Biomacromolecules. 2014;15:1346–1354. doi: 10.1021/bm4018879. PubMed DOI

Wu Q, et al. Thermosensitive hydrogel containing dexamethasone micelles for preventing postsurgical adhesion in a repeated-injury model. Sci. Rep. 2015;5:13553. doi: 10.1038/srep13553. PubMed DOI PMC

Wang Q, et al. Targeted delivery of low-dose dexamethasone using PCL-PEG micelles for effective treatment of rheumatoid arthritis. J. Control. Release. 2016;230:64–72. doi: 10.1016/j.jconrel.2016.03.035. PubMed DOI

Nidhi K, Indrajeet S, Khushboo M, Gauri K, Sen DJ. Hydrotropy: A promising tool for solubility enhancement: A review. Int. J. Drug Dev. Res. 2011;3:26–33.

Wang Y, et al. Effective improvement of the neuroprotective activity after spinal cord injury by synergistic effect of glucocorticoid with biodegradable amphipathic nanomicelles. Drug Deliv. 2017;24:391–401. doi: 10.1080/10717544.2016.1256003. PubMed DOI PMC

Kumi BC, Hammouda B, Greer SC. Self-assembly of the triblock copolymer 17R4 poly(propylene oxide)14–poly(ethylene oxide)24– poly(propylene oxide)14 in D2O. J. Colloid Interface Sci. 2014;434:201–207. doi: 10.1016/j.jcis.2014.07.049. PubMed DOI

Xu R, Winnik Ma, Hallett FR, Riess G, Croucher MD. Light-scattering study of the association behavior of styrene-ethylene oxide block copolymers in aqueous solution. Macromolecules. 1991;24:87–93. doi: 10.1021/ma00001a014. DOI

Fetsch C, Gaitzsch J, Messager L, Battaglia G, Luxenhofer R. Self-Assembly of Amphiphilic Block Copolypeptoids – Micelles, Worms and Polymersomes. Sci. Rep. 2016;6:33491. doi: 10.1038/srep33491. PubMed DOI PMC

Krumm C, et al. Well-Defined Amphiphilic Poly(2-oxazoline) ABA-Triblock Copolymers and Their Aggregation Behavior in Aqueous Solution. Macromol. Rapid Commun. 2012;33:1677–1682. doi: 10.1002/marc.201200192. PubMed DOI

Gourevich D, et al. Ultrasound-mediated targeted drug delivery with a novel cyclodextrin-based drug carrier by mechanical and thermal mechanisms. J. Control. Release. 2013;170:316–324. doi: 10.1016/j.jconrel.2013.05.038. PubMed DOI

Siepmann J, Siepmann F. Mathematical modeling of drug delivery. Int. J. Pharm. 2008;364:328–343. doi: 10.1016/j.ijpharm.2008.09.004. PubMed DOI

Nichols JW, Bae YH. Odyssey of a cancer nanoparticle: from injection site to site of action. Nano Today. 2012;7:606–618. doi: 10.1016/j.nantod.2012.10.010. PubMed DOI PMC

Wurth S, et al. Long-term usability and bio-integration of polyimide-based intra-neural stimulating electrodes. Biomaterials. 2017;122:114–129. doi: 10.1016/j.biomaterials.2017.01.014. PubMed DOI

Ricotti L, Assaf T, Dario P, Menciassi A. Wearable and implantable pancreas substitutes. J. Artif. Organs. 2013;16:9–22. doi: 10.1007/s10047-012-0660-6. PubMed DOI

Morais JM, Papadimitrakopoulos F, Burgess DJ. Biomaterials/tissue interactions: possible solutions to overcome foreign body response. AAPS J. 2010;12:188–196. doi: 10.1208/s12248-010-9175-3. PubMed DOI PMC

Witte H, Seeliger W. Cyclische Imidsaureester aus Nitrilen und Aminoalkoholen. Justus Liebigs Ann. Chem. 1974;6:996–1009. doi: 10.1002/jlac.197419740615. DOI

Néry L, Lefebvre H, Fradet A. Kinetic and Mechanistic Studies of Carboxylic Acid-Bisoxazoline Chain-Coupling Reactions. Macromol. Chem. Phys. 2003;204:1755–1764. doi: 10.1002/macp.200350036. DOI

Petrova S, et al. Novel poly(ethylene oxide monomethyl ether)-b-poly(ε-caprolactone) diblock copolymers containing a pH-acid labile ketal group as a block linkage. Polym. Chem. 2014;5:3884–3893. doi: 10.1039/C4PY00114A. DOI

Effect of Dexamethasone on Thermoresponsive Behavior of Poly(2-Oxazoline) Diblock Copolymers