Abstract
The aim of this work is to study the kinetics of ultrasound (70 kHz) – using a kinetic model that takes into account cavitation events and drug re-encapsulation upon the cessation of the acoustic field. The simulation allowed the determination of three parameters α, β and λ that define the release and re-encapsulation behavior of this drug delivery system (DDS). The results showed that the drug release increased with increasing power density, as evidenced by the correlation between α and power density. The micelle re-assembly, quantified by the parameter β, also increased with increasing power density. The parameter λ, which is associated with the initial phase of the release process, showed a constant value regardless of the power density. The significance of these results was discussed. Additionally, a comparison between these parameters in folate-targeted and non-targeted micelles showed statistically significant differences for several power densities examined. A better understanding of the kinetics involved in this DDS is very important for the determination of the optimum ultrasound parameters to be used in future in vitro and in vivo experiments.
About the authors
Ana M. Martins is a research scientist at the Ultrasound in Cancer Research Group at American University of Sharjah. She obtained her BSc in Biochemistry and her PhD in Biochemistry/Enzymology from the University of Lisbon (Portugal). Dr. Martins has a wide research experience: after completing her PhD she spent 7 years at Virginia Polytechnic Institute and State University, first in Virginia Bioinformatics Institute, later in the Department of Biological Sciences. Dr. Martins has a systems biology approach to research, combining experimental and modeling work to understand the function of biochemical systems. Her current research interests include the development of drug delivery systems using liposomes and ultrasound as a trigger.
Rafeeq Tanbour graduated in 2012 with a BSc degree in Chemical Engineering from An-Najah National University in Nablus, Palestine. Then he moved to the United Arab Emirates in 2013 and began a MSc program in Chemical Engineering at the American University of Sharjah (AUS), and graduated in January, 2015. During his MSc studies, he focused on the use of drug delivery systems as possible cancer therapy, in particular how ultrasound can be utilized as a trigger to release drugs from polymeric micelles. He is also a member of the Ultrasound in Cancer Research Group at AUS and Jordanian Engineering Association.
Mohammed A. Elkhodiry is a Researcher in the American University of Sharjah’s Ultrasound in Cancer Research Group and a senior undergraduate Chemical and Biomedical Engineering student at the same university. His current research areas are drug delivery for chemotherapeutic treatment and regenerative liver tissue engineering. His work focuses on synthesizing protein-modified liposomal nanocarriers for targeting cancer. He is the Chairman and co-founder of the IEEE Engineering in Medicine and Biology Society (EMBS) Student Chapter at AUS.
Ghaleb A. Husseini (BSc 1995–MSc 1997–PhD 2001) graduated with a PhD in Chemical Engineering (Biomedical Engineering emphasis) from Brigham Young University in 2001 and joined the American University of Sharjah as an Assistant Professor in the Chemical Engineering Department in 2004. He was promoted to Associate Professor and Professor in 2008 and 2013, respectively. Dr. Husseini works in the area of ultrasound-activated drug delivery. His research involves sequestering chemotherapeutic agents in liposomes, micelles and other nanoparticles, and studying their controlled release triggered by ultrasound. Dr. Husseini has recently established the Ultrasound in Cancer Research Group at AUS using an internal grant. He has published 78 journal articles (in addition to one book chapter and one patent) and 42 conference papers/abstracts. He has been elected into the Distinguished Lecturer Program-IEEE-EMBS (Jan 2014–Dec 2015).
Acknowledgments
The authors would like to acknowledge the funding from the American University of Sharjah Faculty Research Grant (FRG1-2012), Patient’s Friends Committee-Sharjah, and Al Qasimi Foundation.
Conflict of interest statement: Authors state no conflict of interest. All authors have read the journal’s publication ethics and publication malpractice statement available at the journal’s website and hereby confirm that they comply with all its parts applicable to the present scientific work.
References
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69–90.10.3322/caac.20107Search in Google Scholar
2. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108.10.3322/canjclin.55.2.74Search in Google Scholar
3. Kundu B, Ghosh D, Sinha MK, Sen PS, Balla VK, Das N, et al. Doxorubicin-intercalated nano-hydroxyapatite drug-delivery system for liver cancer: an animal model. Ceram Int 2013;39:9557–66.10.1016/j.ceramint.2013.05.074Search in Google Scholar
4. Gandhi H, Patel VB, Mistry N, Patni N, Nandania J, Balaraman R. Doxorubicin mediated cardiotoxicity in rats: Protective role of felodipine on cardiac indices. Environ Toxicol Pharmacol 2013;36:787–95.10.1016/j.etap.2013.07.007Search in Google Scholar
5. Cuomo F, Mosca M, Murgia S, Avino P, Ceglie A, Lopez F. Evidence for the role of hydrophobic forces on the interactions of nucleotide-monophosphates with cationic liposomes. J Colloid Interface Sci 2013;410:146–51.10.1016/j.jcis.2013.08.013Search in Google Scholar
6. Jhaveri AM, Torchilin VP. Multifunctional polymeric micelles for delivery of drugs and siRNA. Front Pharmacol 2014;5:77.Search in Google Scholar
7. Jones M, Leroux J. Polymeric micelles – a new generation of colloidal drug carriers. Eur J Pharm Biopharm 1999;48:101–11.10.1016/S0939-6411(99)00039-9Search in Google Scholar
8. Torchilin VP. Micellar nanocarriers: pharmaceutical perspectives. Pharm Res 2007;24:1–16.10.1007/s11095-006-9132-0Search in Google Scholar
9. Blanco E, Kessinger CW, Sumer BD, Gao J. Multifunctional micellar nanomedicine for cancer therapy. Exp Biol Med (Maywood) 2009;234:123–31.10.3181/0808-MR-250Search in Google Scholar
10. Alexandridis P, Alan Hatton T. Poly(ethylene oxide) – poly(propylene oxide) – poly(ethylene oxide) block copolymer surfactants in aqueous solutions and at interfaces: thermodynamics, structure, dynamics, and modeling. Colloids Surface A: Physicochemical and Engineering Aspects 1995;96:1–46.10.1016/0927-7757(94)03028-XSearch in Google Scholar
11. Kabanov AV, Alakhov VY. Pluronic block copolymers in drug delivery: from micellar nanocontainers to biological response modifiers. Crit Rev Ther Drug Carrier Syst 2002;19:1–72.10.1615/CritRevTherDrugCarrierSyst.v19.i1.10Search in Google Scholar
12. Kabanov AV, Batrakova EV, Melik-Nubarov NS, Fedoseev NA, Dorodnich TY, Alakhov VY, et al. A new class of drug carriers: micelles of poly(oxyethylene)-poly(oxypropylene) block copolymers as microcontainers for targeting drugs from blood to brain. J Control Release 1992; 22:141–58.10.1016/0168-3659(92)90199-2Search in Google Scholar
13. Kabanov AV, Nazarova IR, Astafieva IV, Batrakova EV, Alakhov VY, Yaroslavov AA, et al. Micelle formation and solubilization of fluorescent probes in poly(oxyethylene-b-oxypropylene-b-oxyethylene) solutions. Macromolecules 1995;28:2303–14.10.1021/ma00111a026Search in Google Scholar
14. Rapoport NY, Christensen DA, Fain HD, Barrows L, Gao Z. Ultrasound-triggered drug targeting of tumors in vitro and in vivo. Ultrasonics 2004;42:943–50.10.1016/j.ultras.2004.01.087Search in Google Scholar
15. Husseini GA, Pitt WG. Ultrasonic-activated micellar drug delivery for cancer treatment. J Pharm Sci 2009;98:795–811.10.1002/jps.21444Search in Google Scholar
16. Husseini GA, Pitt WG. Micelles and nanoparticles for ultrasonic drug and gene delivery. Adv Drug Deliv Rev 2008;60:1137–52.10.1016/j.addr.2008.03.008Search in Google Scholar
17. Adams ML, Lavasanifar A, Kwon GS. Amphiphilic block copolymers for drug delivery. J Pharm Sci 2003;92:1343–55.10.1002/jps.10397Search in Google Scholar
18. Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul 2001;41:189–207.10.1016/S0065-2571(00)00013-3Search in Google Scholar
19. Husseini GA, Pitt WG. The use of ultrasound and micelles in cancer treatment. J Nanosci Nanotechnol 2008;8:2205–15.10.1166/jnn.2008.225Search in Google Scholar
20. Kabanov AV, Batrakova EV, Alakhov VY. Pluronic block copolymers for overcoming drug resistance in cancer. Adv Drug Deliv Rev 2002;54:759–79.10.1016/S0169-409X(02)00047-9Search in Google Scholar
21. Husseini GA, Christensen DA, Rapoport NY, Pitt WG. Ultrasonic release of doxorubicin from Pluronic P105 micelles stabilized with an interpenetrating network of N,N-diethylacrylamide. J Control Release 2002;83:303–5.10.1016/S0168-3659(02)00203-1Search in Google Scholar
22. Gaucher G, Dufresne MH, Sant VP, Kang N, Maysinger D, Leroux JC. Block copolymer micelles: preparation, characterization and application in drug delivery. J Control Release 2005;109:169–88.10.1016/j.jconrel.2005.09.034Search in Google Scholar
23. Torchilin V. Multifunctional and stimuli-sensitive pharmaceutical nanocarriers. Eur J Pharm Biopharm 2009;71:431–44.10.1016/j.ejpb.2008.09.026Search in Google Scholar
24. Yu MK, Park J, Jon S. Targeting strategies for multifunctional nanoparticles in cancer imaging and therapy. Theranostics 2012;2:3–44.10.7150/thno.3463Search in Google Scholar
25. Byrne JD, Betancourt T, Brannon-Peppas L. Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv Drug Deliv Rev 2008;60:1615–26.10.1016/j.addr.2008.08.005Search in Google Scholar
26. Sethuraman VA, Bae YH. TAT peptide-based micelle system for potential active targeting of anti-cancer agents to acidic solid tumors. J Control Release 2007;118:216–24.10.1016/j.jconrel.2006.12.008Search in Google Scholar
27. Hilgenbrink AR, Low PS. Folate receptor-mediated drug targeting: from therapeutics to diagnostics. J Pharm Sci 2005;94:2135–46.10.1002/jps.20457Search in Google Scholar
28. Leamon CP, Reddy JA. Folate-targeted chemotherapy. Adv Drug Deliv Rev 2004;56:1127–41.10.1016/j.addr.2004.01.008Search in Google Scholar
29. Shen Z, Li Y, Kohama K, Oneill B, Bi J. Improved drug targeting of cancer cells by utilizing actively targetable folic acid-conjugated albumin nanospheres. Pharmacol Res 2011;63:51–8.10.1016/j.phrs.2010.10.012Search in Google Scholar
30. Sudimack J, Lee RJ. Targeted drug delivery via the folate receptor. Adv Drug Deliv Rev 2000;41:147–62.10.1016/S0169-409X(99)00062-9Search in Google Scholar
31. Zhao X, Li H, Lee RJ. Targeted drug delivery via folate receptors. Expert Opin Drug Deliv 2008;5:309–19.10.1517/17425247.5.3.309Search in Google Scholar PubMed
32. Yoo HS, Park TG. Folate receptor targeted biodegradable polymeric doxorubicin micelles. J Control Release 2004;96:273–83.10.1016/j.jconrel.2004.02.003Search in Google Scholar
33. Hayama A, Yamamoto T, Yokoyama M, Kawano K, Hattori Y, Maitani Y. Polymeric micelles modified by folate-PEG-lipid for targeted drug delivery to cancer cells in vitro. J Nanosci Nanotechnol 2008;8:3085–90.10.1166/jnn.2008.093Search in Google Scholar
34. Husseini GA, Pitt WG, Martins AM. Ultrasonically triggered drug delivery: breaking the barrier. Colloids Surf B Biointerfaces 2014;123C:364–86.10.1016/j.colsurfb.2014.07.051Search in Google Scholar
35. Husseini GA, Velluto D, Kherbeck L, Pitt WG, Hubbell JA, Christensen DA. Investigating the acoustic release of doxorubicin from targeted micelles. Colloids Surf, B 2013;101:153–5.10.1016/j.colsurfb.2012.05.025Search in Google Scholar
36. Kim D, Gao ZG, Lee ES, Bae YH. In vivo evaluation of doxorubicin-loaded polymeric micelles targeting folate receptors and early endosomal pH in drug-resistant ovarian cancer. Mol Pharm 2009;6:1353–62.10.1021/mp900021qSearch in Google Scholar
37. Husseini GA, Stevenson-Abouelnasr D, Pitt WG, Assaleh KT, Farahat LO, Fahadi J. Kinetics and Thermodynamics of Acoustic Release of Doxorubicin from Non-stabilized polymeric Micelles. Colloids Surf, A 2010;359:18–24.10.1016/j.colsurfa.2010.01.044Search in Google Scholar
38. Stevenson-Abouelnasr D, Husseini GA, Pitt WG. Further investigation of the mechanism of Doxorubicin release from P105 micelles using kinetic models. Colloids Surf, B 2007;55:59–66.10.1016/j.colsurfb.2006.11.006Search in Google Scholar
39. Husseini GA, Myrup GD, Pitt WG, Christensen DA, Rapoport NY. Factors affecting acoustically triggered release of drugs from polymeric micelles. J Control Release 2000;69:43–52.10.1016/S0168-3659(00)00278-9Search in Google Scholar
40. Haynes W. Tukey’s range test. In: Dubitzky W, Wolkenhauer O, Cho K-H, Yokota H, editors. Encyclopedia of systems biology. New York: Springer, 2013:2303–2304.Search in Google Scholar
41. Kramer CYC. Extension of multiple range tests to group means with unequal numbers of replications. Biometrics 1956;12:307–10.10.2307/3001469Search in Google Scholar
42. Staples BJ, Pitt WG, Roeder BL, Husseini GA, Rajeev D, Schaalje GB. Distribution of doxorubicin in rats undergoing ultrasonic drug delivery. J Pharm Sci 2010;99:3122–31.10.1002/jps.22088Search in Google Scholar PubMed PubMed Central
43. Staples BJ, Roeder BL, Pitt WG. Quantification of doxorubicin concentration in rat tissues using polymeric micelles in ultrasonic-drug delivery. In: Annual Meeting of the Society for Biomaterials; 2006. Pittsburgh, PA, USA, 2006:476.Search in Google Scholar
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