Co-administration of Microbubbles and Drugs in Ultrasound-Assisted Drug Delivery: Comparison with Drug-Carrying Particles
There are two alternative approaches to ultrasound-assisted drug delivery. First, the drug can be entrapped into or attached onto the ultrasound-responsive particles and administered in the vasculature, to achieve ultrasound-triggered drug release from the particles and localized tissue deposition in response to ultrasound treatment of the target zone. Second, the drug can be co-administered with the microbubbles or other sonosensitive particles. In this case, the action of ultrasound on the particles (which act as cavitation nuclei) results in the transient improvement of permeability of the physiological barriers, so that the circulating drug can exit the bloodstream and get into the target tissues and cells. We discuss and compare both of these approaches, their characteristic advantages and disadvantages for the specific drug delivery scenarios. Clearly, the system based on the off-label use of the existing approved microbubbles and drugs (or drug carriers) will have a chance of getting to clinical trials faster and with lesser resources spent. However, if a superior curative potential of a sonosensitive drug carrier is proven, and formulation stability problems are addressed properly, this approach may find its way to practical use, especially for nucleic acid delivery scenarios.
KeywordsCo-administration of microbubbles Drug-carrying particles Drug delivery Ultrasound
This study was supported in part via NIH R21 EB016752.
- Chen S, Bastarrachea RA, Roberts BJ, Voruganti VS, Frost PA, Nava-Gonzalez EJ, Arriaga-Cazares HE, Chen J, Huang P, DeFronzo RA, Comuzzie AG, Grayburn PA (2014) Successful beta cells islet regeneration in streptozotocin-induced diabetic baboons using ultrasound-targeted microbubble gene therapy with cyclinD2/CDK4/GLP1. Cell Cycle 13:1145–1151PubMedCentralCrossRefPubMedGoogle Scholar
- Gemzar (1996) Prescribing information: http://pi.lilly.com/us/gemzar.pdf. Accessed 10 Jan 2015
- Koebis M, Kiyatake T, Yamaura H, Nagano K, Higashihara M, Sonoo M, Hayashi Y, Negishi Y, Endo-Takahashi Y, Yanagihara D, Matsuda R, Takahashi MP, Nishino I, Ishiura S (2013) Ultrasound-enhanced delivery of morpholino with Bubble liposomes ameliorates the myotonia of myotonic dystrophy model mice. Sci Rep 3:2242PubMedCentralCrossRefPubMedGoogle Scholar
- Meijering BD, Juffermans LJ, van Wamel A, Henning RH, Zuhorn IS, Emmer M, Versteilen AM, Paulus WJ, van Gilst WH, Kooiman K, de Jong N, Musters RJ, Deelman LE, Kamp O (2009) Ultrasound and microbubble-targeted delivery of macromolecules is regulated by induction of endocytosis and pore formation. Circ Res 104:679–687CrossRefPubMedGoogle Scholar
- Nance E, Timbie K, Miller GW, Song J, Louttit C, Klibanov AL, Shih TY, Swaminathan G, Tamargo RJ, Woodworth GF, Hanes J, Price RJ (2014a) Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound. J Control Release 189:123–132PubMedCentralCrossRefPubMedGoogle Scholar
- Panje CM, Wang DS, Pysz MA, Paulmurugan R, Ren Y, Tranquart F, Tian L, Willmann JK (2012) Ultrasound-mediated gene delivery with cationic versus neutral microbubbles: effect of DNA and microbubble dose on in vivo transfection efficiency. Theranostics 2:1078–1091PubMedCentralCrossRefPubMedGoogle Scholar
- Phillips LC, Dhanaliwala AH, Klibanov AL, Hossack JA, Wamhoff BR (2011) Focused ultrasound-mediated drug delivery from microbubbles reduces drug dose necessary for therapeutic effect on neointima formation--brief report. Arterioscler Thromb Vasc Biol 31:2853–2855PubMedCentralCrossRefPubMedGoogle Scholar
- Rapoport N, Nam KH, Gupta R, Gao Z, Mohan P, Payne A, Todd N, Liu X, Kim T, Shea J, Scaife C, Parker DL, Jeong EK, Kennedy AM (2011) Ultrasound-mediated tumor imaging and nanotherapy using drug loaded, block copolymer stabilized perfluorocarbon nanoemulsions. J Control Release 153:4–15PubMedCentralCrossRefPubMedGoogle Scholar
- Rodallec M, Vilgrain V, Couvelard A, Rufat P, O’Toole D, Barrau V, Sauvanet A, Ruszniewski P, Menu Y (2006) Endocrine pancreatic tumours and helical CT: contrast enhancement is correlated with microvascular density, histoprognostic factors and survival. Pancreatology 6:77–85CrossRefPubMedGoogle Scholar
- Sirsi SR, Hernandez SL, Zielinski L, Blomback H, Koubaa A, Synder M, Homma S, Kandel JJ, Yamashiro DJ, Borden MA (2012) Polyplex-microbubble hybrids for ultrasound-guided plasmid DNA delivery to solid tumors. J Control Release 157(2):224–234. doi: 10.1016/j.jconrel.2011.09.071 CrossRefPubMedGoogle Scholar
- Tlaxca JL, Rychak JJ, Ernst PB, Konkalmatt PR, Shevchenko TI, Pizarro TT, Rivera-Nieves J, Klibanov AL, Lawrence MB (2013) Ultrasound-based molecular imaging and specific gene delivery to mesenteric vasculature by endothelial adhesion molecule targeted microbubbles in a mouse model of Crohn's disease. J Control Release 165:216–225PubMedCentralCrossRefPubMedGoogle Scholar
- Un K, Kawakami S, Yoshida M, Higuchi Y, Suzuki R, Maruyama K, Yamashita F, Hashida M (2012) Efficient suppression of murine intracellular adhesion molecule-1 using ultrasound-responsive and mannose-modified lipoplexes inhibits acute hepatic inflammation. Hepatology 56:259–269CrossRefPubMedGoogle Scholar