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Int. J. Mol. Sci. 2013, 14(5), 9737-9750; doi:10.3390/ijms14059737
Article

Ultrasound Targeted Microbubble Destruction Stimulates Cellular Endocytosis in Facilitation of Adeno-Associated Virus Delivery

1,†
, 1,†
, 2
, 2
, 3
 and 1,*
1 Department of Ultrasound, Shanghai Jiaotong University Affiliated First People's Hospital, 100 Haining Road, Shanghai 200080, China 2 Experimental Research Center, Shanghai Jiaotong University Affiliated First People's Hospital, 100 Haining Road, Shanghai 200080, China 3 Department of Instrumentation Science and Engineering, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai 200240, China These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 7 March 2013 / Revised: 24 April 2013 / Accepted: 27 April 2013 / Published: 7 May 2013
(This article belongs to the Section Bioinorganic Chemistry)
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Abstract

The generally accepted mechanism for ultrasound targeted microbubble destruction (UTMD) to enhance drug and gene delivery is through sonoporation. However, passive uptake of adeno-associated virus (AAV) into cells following sonoporation does not adequately explain observations of enhanced transduction by UTMD. This study investigated alternative mechanisms of UTMD enhancement in AAV delivery. UTMD significantly enhanced transduction efficiency of AAV in a dose-dependent manner. UTMD stimulated a persistent uptake of AAV into the cytoplasm and nucleus. This phenomenon occurred over several hours, suggesting that some viral particles are endocytosed by cells rather than exclusively passing through pores created by sonoporation. Additionally, UTMD enhanced clathrin expression and accumulation at the plasma membrane suggesting greater clathrin-mediated endocytosis following UTMD. Transmission electron microscopy (TEM) revealed that UTMD stimulated formation of clathrin-coated pits (CPs) and uncoated pits (nCPs). Furthermore, inhibition of clathrin-mediated endocytosis partially blocked the enhancement of AAV uptake following UTMD. The results of this study implicate endocytosis as a mechanism that contributes to UTMD-enhanced AAV delivery.
Keywords: ultrasound; microbubbles; endocytosis; adeno-associated virus; sonoporation ultrasound; microbubbles; endocytosis; adeno-associated virus; sonoporation
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Jin, L.-F.; Li, F.; Wang, H.-P.; Wei, F.; Qin, P.; Du, L.-F. Ultrasound Targeted Microbubble Destruction Stimulates Cellular Endocytosis in Facilitation of Adeno-Associated Virus Delivery. Int. J. Mol. Sci. 2013, 14, 9737-9750.

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