Abstract 19114: Ultrasound-targeted Destruction of Nucleic-acid Loaded Microbubbles Enhances Payload Delivery at the Treatment Site: A Quantitative Comparison of Delivery Strategies
Background: Custom designed microbubbles (MB) can carry therapeutic agents to target tissues. It has been posited, but not proven, that when MB are exposed to ultrasound (US) directed at the target, therapeutic agents are locally released and concentrated at the target site. Accordingly, we studied local delivery using MB and US, utilizing STAT3 transcription factor decoy as a model therapeutic, which has previously been shown to suppress tumor growth by inhibiting STAT3 signaling.
Methods: Cationic MB loaded with P32 labeled STAT3 decoy (8 μg per 1х109 MBs) were intravenously infused into mice bearing squamous cell carcinoma (n=6). US was delivered to the tumor with a clinical scanner (MI setting 1.6; 4 frames/burst, burst interval 2 s, f=1.3MHz) during a 20 min MB infusion and 5 min thereafter. Tumors were harvested at 5 min or 8 hrs after therapy and analyzed for decoy content. Intact decoy was isolated by ethanol precipitation, quantified by scintillation counting, and expressed as percent input signal/gram tissue. Controls (no US) received decoy alone or decoy-loaded MB (decoy-MB).
Results: 5 min after treatment, total decoy in the tumor was higher in the decoy-only group (0.74±0.20%/g) compared to decoy-MB (0.24±0.08%/g) or decoy-MB+US groups (0.46±0.15%/g; p<0.01). However, 8 hrs after therapy, total decoy concentration in decoy-MB+US treated tumors more than doubled, whereas concentrations in the control groups decreased or remained the same, such that decoy content in decoy-MB+US tumors was 2-3 fold higher (1.00±0.35%/g) compared to decoy-MB (0.32±0.07%/g) or decoy only (0.51±0.21%/g; p<0.03). Similarly, at 8 hrs, tumor concentrations of intact decoy were 2-3 fold higher in decoy-MB+US treated mice (0.26±0.16%/g) compared to decoy-MB (0.09±0.08%/g) or decoy alone (0.09±0.02%/g).
Conclusions: To our knowledge, this is the first comparative quantification of molecular therapeutic delivery to target tissue resulting from directed US-induced destruction of circulating MBs. Decoy-MB + US treatment enhanced transcription factor decoy deposition in target tissue at 8 hours compared to control groups subjected to non-US targeted delivery strategies. These data substantiate the rationale for targeted therapeutics using US and loaded MBs.
Author Disclosures: A.R. Carson: None. J.A. Kopechek: None. X. Chen: None. C.F. McTiernan: None. L. Lavery: None. B. Hasjim: None. M. Sen: None. J.R. Grandis: None. F.S. Villanueva: None.
- © 2014 by American Heart Association, Inc.