Polymer ultrasound contrast agents for targeted drug and gene delivery
Abstract
Ultrasound contrast agents (UCA) are encapsulated gas microbubbles that can respond to ultrasound by rapidly expanding and contracting (exhibiting cavitation) while also reflecting the acoustic signal. This ultrasound induced cavitation can be utilized to increase the permeability of blood vessels or to create transient pores in cell membranes. It may be possible to take advantage of these biological effects for ultrasound targeted drug and gene delivery. Microbubbles made with a poly(lactic acid) shell and loaded with Doxorubicin (Dox) were previously developed in this lab and shown to rupture into 200-400nm drug loaded polymer fragments when exposed to ultrasound. The ability of this platform to provide ultrasound-targeted drug delivery in vivo was examined with a rat hepatocellular carcinoma model and compared with free Dox. Microbubbles were able to deliver significantly more drug to the tumor compared to free Dox (2.491 ± 0.501%/g tissue, vs. 0.373 ± 0.087%/g tissue, p= 0.047). However, significantly higher drug levels were also found in the spleen and liver of animals treated with microbubbles compared to free Dox. Microbubbles were also loaded with more hydrophobic drugs including paclitaxel and docetaxel. Total payloads of 129.5 ± 1.8 and 80.8 ± 3.0[mu]g drug/mg UCA were achieved for paclitaxel and docetaxel loaded microbubbles while maintaining the agents' acoustic activities. Both agents were able to provide a sustained in vitro release of drug from the shell over…
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