9. ULTRASOUND RUPTURED LIPOSOMES FOR LOCAL DELIVERY OF THERAPEUTIC BIOMOLECULES

Department: Bioengineering
Faculty Advisor(s): Sadik Esener

Primary Student
Name: Michael Jerome Benchimol
Email: mbenchim@ucsd.edu
Phone: 619-699-9620
Grad Year: 2012

Abstract
Achieving tissue-specific delivery of anti-cancer drugs is critical to overcoming the dose-limiting side effects of chemotherapy. Ultrasound is a safe, non-invasive means for controlling the fate of the drugs independent of tumor biochemistry. Focused ultrasound is capable of depositing energy deep within the body with millimeter precision and without causing adverse bioeffects. Liposomes have been engineered to rupture and release their contents in response to ultrasound, granting external control over when and where the drug is released. This has been enabled by the incorporation of nanoparticles which interact with ultrasound to cause strong forces, sensitizing their vicinity. The carriers containing these sensitizers can circulate throughout the body and release their payload where ultrasound is applied. Adjacent tissues will not experience a high enough pressure to cause drug release, since the acoustic energy will be concentrated in all 3 dimensions. In vitro experiments have visually and quantitatively demonstrated the rapid and localized release of entrapped molecules. Localized in vivo deposition of fluorescent molecules has been achieved by intravenous administration of liposomes and application of focused ultrasound to the ear of a mouse. As a platform vehicle for many possible payloads, this particle offers the flexibility necessary to complement the ongoing progress in drug discovery. Beyond small molecule payloads, the delivery of biomolecules and nucleic acids is of particular interest. One strategy being pursued is the deposition of membrane bound enzyme for prodrug therapy. Foreign enzyme has been conjugated and hidden on the inner liposome membrane and can be exposed with focused ultrasound to cause an increase in enzyme activity. Unstable membrane fragments generated during rupture have the potential to fuse with nearby cells, creating a stable presence of enzyme in the tumor. Additionally, the ultrasound-ruptured liposome can address a major challenge in nucleic acid delivery. For efficient delivery, a particle must be both long circulating and taken up by the target cells. Without the appropriate receptor to trigger uptake, an alternative mechanism is needed to achieve both properties. The liposome protects the transfection complexes and allows long circulation until reaching the tumor where the particles will be exposed and subsequently taken up by nearby cells. Preliminary results show that the liposome can hide a plasmid-transfection reagent complex and breaking the liposome results in increased transfection efficiency and gene expression.

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