Acoustically Activated Micellar Drug Delivery

University Of Utah, Salt Lake City UT

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Abstract

The goal of this project is to develop a novel chemotherapeutic modality for the ultrasound image-guided targeted tumor therapy. This is realized by developing a new class of agents that combine the properties of a drug carrier and ultrasound contrast agent in a nano- or micro-particle system. The system comprises a mixture of drug-loaded polymeric micelles and nano- or micro-emulsion droplets stabilized by the same or different biodegradable block copolymer. The nano- or micro-emilsion droplets convert into microbubbles in situ upon heating to physiological temperatures. Upon injection, the drug-loaded polymeric micelles cross the tumor vasculature and accumulate in the tumor interstitium while the microbubbles remain in circulation and can be molecularly targeted to a neovascular endothelium of primary tumors and micrometastases. The designed systems are highly echogenic, which allows contrast-enhanced diagnostic tumor imaging prior to therapy. Following tumor imaging, therapeutic ultrasound is directed to tumor to effectively release drug from the micelles and nano/microbubbles and enhance intracellular drug uptake. The designed microbubbles combine four important functions: (i) drug carriers; (ii) enhancers of drug release from the carrier; enhancers of intracellular drug uptake by tumor cells; and (iii) ultrasound contrast agents. Specific Aims include: 1. Characterize novel imaging/delivery systems with respect to phase state, particle size, drug loading and release. 2. Measure and optimize ultrasound responsiveness (cavitation properties) of drug-loaded microbubbles depending on the type of the stabilizing copolymer, bubble size, and therapeutic ultrasound parameters. 3. Optimize ultrasound parameters and drug delivery properties of the micelle/microparticle systems using breast cancer tumor model. 4. Test and optimize ultrasound imaging properties of the designed systems. 5. Synthesize molecularly targeted nano/microparticle systems by conjugating VEGF to a bubble-stabilizing copolymer. Measure microbubble retention by neovasculature endothelial cells. Relevance: The development of dual-modality imaging/chemotherapy drug delivery systems for use with dual-modality imaging/treatment ultrasound instruments is very timely. The proposed imaging/treatment modality avoids limitations associated with current ultrasonic ablative therapies and is expected to reduce side effects of chemotherapy and enhance treatment outcome and quality of life of cancer patients.