Cancer chemotherapy employs systemic delivery of antitumor drugs with limited specificity, causing toxic side effects in normal tissues and inefficient/insufficient drug delivery to tumor cells, leading to recurrence. To address these problems, liposomal stealth drug delivery systems (e.g. Doxil) have been developed to selectively accumulate in tumors, permitting enhanced intratumoral drug delivery while reducing drug exposure and toxicity to normal tissue. However, available clinically-approved nanocarriers release their payload only within the perivascular space of tumors, impeding or preventing distribution to poorly-perfused remote cells in the tumor core that contribute to drug resistance and tumor recurrence. Thus the tumor-directed dose escalations achieved to date via stealth liposome technology have not yet improved treatment efficacy. To overcome these limitations, the long-term goal of our research is to optimize and provide uniform intratumoral delivery of antitumor drugs with real-time control, thereby providing physicians more precise dosing control. In preliminary studies we achieved improved intratumoral distribution of systemically administered doxorubicin (Dox), within tumor periphery and core alike, by inducing rapid intravascular Dox release from Low Temperature-Sensitive Liposomes (LTSL), a technology that permits induction of liposomal drug release using mild local elevations in tissue temperature. The objective of the proposed project is to test the feasibility of and validate an innovative approach for homogeneous, tightly-controlled intratumor delivery of antineoplastic drugs using novel ultrasound-imageable echogenic LTSL (E-LTSL), that will permit image-guided drug delivery (IGDD)-based therapy. We hypothesize that E-LTSL will permit real-time control and monitoring of the release of liposome-encapsulated drugs. By combination with local hyperthermia applied precisely using High-intensity Focused Ultrasound (HIFU), this will allow thermally-induced liposomal drug release, providing enhanced intratumoral drug delivery to otherwise inaccessible tumor cells. The concept builds upon our expertise in biodegradable LTSL synthesis and their application in magnetic resonance-high intensity focused ultrasound- based IGDD.
The Specific Aims are: 1: To optimize in vitro and in vivo stability, release and imageability of E- LTSL. 2: To determine E-LTSL-mediated doxorubicin delivery, distribution and efficacy in vivo, using a mouse model. This cutting-edge translational research will enhance the research environment and capabilities of our Center for Veterinary Health Sciences at Oklahoma State University, will provide a rich training and learning experience for our graduate and undergraduate students, and will provide an innovative pathway to improve cancer chemotherapy outcomes by strategically modifying currently approved therapies.
Title: Image-guided tumor drug delivery by ultrasound-detected heat-released liposomes. This proposal aims to encapsulate ultrasound contrast agent on our established LTSL nanoplatform for achieving spatio-temporal control of drug distribution in tumor. The investigation of ultrasound-mediated Image Guided Drug Delivery (IGDD) is especially attractive for its relatively greater simplicity, cost- effectiveness, speed of image acquisition compared to Magnetic Resonance guided HIFU (MR-HIFU), and for their ability to permeabilize cell membrane to enhance drug extravasations. Success of this study will be a milestone in IGDD for providing real time control of drug delivery, better response to treatment and prevent tumor recurrence.