Abstract 2469: Image-guided focused ultrasound-mediated drug delivery for improved cancer treatment

Abstract

Abstract Introduction: The first option for cancer treatment is often chemotherapy. However, studies have shown that only 1% of the injected dose reaches the target cancer as the tumor microenvironment presents a physical barrier for optimal drug delivery. Focused ultrasound (FUS) in combination with microbubble (MB) contrast agents is an emerging therapy to improve drug delivery by temporarily increasing microvascular permeability. This research details the development and testing of a novel ultrasound (US) image-guided FUS system and method for enhancing drug delivery to tumor tissue and volume space with comparison to a 2-dimensional (2-D) US therapeutic technology. Methods: Real-time US therapy was implemented on a programmable US system (Vantage 256, Verasonics Inc) equipped with a dual US transducer configuration for interleaved anatomical imaging and volumetric treatment delivery (HIFU-Plex, Sonic Concepts Inc). Both US imaging and therapeutic transducers are co-registered 128 element arrays with center frequencies of 3.5 and 2.0 MHz, respectively. The latter is a concentric array that enables beam steering in 3-dimensional (3-D) space. US treatment was performed at a peak negative pressure of 0.7 MPa (mechanical index, MI of 0.45), pulse repetition frequency of 10 Hz, and duty cycle of 10%. BALB/c mice (N = 22, Charles River Laboratory) were implanted with 2.0 × 105 breast cancer cells (4T1, ATCC). Once tumors reached 0.6 cm in size, mice were randomly divided into a 3-D or 2-D US therapy group or sham control. US therapy was performed following an intravascular injection of microbubbles (Definity, Lantheus Medical Imaging) and IR-780 dye. Note microbubbles function as a therapeutic mediator whereas the fluorescent dye represents a surrogate small molecule drug. Live animal fluorescent imaging was performed at baseline before US therapy (0 h) and again at 1, 24, and 48 h. Following the 48 h timepoint, animals were euthanized and tumors surgically excised for ex vivo analysis. Results: 3-D US-mediated therapy improved molecular delivery to tumor tissue by 150 and 180% at 24 and 48 h, respectively, when compared to our previously established 2-D US therapeutic approach (p = 0.22) or sham therapy (p = 0.07). A similar trend was observed during ex vivo imaging of excised tumor samples treated with 3-D US therapy as compared to the 2-D US therapeutic approach (p = 0.41) or sham therapy (p = 0.04). Dye extraction further confirmed these observations (p > 0.12). Conclusions: 3-D US therapy improved molecular delivery to the tumor volume compared to our previously established 2-D US-based method as confirmed by a series of optical imaging studies. Citation Format: Ryan Margolis, Junjie Li, Lokesh Basavarajappa, Kenneth Hoyt. Image-guided focused ultrasound-mediated drug delivery for improved cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2469.