In this proposal, we seek to develop a set of new tools to assess and enhance the efficacy of anti-cancer therapies that have immediate clinical relevance. In particular, we have developed and embedded methods for real-time quantitative parametric ultrasound imaging of vascular volume/density and flow rate to assess tumor therapies in a clinical scanner and will evaluate and validate those methods here.
Our aims for the assessment of therapeutic efficacy include: evaluate the use of ultrasound methods to estimate flow rate and vascular volume/density in the assessment of therapeutic response;migrate the methods to real-time, on-scanner measurement;and use ultrasound feedback together with histology to optimize treatment with a cocktail of appropriate drugs. Further, we endeavor to enhance therapeutic efficacy by increasing vascular permeability and nanoparticle accumulation using ultrasound. In our initial studies using 2-minute insonation with a low thermal dose, we found that accumulation of liposomes in an insonified tumor increases ~three-fold to as much as 22%ID/g and the accumulation within insonified muscle or lymph nodes increased 3-10 fold. At our site and others the combination of ablative therapies and nanoparticle drug administration has already begun and as MR-guided ultrasound enters the clinic, this combination will be used more frequently.
Our aims for the enhancement of efficacy with ultrasound are to: determine the mechanism for ultrasound-enhanced increases in vascular permeability;maximize ultrasound enhancement of the accumulation of particles in a tumor and surrounding tissue;establish a pharmacokinetic model that describes ultrasound-enhanced permeability;and compare the efficacy of particle injection immediately before and after ultrasound and incorporate US- enhanced delivery into a strategy that includes an anti-angiogenic drug, chemotherapeutics an ultrasound monitoring of response.
Currently, one in 4 deaths in the United States is due to cancer. Many new therapeutic strategies can be employed;however, efficient methods to test these strategies are required. We are completing the development of an ultrasound-based strategy for the assessment of therapeutic efficacy that provides quantitative, repeatable and user-independent measures. Further, we are developing methods to enhance therapeutic efficacy using ultrasound by enhancing the accumulation of drug within the tumor.
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|Shapiro, Galina; Wong, Andrew W; Bez, Maxim et al. (2016) Multiparameter evaluation of in vivo gene delivery using ultrasound-guided, microbubble-enhanced sonoporation. J Control Release 223:157-64|
|Wong, Andrew W; Fite, Brett Z; Liu, Yu et al. (2016) Ultrasound ablation enhances drug accumulation and survival in mammary carcinoma models. J Clin Invest 126:99-111|
|Liu, Jingfei; Foiret, Josquin; Stephens, Douglas N et al. (2016) Development of a spherically focused phased array transducer for ultrasonic image-guided hyperthermia. Phys Med Biol 61:5275-96|
|Seo, Jai Woong; Ang, JooChuan; Mahakian, Lisa M et al. (2015) Self-assembled 20-nm (64)Cu-micelles enhance accumulation in rat glioblastoma. J Control Release 220:51-60|
|Seo, Jai Woong; Mahakian, Lisa M; Tam, Sarah et al. (2015) The pharmacokinetics of Zr-89 labeled liposomes over extended periods in a murine tumor model. Nucl Med Biol 42:155-63|
|Liu, Yu; Fite, Brett Z; Mahakian, Lisa M et al. (2015) Concurrent Visualization of Acoustic Radiation Force Displacement and Shear Wave Propagation with 7T MRI. PLoS One 10:e0139667|
|Zhang, Hua; Tam, Sarah; Ingham, Elizabeth S et al. (2015) Ultrasound molecular imaging of tumor angiogenesis with a neuropilin-1-targeted microbubble. Biomaterials 56:104-13|
|Kheirolomoom, Azadeh; Ingham, Elizabeth S; Mahakian, Lisa M et al. (2015) CpG expedites regression of local and systemic tumors when combined with activatable nanodelivery. J Control Release 220:253-64|
|Fite, Brett Z; Wong, Andrew; Liu, Yu et al. (2015) Magnetic resonance imaging assessment of effective ablated volume following high intensity focused ultrasound. PLoS One 10:e0120037|
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