The overall goal of this biomedical research partnership is to couple cancer imaging and therapy using nanoparticles that provide ultrasonic activation, multimodality imaging, and efficient and stable drug transport. These methods enable efficacious drug delivery with minimal systemic toxicity in the treatment of multifocal and metastatic cancers, and in particular in melanoma, head and neck, prostate, and breast tumors. There is great momentum for image-guided interventions in general and image-guided drug delivery in particular, with many activatable particles under development. In our first grant cycle, we established the feasibility of ultrasound drug delivery to tumors, demonstrating that we can: target a significant fraction of drug carrying particles to tumors (averaging 20% of the injected dose per cubic centimeter of tissue following systemic administration), obtain a high (up to 33 dB) target-to-background ratio image of the vehicles within the cancerous lesion, image tumors with a diameter of 4 mm or greater, achieve at least a 50-fold increase in drug delivery to tumors (as compared with systemic administration of free model drugs), and demonstrate a therapeutic response in vivo with the combination of ultrasound and liposomal cisplatin in as little as 24 hours. We have also created ultrasound infrastructure for imaging and therapy, embedding therapeutic capabilities within the clinical ultrasound system of our partner Siemens Medical Solutions, creating a positron emission tomography (PET) labeling method for liposomes, synthesizing a near-infrared probe, and cross-validating these components. Our ultrasound imaging and therapy system can operate independently or in combination with PET and computed tomography (CT). The primary goal for this renewal is to establish efficacious infrastructure and protocols for ultrasound-enhanced particle-based drug delivery for the treatment of primary and metastatic tumors. In order to accomplish this goal we will create a combined PET-CT-US system for image-guided-interventions, optimize the 3D-ultrasound heating protocol, maximize the target-to-background ratio for guiding interventions with PET-CT-US, finalize the loading and formulation for an activatable cisplatin liposome and evaluate ultrasound-enhanced intravenous therapy under PET-CT guidance.

Public Health Relevance

Currently, one in 4 deathsin the United States is due to cancer. Available options for preemption and treatment are limited by the toxicity profiles of various drugs. As a result, substantial efforts have been directed to develop nanotechnology-based methods for increasing the efficacy and decreasing the toxicity of drug therapies. Using multifunctional particles for imaging and therapy, we have shown that ultrasound-enhanced drug delivery is feasible and efficacious. In the renewal, we will develop infrastructure and protocols for successful image- guided drug delivery in models of head and neck and metastatic breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA103828-09
Application #
8232134
Study Section
Special Emphasis Panel (ZRG1-SBIB-V (50))
Program Officer
Farahani, Keyvan
Project Start
2004-05-25
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$688,753
Indirect Cost
$235,751
Name
University of California Davis
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Fite, Brett Z; Kheirolomoom, Azadeh; Foiret, Josquin L et al. (2017) Dynamic contrast enhanced MRI detects changes in vascular transport rate constants following treatment with thermally-sensitive liposomal doxorubicin. J Control Release 256:203-213
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
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
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 223:157-164
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 220:253-264
Foiret, Josquin; Ferrara, Katherine W (2015) Spatial and Temporal Control of Hyperthermia Using Real Time Ultrasonic Thermal Strain Imaging with Motion Compensation, Phantom Study. PLoS One 10:e0134938
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
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
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
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

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