We have developed temperature-sensitive nanoparticles in which a drug is sequestered in a crystal at neutral pH and encapsulated in a lipid shell with a low melting point. After temperature-mediated release, the crystal is dissolved in a tumor or lysosome. By combining these particles with ultrasound, a large fraction of drug is delivered into tumors without systemic toxicity and we are achieving a complete response in local disease in a protocol that is not possible with existing agents. Combining this treatment with an immune adjuvant, we observe a powerful systemic anti-tumor response. We focus here on developing the image-guided delivery technology for practical pre-clinical studies and applying this technology to optimize the combination of temperature sensitive particles, ultrasound and immune adjuvants. Within this application, image-guidance is incorporated to control or assess the region of insonation (real-time ultrasound imaging), the temperature achieved (real-time ultrasound thermometry), and the drug released (MRI imaging after the completion of treatment). In preliminary data, we demonstrate the ability to create accurate and repeatable temperature maps at a 5 Hz frame rate with a high signal to noise ratio in the presence of in plane and out of plane motion and strain that results in tissue compression. With this approach: 1) the drug does not need to accumulate via the enhanced permeability and retention effect; instead it is released in the tumor vasculature; 2) depending on the size of the region of release and the time of activation, accumulation can be 100 fold or more greater than typical cancer nanotherapeutics; 3) the released drug is rapidly internalized; 4) the release of the drug in the vascular space transiently enhances vascular permeability facilitating the release of additional drug, plasma and some red blood cells; 5) repeated application of this technique results in infiltration of macrophages with an enhanced anti-tumor M1 phenotype; 6) the technique is effectively combined with immune adjuvants to create a very strong systemic anti-cancer effect. In order to translate an effective therapy, we need to optimize the multiple components using carefully-controlled conditions. An integrated imaging and therapy system is now required in that temperature must be estimated and ultrasound controlled with an integrated control loop (as is done in MR-guided focused US (MRgFUS)). Such a system will maximize the frame rate since the therapeutic and imaging beams cannot be simultaneously fired and the integrated system will maximize the combined frame rate. We will apply this technology in the systematic tri-modality (drug, ultrasound, and immunotherapy) studies of breast and bladder cancer.
Our specific aims are to: create a multi-frequency imaging/therapy array, optimize ultrasound thermometry for real-time feedback in a realistic scenario that includes tissue motion and evaluate ultrasound-guided drug delivery to rodent models with and without an immune adjuvant. The team assembled here is uniquely qualified to develop image-guided therapy, including the PI (ultrasound imaging and therapy), Douglas Stephens (ultrasound transducers), Imasonics, Ralph De Vere White (UCD Cancer Center Director) and William Murphy (cancer immunologist).

Public Health Relevance

We focus on developing a cure for systemic cancers based on combining local delivery of chemotherapy with immunotherapy. To accomplish this goal, we will develop an ultrasound system for well-controlled mild hyperthermia and will optimize the resulting multi-component therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA199658-01
Application #
8971556
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Farahani, Keyvan
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Davis
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Foiret, Josquin; Zhang, Hua; Ilovitsh, Tali et al. (2017) Ultrasound localization microscopy to image and assess microvasculature in a rat kidney. Sci Rep 7:13662
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
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Liu, Yu; Liu, Jingfei; Fite, Brett Z et al. (2017) Supersonic transient magnetic resonance elastography for quantitative assessment of tissue elasticity. Phys Med Biol 62:4083-4106
Silvestrini, Matthew T; Ingham, Elizabeth S; Mahakian, Lisa M et al. (2017) Priming is key to effective incorporation of image-guided thermal ablation into immunotherapy protocols. JCI Insight 2:e90521
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

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