Inorganic nanoparticles (INPs) exhibit unique properties that favor their diverse application in medicine, engineering, science, and technology. The large surface-to-volume ratio of these INPs provides sites for the attachment of multiple drugs and/or imaging agents for therapy and imaging of diverse human diseases. Further conjugation of biological entities, such as proteins, nucleic acids, and lipids confers specific targeting of these INPs to desired tissues in vivo. Recent studies have shown that the intrinsic properties of some INPs can be harnessed for therapeutic outcomes, but spontaneous stimulation of intrinsic therapeutic effects through interactions of the NPs with intracellular organelles, proteins, or molecular processes is difficult to control, leading to significant off taget toxicity. An alternative therapeutic approach can be achieved by harnessing the ability of some INPs to serve as efficient nanoscale energy transducers. Quantum dots, upconversion NPs, carbon nanomaterials, and photocatalytic NPs such as titanium dioxide nanoparticles are some nanoscale energy transducers that have shown promise in the treatment of human diseases. The excellent redox properties of these nanophotosensitizers offer high spatiotemporal control and precision phototherapy upon absorption of light. Two major limitations of current phototherapeutic interventions are the limited penetration of light used to activate the photosentizers, which confines therapy to shallow lesions, and the frequent reliance on oxygen to generate cytotoxic reactive oxygen species, which precludes effective treatment under the hypoxic conditions found in many solid tumors. We hypothesize that photoactivation of low radiance-sensitive nanophotosensitizers via depth-independent Cerenkov radiation will generate cytotoxic free radicals in an oxygen- independent manner for effective therapy. In this proposal, we will (1) Synthesize and optimize tumor-targeting nanophotosensitizers for effective spatiotemporal therapy of diseases; and (2) optimize orthogonally targeted radionuclides for selective delivery of Cerenkov radiation to pathologic cells and tissue. Using animal models of cancer, we will determine the efficacy of Cerenkov radiation mediated nano-phototherapy.

Public Health Relevance

We will develop an oxygen- and tissue depth-independent nano-phototherapy platform using nanophotosensitizers to treat diverse human diseases and extend therapy to lesions that are not amenable to current phototherapeutic methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
1R01EB021048-01
Application #
8977000
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Krosnick, Steven
Project Start
2015-06-01
Project End
2019-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Cui, Grace; Akers, Walter J; Scott, Michael J et al. (2018) Diagnosis of LVAD Thrombus using a High-Avidity Fibrin-Specific 99mTc Probe. Theranostics 8:1168-1179
Hathi, Deep K; DeLassus, Elizabeth N; Achilefu, Samuel et al. (2018) Imaging Melphalan Therapy Response in Preclinical Extramedullary Multiple Myeloma with 18F-FDOPA and 18F-FDG PET. J Nucl Med 59:1551-1557
Ghai, Anchal; Maji, Dolonchampa; Cho, Nicholas et al. (2018) Preclinical Development of CD38-Targeted [89Zr]Zr-DFO-Daratumumab for Imaging Multiple Myeloma. J Nucl Med 59:216-222
Zheleznyak, Alexander; Shokeen, Monica; Achilefu, Samuel (2018) Nanotherapeutics for multiple myeloma. Wiley Interdiscip Rev Nanomed Nanobiotechnol 10:e1526
Kotagiri, Nalinikanth; Cooper, Matthew L; Rettig, Michael et al. (2018) Radionuclides transform chemotherapeutics into phototherapeutics for precise treatment of disseminated cancer. Nat Commun 9:275
Raliya, Ramesh; Saha, Debajit; Chadha, Tandeep S et al. (2017) Non-invasive aerosol delivery and transport of gold nanoparticles to the brain. Sci Rep 7:44718
Tang, Rui; Habimana-Griffin, LeMoyne M; Lane, Daniel D et al. (2017) Nanophotosensitive drugs for light-based cancer therapy: what does the future hold? Nanomedicine (Lond) 12:1101-1105
Gilson, Rebecca C; Black, Kvar C L; Lane, Daniel D et al. (2017) Hybrid TiO2 -Ruthenium Nano-photosensitizer Synergistically Produces Reactive Oxygen Species in both Hypoxic and Normoxic Conditions. Angew Chem Int Ed Engl 56:10717-10720
Mondal, Suman B; Gao, Shengkui; Zhu, Nan et al. (2017) Optical See-Through Cancer Vision Goggles Enable Direct Patient Visualization and Real-Time Fluorescence-Guided Oncologic Surgery. Ann Surg Oncol 24:1897-1903
Som, Avik; Raliya, Ramesh; Tian, Limei et al. (2016) Monodispersed calcium carbonate nanoparticles modulate local pH and inhibit tumor growth in vivo. Nanoscale 8:12639-47

Showing the most recent 10 out of 12 publications