The central hypothesis driving Project 1 is that the clinical efficacy of magnetic nanoparticle (mNP)-based cancer therapies can be substantially enhanced by precise targeting ofthe particles to cancer cells. Previous efforts using antibody and antibody fragments to target nanoparticles has yielded mixed results, and the fragmented nature ofthe related literature does not permit drawing informative conclusions that might guide future studies. To remedy this stark deficit of knowledge regarding targeting of mNP cancer therapies. Project 1 will, in a controlled fashion, conjugate genetically engineered single-chain antibody fragments (scFvs) to the surface of custom-designed mNPs. These mNP immunoconjugates will be subjected to rigorous physical, biochemical, and functional characterization. Upon establishing stringent control of mNP immunoconjugate manufacturing and characterization processes, controlled studies will systematically evaluate three key parameters believed to be critical for clinical efficacy of targeted mNP cancer therapies: (1) mNP specificity and affinity for target cells;(2) the subcellular localization of mNP upon reaching their targets;and (3) the relationship between mNP size and cellular/tumor accumulation of mNP, as assessed in two different cancer models?breast cancer and ovarian cancer.
Aim 1 will test the hypothesis that simultaneously targeting two different cancer-associated cell surface receptors with a single mNP will increase avid interactions between targeted particles and cancer cells, thereby improving specificity and biodistribution.
Aim 2 will test the hypothesis that mNPs are targeted to cancer-antigen-expressing cells more effectively by internalizing antibodies than by non-internalizing antibodies.
Aim 3 will test the hypothesis that smaller (10-20 nm) mNP immunoconjugates accumulate in antigen-expressing tumors to a higher level than larger (50-100 nm) mNP immunoconjugates. The objectives of these aims will be achieved by integrating knowledge of antibody-engineering technologies, experience with bioconjugation chemistry, and expertise with in vitro analysis of cellular mNP accumulation. The project will draw on the Nanoparticle Development, Production, and Characterization Core for mNP fabrication, on Projects 3 &4 for coordinated testing of mNP immunoconjugates in vivo, and on the Toxicology, Pathology, and Biodistribution Core and the Biostatistics, Data Analysis, and Computation Core for analysis of those in vivo results.
The key to any cancer therapy is preferential toxicity toward malignant cells verses healthy tissue. In the context of magnetic nanoparticle therapies, it is clear that passive targeting of tumors is insufficient for practical clinical efficacy. Looking to the future, the nanotechnologist will employ genetically engineered biomolecules to precisely guide magnetic nanoparticle therapies to cancerous cells.
|Hoopes, P Jack; Wagner, Robert J; Duval, Kayla et al. (2018) Treatment of Canine Oral Melanoma with Nanotechnology-Based Immunotherapy and Radiation. Mol Pharm 15:3717-3722|
|Pearce, John A; Petryk, Alicia A; Hoopes, P Jack (2017) Numerical Model Study of In Vivo Magnetic Nanoparticle Tumor Heating. IEEE Trans Biomed Eng 64:2813-2823|
|Fang, Yongliang; Chu, Thach H; Ackerman, Margaret E et al. (2017) Going native: Direct high throughput screening of secreted full-length IgG antibodies against cell membrane proteins. MAbs 9:1253-1261|
|Hoopes, P Jack; Wagner, Robert J; Song, Ailin et al. (2017) The effect of hypofractionated radiation and magnetic nanoparticle hyperthermia on tumor immunogenicity and overall treatment response. Proc SPIE Int Soc Opt Eng 10066:|
|Hoopes, P Jack; Moodie, Karen L; Petryk, Alicia A et al. (2017) Hypo-fractionated Radiation, Magnetic Nanoparticle Hyperthermia and a Viral Immunotherapy Treatment of Spontaneous Canine Cancer. Proc SPIE Int Soc Opt Eng 10066:|
|Ficko, Bradley W; NDong, Christian; Giacometti, Paolo et al. (2017) A Feasibility Study of Nonlinear Spectroscopic Measurement of Magnetic Nanoparticles Targeted to Cancer Cells. IEEE Trans Biomed Eng 64:972-979|
|Hoopes, P Jack; Mazur, Courtney M; Osterberg, Bjorn et al. (2017) Effect of intra-tumoral magnetic nanoparticle hyperthermia and viral nanoparticle immunogenicity on primary and metastatic cancer. Proc SPIE Int Soc Opt Eng 10066:|
|Davis, Scott C; Tichauer, Kenneth M (2016) Small-Animal Imaging Using Diffuse Fluorescence Tomography. Methods Mol Biol 1444:123-37|
|Reeves, Daniel B; Shi, Yipeng; Weaver, John B (2016) Generalized Scaling and the Master Variable for Brownian Magnetic Nanoparticle Dynamics. PLoS One 11:e0150856|
|Stigliano, Robert V; Shubitidze, Fridon; Petryk, James D et al. (2016) Mitigation of eddy current heating during magnetic nanoparticle hyperthermia therapy. Int J Hyperthermia 32:735-48|
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