Applications for a Radio-Theranostic Nanoparticle with High Specific Drug Loading

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  • March 20, 2019
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  • Satterlee, Andrew
    • Affiliation: School of Medicine, UNC/NCSU Joint Department of Biomedical Engineering
Abstract
  • Since its initial publication over four years ago, the Lipid-Calcium-Phosphate (LCP) nanoparticle platform has shown success in a wide range of treatment strategies, encapsulating small molecules, peptides, and nucleic acids for cancer therapy. recently including theranostics. Herein, we describe how this platform was used to encapsulate and deliver several radiometals for cancer therapy and imaging, including 177Lu, 90Y, and 64Cu. Characterization of 177Lu-LCP has shown that radionuclide loading can be increased by several orders of magnitude without affecting the encapsulation efficiency or the morphology of 177Lu-LCP, allowing consistency during fabrication and overcoming scale-up barriers typical of nanotherapeutics. The choice of 177Lu as a model radionuclide has allowed in vivo anticancer therapy in addition to radiographic imaging via the dual decay modes of 177Lu. Tumor accumulation of 177Lu-LCP was measured using both SPECT and Cerenkov imaging modalities in live mice, and treatment with just one dose of 177Lu-LCP showed significant in vivo tumor inhibition in two subcutaneous xenograft tumor models. Microenvironment and cytotoxicity studies suggest that 177Lu-LCP inhibits tumor growth by causing apoptotic cell death via double-stranded DNA breaks while causing a remodeling of the tumor microenvironment to a more disordered and less malignant phenotype. Although smaller tumors show a favorable response when treated with 177Lu-LCP, aggressive, desmoplastic tumors are notoriously difficult to treat because of their extensive stroma, high interstitial pressure, and resistant tumor microenvironment. We have developed a combination therapy that can significantly slow the growth of large, stroma-rich tumors by causing massive apoptosis in the tumor center while simultaneously increasing nanoparticle uptake through a treatment-induced increase in the accumulation and retention of nanoparticles in the tumor. The vascular disrupting agent CA4P is able to increase the accumulation of radiation-containing nanoparticles for internal radiation therapy, and the retention of these delivered radioisotopes is maintained over several days. We use ultrasound to measure the effect of CA4P in live tumor-bearing mice, and we encapsulate the radio-theranostic isotope 177Lu as a therapeutic agent as well as a means to measure nanoparticle accumulation and retention in the tumor. This combination therapy induces prolonged apoptosis in the tumor, decreasing both the fibroblast and total cell density and allowing further tumor growth inhibition using a cisplatin-containing nanoparticle. Of course, clinical implementation of this combination therapy must be modified to minimize systemic toxicity. While intravenous administration of radiation-labeled LCP presents a good model of internal radiation therapy’s effectiveness in combination with CA4P, the well-known uptake of nanoparticles into clearing organs presents a compelling argument against this injection route. Perhaps the best future use for 177Lu/90Y-LCP is in a modified form of selective internal radiation therapy (SIRT), in which the nanoparticles are locally delivered to hepatic tumors via catheterization of the hepatic artery. Combination therapy with CA4P against desmoplastic tumors would not only cause massive apoptosis in the tumor centers, but also induce an increased accumulation of nanoparticles in the tumor and prime the microenvironment for further treatment.
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  • In Copyright
Advisor
  • Wang, Andrew
  • Jay, Michael
  • Huang, Leaf
  • Dayton, Paul
  • Lai, Samuel
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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