Controlled Drug-delivery microcapsules tagged with zirconium-89

Significance 

There is an increasing interest in the biomedical field of agents that can  reveal the in vivo behavior of encapsulated therapeutics with high sensitivity. However, the majority of current PET-guided theranostic agents suffer from poor retention of radiometal over time, low drug loading capacities, and time-limited PET imaging capability.

To this note researchers at the University of Alabama led by Professor Eugenia Kharlampieva and published in the journal ACS Applied Materials & Interfaces developed a new drug delivery system which after surface modifications to boost targeting capabilities could offer a non-invasive alternative to cancer surgery or systemic chemotherapy for solid tumors. The microcapsules labeled with radioactive zirconium-89 are the first example of hollow polymer capsules capable of long-term, multiday positron emission tomography, or PET, imaging in vivo. In previous work, the same research team showed that the hollow capsules could be filled with a potent dose of the cancer drug doxorubicin, which could then be released by therapeutic ultrasound that ruptures the microcapsules.

The authors developed hollow microcapsules with a thin (<100 nm) multilayer shell as advanced theranostic delivery systems for multiday PET tracking in vivo. The 3 μm capsules were fabricated via the aqueous multilayer assembly of a natural antioxidant, tannic acid (TA), and a poly(N-vinylpyrrolidone) (PVPON) copolymer containing monomer units functionalized with deferoxamine to chelate the 89Zr radionuclide, which has a half-life of 3.3 days

The relative paucity of zirconium-89 functionalized particles, the researchers suggest, may be due to both the scarcity of laboratories able to work with this isotope and the challenges associated with its stable incorporation into a polymeric drug carrier. At UAB, Kharlampieva is a professor in the UAB College of Arts and Sciences Department of Chemistry and a co-director of the UAB Center for Nanomaterials and Biointegration. Her polymer chemistry lab has pioneered research into hollow microcapsules that are built with alternating layers of biocompatible tannic acid and poly(N-vinylpyrrolidone), or TA/PVPON. The layers are formed around a sacrificial core that is dissolved after the layers are complete. In the current research, the chelator DFO was covalently linked to the PVPON, and the capsules were composed of alternating layers of TA and PVPON-DFO, for a total of six or 12 bilayers.

Lapi is professor of radiology and vice chair of Translational Research, and she is the director of the UAB Cyclotron Facility, which produces both clinical and investigational radionuclides. Lapi also directs the Radiochemistry Laboratory and the Division of Advanced Medical Imaging Research.

The UAB researchers found that (TA/PVPON-DFO) six-bilayer capsules retained, on average, 17 percent more zirconium-89 than their (TA/PVPON) counterparts, evidence that linking DFO to PVPON provides stable chelation. In vivo PET imaging of mice showed excellent stability and imaging contrast that was still present seven days post-injection. The capsules accumulated primarily in the spleen, liver and lungs, and there was negligible accumulation in the femur. Since the femur is the site where free zirconium-89 accumulates, this lack of accumulation in the femur confirmed stable binding of the radiotracer to the capsule. Finally, applying therapeutic levels of ultrasound to the zirconium-functionalized capsules released the anticancer drug doxorubicin loaded inside the microcapsules in therapeutic amounts.

Thus, the microcapsules overcome three limitations seen in the majority of current PET-guided theranostic agents: 1) poor retention of radiometal over time, 2) low drug-loading capacities, and 3) time-limited PET imaging capability.

The produced systems represent an example of an advanced theranostic agent with the possibility to combine controlled drug delivery with stable PET imaging capabilities, they believe this system also provides the groundwork for a universal drug delivery carrier that can be coupled with advanced targeted treatments, such as patient-tailored gene therapeutics, and can lead to the advancement of human health through molecularly targeted, image-guided precision drug delivery. In a statement to Medicine Innovates the authors explained their results may represent a major step forward in microcapsule drug delivery systems

Controlled Drug-delivery microcapsules tagged with zirconium-89 - Medicine Innovates

About the author

Eugenia Kharlampieva is a polymer and materials chemist with research interests in the design and synthesis of polymeric materials for biomedical applications. She received her PhD in Polymer Science from the Stevens Institute of Technology and postdoctoral training in Materials Science and Engineering at the Georgia Institute of Technology. She joined UAB in 2010.

Dr. Kharlampieva has authored more than 80 peer-reviewed publications, four book chapters, and six patents. She was awarded funding through the NSF CAREER program in 2014, which supports junior faculty who exemplify the role of teacher-scholars through outstanding research, excellent education, and the integration of education and research. She is an Executive Committee member at Oak Ridge National Laboratory, SHUG (SNS and HFIR User Group). She also serves on an Advisory Committee in Neutron Scattering at Oak Ridge National lab, UT/ORNL DOE EPSCoR, and at the Editorial Board of Journal of Analytical & Bioanalytical Techniques. She is interested in the synthesis of novel stimuli-responsive polymers; Design of polymeric and bio-materials at nano- and micro-scales with tunable properties and functionalities of biomedical relevance; Development of multifunctional nanocomposites through controlled synthesis and assembly of stimuli-responsive polymers and functional nanostructures for environmental applications and biosensing; Probing mechanisms of polymer and protein assembly at water/solid and biomaterial/cell interfaces; advanced structural and compositional characterization of materials at the nanoscale including in situ Vibrational spectroscopy and Neutron scattering; and exploration of materials performance in ecological and bio-environments through collaborative partnerships with universities, national labs, and industry.

Reference

veronika Kozlovskaya, Aaron Alford, Maksim Dolmat, Maxwell Ducharme, Racquel Caviedes, Lauren Radford, Suzanne E. Lapi, and Eugenia Kharlampieva. Multilayer Microcapsules with Shell-Chelated 89Zr for PET Imaging and Controlled Delivery. ACS Appl. Mater. Interfaces 2020, 12, 51, 56792–56804

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