The best cancer-fighting nanovesicles will have three functions: 1) a targeted molecule to effectively bind to and label the surface of cancer cells, 2) an integrated radionuclide signal that will allow PET scans to find the vesicles in the body, and 3) the ability to carry out and leave drug treatment, such as chemotherapy, in the cancer.
It will also fulfill two other requirements – to have a simple and easy manufacturing process and to be flexible and biodegradable.
A team from the University of Alabama at Birmingham has described a small polymersome that – in preliminary experiments – appears to solve these problems. Each polymersome is a hollow cavity with thin walls, but it is the coating on the polymersome that shows the path forward.
60 nanometer triblock copolymer polymers with biodegradable tannic acid, or TA, attached to the surface by hydrogen bonding. This TA, in turn, is able to quickly and stably bind molecules targeted for monoclonal antibodies to the radionuclide of zirconium, or Zr, without the need for direct binding, such as chelators, said Eugenia Kharlampieva, Ph. .D., and Suzanne E. Lapi, Ph.D., UAB team leaders. Their study is published in the journal Biomacromolecules.
“In this study, we developed a simple method for the chelator-free modification of PVPON5-PDMS30-PVPON5 triblock copolymer nanovesicles, about 60-80 nanometers in diameter, with a polyphenol layer that can simultaneously using the anchor 89Zr radiotracer. or other ions that work well for molecular imaging, and the HER2-targeted ligand, trastuzumab monoclonal antibody, for targeting nanovesicles in HER2-positive breast cancer cells, “Kharlampieva, Professor known in the Department of Chemistry from the UAB College of Arts and said. Science. . PVPON5 is a 5-mer short block hydrophilic polymer and PDMS30 is a 30-mer long hydrophobic block copolymer triblock copolymer.
Breast cancer is one of the most common cancers and the death rate worldwide remains high. Systemic drugs or anti-inflammatory drugs are the current treatment, but they are often associated with heart damage and dysfunction. Image-guided drug delivery to solid tumors may allow better drug activity and reduced drug toxicity.
“To the best of our knowledge, our work represents the first example of a chelator-free radiolabeled polymersome capable of long-term, multi-day PET imaging studies in vivo,” said Lapi, director of the UAB Cyclotron Facility. and Professor. in the Department of Radiology at UAB. “The radiolabeling system developed here can provide stable binding of a variety of non-radioactive isotopes of radiometals from the vesicle membrane in vivo. breast cancer cells.
In the study, TA and polymersome-bound 89Zr4+ radionuclide through non-specific ion pairing, and TA also binds to the monoclonal antibody trastuzumab, or Tmab, through hydrogen bonding and ion pairing. There is good retention of 89Zr for up to seven days, as shown by PET scans in healthy mice.
“The non-covalent anchoring of Tmab in the polymeric membrane can be very beneficial for nanoparticle modification compared to the currently developed covalent method, as it allows easy and quick integration of a variety of targets that are processed protein,” said Kharlampieva. “Given the ability of these polymersomes to incorporate and release cancer therapies, they can be developed as targeted therapeutic carriers for improving human health through effective drug delivery systems.”
One hour of incubation of TA-polymersomes in 89Zr-oxalate solution resulted in a radio labeling yield of 97%, and these extracts remained stable for more than one, three and seven days. The labeled polymersomes were not cytotoxic when incubated in vitro with two cancer cell lines for up to four days. In addition, conjugation of 89Zr to polymersomes with added Tmab also had a high yield of 97% and stability up to 7 days. These compounds are advanced for clinical use, according to UAB researchers.
Then, stable binding of 89Zr to TA-polymersomes was demonstrated in mice.
The biodistribution of free radiotracer 89Zr was previously reported to occur in the spine and femurs of animals due to chelation of zirconium with phosphate moieties in the bone. The UAB researchers found that when mice were injected with free 89Zr, almost everything was in the femur bone after 24 hours, as measured by a PET scan. A very different biodistribution was observed when 89Zr-TA polymers were injected into mice. Negative radioactivity was found in the bones; instead, almost all of the radioactivity is in the spleen and liver. This area represents the expected elimination of nanovesicles by the mononuclear phagocytic system for nanomaterials larger than 6–8 nanometers.
“The striking difference observed between the biodistribution of free 89Zr and the radiotracer labeled vesicle is significant, as it demonstrates the unrestricted ability of the polymeric nanocarrier to follow in vivo,” said Lapi.
Solid imaging was maintained in mice for up to seven days, further evidence for the strong binding of 89Zr to TA-polymersomes.
The ability of 89Zr-Tmab-TA polymers to target HER2-positive cancer cells in vitro was demonstrated by different binding of nanovesicles to HER2-positive and HER2-negative breast cancer cells. The researchers said further experiments to target breast tumors in animals are needed.
Source: University of Alabama at Birmingham
