A new approach to the design of cancer-drug-carrying nanovesicles promises to meet five key criteria:

  1. Binding of cancer cell surface markers.
  2. Strong, persistent radionuclide signaling.
  3. Ability to release the cancer drug where needed.
  4. Ease of manufacture.
  5. Biocompatibility and biodegradability.

The new approach has been developed at the University of Alabama at Birmingham, where a research team has shown that a familiar tool—the tiny polymersome—can be given a novel and highly functional coating. This coating, the researchers insist, avoids difficulties common with existing polymersomes.

Details about the new polymersome approach appeared in Biomacromolecules, in an article titled, “Direct Radiolabeling of Trastuzumab-Targeting Triblock Copolymer Vesicles with 89Zr for Positron Emission Tomography Imaging.”

“[We] developed 89Zr-labeled triblock copolymer polymersomes of 60 nm size through chelator-free radiolabeling,” the article’s authors wrote. “The polymersomes are assembled from PVPON5-PDMS30-PVPON5 triblock copolymers followed by adsorption of a degradable tannin, tannic acid (TA), on the polymersome surface through hydrogen bonding. TA serves as an anchoring layer for both 89Zr radionuclide and targeting recombinant humanized monoclonal antibody, trastuzumab (Tmab).”

A layer of polyphenol is used to anchor the PVPON5 (a short, five-monomer hydrophilic polymer block) and PDMS30 (a longer, 30-monomer, hydrophobic polymer block within the triblock copolymer). Thus far, the triblock copolymer system has also been used to anchor the 89Zr radiotracer for molecular imaging, and a HER2-targeting ligand, trastuzumab monoclonal antibody, for targeting the nanovesicle to HER2-positive breast cancer cells. (Other radiotracers and ligands may be used.)

The leaders of the UAB team—Eugenia Kharlampieva, PhD, and Suzanne E. Lapi, PhD—emphasized that the UAB team was able to quickly and stably attach 89Zr and Tmab to the nanovesicle without the need to build specific linkers, such as chelators.

Breast cancer is one of the most common cancer diseases, and global rates of death are still high. Systemic drugs or therapeutic antibodies are current therapies, but they are often associated with heart damage and dysfunction. Image-guided drug delivery to a solid tumor could allow effective drug activity with reduced drug toxicity.

“To the best of our knowledge, our work represents the first example of a chelator-free-radiolabeled polymersome capable of a long-term multiday PET imaging study in vivo,” Lapi said. “The radiolabeling approach developed herein can potentially provide stable binding of a wide spectrum of isotopes without radiometal leaching from the vesicle membrane in vivo. Notably, this approach integrates the inherent advantages of a polyphenolic polymersome membrane with the benefit of quickly anchoring breast cancer cell-targeting ligands.”

In the study, TA on the polymersome bound 89Zr4+ radionuclide through nonspecific ionic pairing, and the TA also bound the trastuzumab monoclonal antibody, or Tmab, through hydrogen bonding and ionic pairing. There was excellent retention of the 89Zr for up to seven days, as confirmed by PET scans in healthy mice.

“The noncovalent Tmab anchoring to the polymersome membrane can be highly advantageous for nanoparticle modification compared to currently developed covalent methods, as it allows easy and quick integration of a broad range of targeting proteins,” Kharlampieva said. “Given the ability of these polymersomes to encapsulate and release anticancer therapeutics, they can be further expanded as precision-targeted therapeutic carriers for advancing human health through highly effective drug-delivery strategies.”

Essential observations cited in the paper include the following:

  • Unlike bare PVPON5-PDMS30-PVPON5 polymersomes, TA- and Tmab-modified polymersomes demonstrated a high radiochemical yield of more than 95%.
  • Excellent retention of 89Zr by the vesicle membrane for up to 7 days was confirmed by PET in vivo imaging.
  • Animal biodistribution using healthy BALB/c mice confirmed the clearance of 89Zr-labeled polymersomes through the spleen and liver without their accumulation in bone, unlike the free nonbound 89Zr radiotracer.
  • The 89Zr-radiolabeled polymersomes were found to specifically target BT474 HER2-positive breast cancer cells via the Tmab-TA complex on the vesicle surface.

“The observed drastic difference between the biodistribution of the free 89Zr and the metal radiotracer-labeled vesicle is important, as it demonstrates an unimpeded capability of the polymeric nanocarrier to be tracked in vivo,” Lapi said.

The researchers say that the noncovalent Tmab anchoring to the polymersome membrane can be highly advantageous for nanoparticle modification compared to currently developed covalent methods, as it allows easy and quick integration of a broad range of targeting proteins. The researchers add that further testing to target breast cancer tumors in animals is warranted.

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