Chelator-free labeling of layered double hydroxide nanoparticles for in vivo PET imaging

Objectives Layered double hydroxide (LDH) is a material consisting of cationic brucite-like layers, interlayer anions, and water molecules. LDH has been used in various drug delivery systems. Our goal is to investigate chelator-free radiolabeling of Mg₂Al-CO₃-based LDH nanoparticles with a variety of PET isotopes for in vivo positron emission tomography (PET) imaging.

Methods LDH nanoparticles were prepared by quick precipitation and subsequent hydrothermal treatment, which were coated with bovine serum albumin (BSA) to improve aqueous solubility and biocompatibility. As-prepared LDH-BSA nanoparticles were directly mixed with ⁶⁴Cu²⁺, ⁴⁴Sc³⁺, or ⁸⁹Zr⁴⁺ for chelator-free labeling. Serial PET and biodistribution studies were carried out to examine passive tumor targeting of ⁶⁴Cu-LDH-BSA. Chelator-free labeling of BSA was also tested in vitro/in vivo to demonstrate that BSA coating does not affect chelator-free labeling of LDH nanoparticles.

Results LDH-BSA was prepared with excellent water solubility. Since LDH can allow incorporation of multiple 2⁺ and 3⁺ cations, ⁶⁴Cu²⁺ and ⁴⁴Sc³⁺ were successfully labeled on LDH and LDH-BSA with desirable labeling yield and stability in a chelator-free manner. As expected, ⁸⁹Zr⁴⁺ could not be labeled since it does not match the LDH crystal structure well. In addition, it was confirmed that labeling of ⁶⁴Cu²⁺ and ⁴⁴Sc³⁺ was mostly on the LDH nanoparticles, but not on BSA. Due to the prolonged blood circulation t_1/2 conferred by BSA coating, prominent tumor uptake was achieved in 4T1 breast cancer xenografts with ⁶⁴Cu-LDH-BSA via passive targeting alone (7.7±0.1 %ID/g at 16 h post-injection; n=3), much higher than ⁶⁴Cu-BSA (4.1±0.5 %ID/g; n=3), further confirming the labeling/imaging capacity of LDH.

Conclusions We report the first chelator-free labeling and in vivo PET imaging with LDH nanoparticles. Upon surface modification, LDH is a versatile platform that can be labeled with various 2+ and 3+ radiometals (e.g. ⁶⁴Cu²⁺ & ⁴⁴Sc³⁺) without altering the native properties (e.g. drug loading and PK), highly desirable for PET image-guided drug delivery.