Quantitative PET tracking of intra-articularly administered ⁸⁹Zr-peptide-decorated nanoemulsions

Intra-articular (IA) administration of drugs for the treatment of diseases such as rheumatoid arthritis, osteoarthritis and psoriatic arthritis is a common strategy; however, the rapid clearance from the synovial fluid restricts their effectivity due to the limited retention time. Drug Delivery Systems (DDS) are currently being developed to increase their joint retention time. This study compares the biodistribution and retention time of a senolytic peptide (PEP), with potential application in osteoarthritis disease, and this senolytic peptide encapsulated in a DDS based on a lipid nanoemulsion (PEPNE) by using positron emission tomography (PET) imaging. To this aim, the PEP was conjugated with a chelating agent (DFO) and radiolabeled with zirconium-89 (⁸⁹Zr). Then, [⁸⁹Zr]-PEP was encapsulated in a novel nanoemulsion formulation, composed by vitamin E, sphingomyelin, and a lipid-PEG. Afterward, healthy rats were administered with either the [⁸⁹Zr]-PEP or the [⁸⁹Zr]-PEP-NE via IA injection and underwent PET scans at 0.5-, 24-, 48-, 72-, 168-, 240- and 336 h post-injection. To assess the biodistribution of both radiotracers, several volume-of-interest were manually drawn in different organs of the rat body and the %ID/organ was calculated. The [⁸⁹Zr]-PEP was successfully encapsulated in the NE and their physicochemical properties were minimally affected by the radiolabeling buffer. Adequate stability of both [⁸⁹Zr]-PEP and [⁸⁹Zr]-PEP-NE was found in synovial fluid over 72 h. Quantitative data from PET images revealed a significantly higher [⁸⁹Zr]-PEP-NE retention in the injected knee than with [⁸⁹Zr]-PEP in all follow-up PET scans. The [⁸⁹Zr]-PEP %ID/organ values in the liver and kidney were significantly higher than those from [⁸⁹Zr]-PEP-NE, which might indicate a faster elimination of the [⁸⁹Zr]-PEP. Therefore, the study highlights the higher retention time on the target site of the [⁸⁹Zr]-PEP-NE which may improve the therapeutic effects of the peptide. Thereby, the novel nanoemulsion formulation seems to be a successful DDS for IA injection. In addition, these results represent the first study that evaluates the distribution of a PET-guided DDS after its IA administration.