Details

Autor(en) / Beteiligte

• Swastika
• Chaturvedi, Shubhra
• Kaul, Ankur
• Hazari, Puja Panwar
• Jha, Preeti
• Pal, Sunil
• Lal, Sangeeta
• Singh, B.
• Barthélémy, Philippe
• Mishra, Anil K.

Titel

Evaluation of BBB permeable nucleolipid (NLDPU): A di-C15-ketalised palmitone appended uridine as neuro-tracer for SPECT

Ist Teil von

• International journal of pharmaceutics, 2019-06, Vol.565, p.269-282

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• [Display omitted] •Nucleolipid-potential ligand to cross the intact BBB and application in early diagnosis.•Synthesis of non-lipidic and di-C15 ketalised lipidic uridine.•Comparative physico-chemical, biocompatibility and pharmacological evaluation.•Brain uptake of lipidic uridine three times higher than non-lipid uridine.•First-of-its-kind work presents biocompatible nucleolipid as 99mTc-SPECT neuro-tracer. Despite being in routine for onco-diagnostics for years, the applicability of nucleosidic molecular imaging probes is severely restricted in neurological applications due to their low permeability across blood-brain-barrier (BBB). For extending nucleoside tracers utility for neuro-onco early diagnostics, suitable modification which enhances their BBB permeation needs investigation. Among various modifications, lipidization of nucleosides has been reported to enhance cellular permeability. Extending the concept, the aim was to exemplify the possibility of lipidized nucleosides as potential brain tracer with capability to cross intact BBB and evaluate as metal based neuro-imaging SPECT agent. Uridine based non-lipidic (NSDAU) and di-C15-ketal appended lipidic (NLDPU) ligands were conjugated to chelator, DTPA (DTPA-NSDAU and DTPA-NLDPU) using multi-step chemistry. The ligands were evaluated in parallel for comparative physical and biological parameters. Additionally, effects of enhanced lipophilicity on UV-absorption, acid strength, fluorescence and non-specific protein binding were evaluated. Fluorescence quenching of BSA indicated appreciable interaction of DTPA-NLDPU with protein only above 10 mM without inducing conformational changes. In addition, DTPA-NLDPU was found to be haematocompatible and cytocompatible with low dose-dependent toxicity in HEK-cells. The chelator DTPA was used for 99mTc-complexation for SPECT imaging. Optimized 99mTc-radiolabeling parameters resulted in quantitative (≥97%) labeling with good stability parameters in in-vitro serum and cysteine challenge studies. We demonstrate that the nucleolipid radiotracer (99mTc-DTPA-NLDPU) was successfully able to permeate the BBB with brain uptake of 0.2% ID/g in normal mice as compared to 0.06% ID/g uptake of 99mTc-DTPA-NSDAU at 5 min. Blood kinetics indicate biphasic profile and t1/2(distribution) 46 min for 99mTc-DTPA-NLDPU. The preferential accumulation of 99mTc-DTPA-NLDPU in brain tumor intracranial xenograft indicate the targeting capability of the nucleoside. We conclude that as first-of-its-kind, this work presents the potential of the biocompatible nucleolipidic system for brain targeting and early diagnostics.