Assessment of ¹⁷⁷ Lu-labeled carboxyl-terminated polyamidoamine (PAMAM) dendrimer-RGD peptide conjugate

Structurally unique polyamidoamine (PAMAM) dendrimers implanted with targeting biological moiety along with complexed radiometal constitute a favorable nano-system for diagnosis and therapy of targeted tumor sites. In the present study, carboxyl functionalities of PAMAM- generation 4 dendrimer (PAMAM-G4-COOH) were conjugated with ε-amino group of lysine of cRGDfK peptide to impart integrin α_v β₃ targeting capability. Reaction of p-NH₂ -Bn-DOTA with PAMAM was accomplished via acid-amine coupling using EDC/NHS for ¹⁷⁷ Lu-complexation. ¹⁷⁷ Lu-labeled nano-system, ¹⁷⁷ Lu-PAMAM-DOTA-cRGDfK demonstrated receptor-mediated uptake in murine melanoma B16F10 cells during in vitro cell uptake studies. In vivo biodistribution studies demonstrated low tumor uptake and retention of ¹⁷⁷ Lu-PAMAM-DOTA-cRGDfK which may be attributed to rapid blood clearance. However, fast clearance from non-target organs resulted in higher target to background ratio. Tumor uptake of targeted nano-system, ¹⁷⁷ Lu-PAMAM-DOTA-cRGDfK was observed to be significantly (p < 0.05) higher in comparison to ¹⁷⁷ Lu-PAMAM-DOTA without the targeting peptide. Inhibition studies with unlabeled cRGDfK resulted in 60% reduction in tumor uptake of ¹⁷⁷ Lu-PAMAM-DOTA-cRGDfK, indicating specificity of the developed nano-system towards integrin α_v β₃ receptors.