Assessment of 177Lu‐labeled carboxyl‐terminated polyamidoamine (PAMAM) dendrimer‐RGD peptide conjugate. (30th August 2021)

• Record Type: Journal Article
• Authors: Vats, Kusum; Sharma, Rohit; Sharma, Amit Kumar; Sarma, Haladhar D.; Satpati, Drishty
• Is Part Of: Journal of peptide science. Volume 28:Number 2(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-08-30
• Subjects: biodistribution -- cRGDfK peptide -- dendrimer -- integrin -- Lu‐177 -- melanoma; Peptides -- Periodicals; Peptides -- Periodicals; 572.65
• DOI: 10.1002/psc.3366
• Languages: English
• ISSNs: 1075-2617

Abstract

Abstract : 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 αv 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 αv β3 receptors. Abstract : Radiolabeled dendrimer nano‐system, 177 Lu‐PAMAM‐DOTA‐cRGDfK was prepared by surface modification of carboxy‐terminated G4 PAMAM dendrimer with cRGDfK peptide and bifunctional chelator p‐NH2 ‐Bn‐DOTA. 177 Lu‐PAMAM‐DOTA‐cRGDfK exhibited high cytocompatibility as well as receptor‐mediated uptake in αv β3 integrin receptor‐positive tumor xenografts.