Synthesis and evaluation of [177Lu]Lu‐labeled porphyrin loaded PAMAM dendrimer: Impact on tumor uptake and pharmacokinetics

Abstract The objective of the present work is to evaluate the ability of the radiolabeled PAMAM dendrimers (polyamidoamine) towards facilitating the delivery of an in‐house synthesized porphyrin derivative in the tumorous lesions to evaluate their candidature for possible application in endo‐radionuclide therapy. For this, PAMAM particles were conjugated with a porphyrin derivative namely, 5,10,15,20‐tetrakis‐(4‐carboxymethyleneoxyphenyl)porphyrin (STAP), synthesized in‐house following a two‐step reaction. The average number of porphyrin molecules loaded per PAMAM particle was evaluated using ultraviolet‐visible spectrophotometry and was found to be approximately 2. STAP conjugated PAMAM particles were further conjugated with p ‐NCS‐benzyl‐DOTA (subsequently referred as DOTA) to facilitate radiolabeling with 177 Lu. On an average, two p ‐NCS‐benzyl‐DOTA molecules were observed to be attached per PAMAM‐STAP particle. DOTA‐PAMAM‐STAP conjugate was radiolabeled with 177 Lu with a final radiochemical purity of >95%, which was determined by paper chromatography using two different mobile phases viz. 0.1 M sodium citrate buffer (pH 5.0) and 10 mM DTPA. Biological behavior of [ 177 Lu]Lu‐DOTA‐PAMAM‐STAP conjugate was investigated in fibrosarcoma bearing Swiss mice model wherein accumulation of radiolabeled particles was observed in liver, GIT, spleen, and kidneys at 3 h post‐administration. However, accumulated activity exhibited rapid clearance from majority of the organs at 24 h post‐administration. [ 177 Lu]Lu‐DOTA‐PAMAM‐STAP conjugate exhibited an appreciable uptake in tumor mass [6.09 ± 1.22 percentage injected activity/organ (% IA/organ)] at 3 h post‐administration (p.i.) which was found to reduce to 1.05 ± 0.13 % IA/organ at 24 h post‐administration. The results obtained in biodistribution studies were further corroborated through scintigraphic imaging performed in the same animal model. Despite of an appreciable accumulation in tumor mass, the lower retention of the [ 177 Lu]Lu‐DOTA‐PAMAM‐STAP conjugate therein, at longer time point (24 h p.i.) may limit its possible potential as a radio‐therapeutic agent and indicates towards need for further structural manoeuvring to attain favorable in vivo performance.