Tuning the pharmacokinetics and efficacy of irinotecan (IRI) loaded gelatin nanoparticles through folate conjugation

Gelatin based nanocarriers have major limitation of shorter circulation half-life (t_1/2). Present study addressed this issue by conjugating gelatin with folate followed by nanoprecipitation in presence of polysorbate 80 to form folate attached gelatin nanoparticles (GNP-F). The folic acid was conjugated with gelatin through the formation of amide linkage with a maximum conjugation yield of ~69%. Cryo-SEM analysis indicated that unconjugated gelatin nanoparticles (GNP) and GNP-F were spherical of nearly identical size of ~200 nm. The irinotecan (IRI)-loading efficiency estimated for IRI-GNP and IRI-GNP-F was 6.6 ± 0.42% and 11.2 ± 0.73% respectively and both formulations showed faster release of IRI at acidic pH (~5) than at physiological pH (~7). Further IRI-GNP-F demonstrated significantly higher cytotoxicity in folate receptor (FR)-positive HeLa cells than the unconjugated IRI-GNP nanoparticles confirming active targeting. Subsequently the antitumor activity of above formulations in FR-positive fibrosarcoma (syngeneic) tumor-bearing mice followed the order of IRI-GNP-F > IRI-GNP > free IRI. The pharmacokinetic evaluation of IRI-GNP and IRI-GNP-F revealed that encapsulation of IRI within GNP without folate improved its plasma maximum concentration (C_max). However, folate conjugation of GNP remarkably improved the t_1/2 of IRI. Taken together, folate as a targeting ligand modulates the pharmacokinetic property of IRI loaded GNP to favor active verses passive targeting.

Keywords: Folate conjugation; Gelatin; Nanomedicine; Pharmacokinetics; Protein nanoparticles; Tumor suppression.