Carvalheiro, ManuelaFerreira-Silva, MargaridaHolovanchuk, DenysMarinho, H. SusanaMoreira, João NunoSoares, HelenaCorvo, M. LuisaCruz, Maria Eugénia M.2022-03-042024-03-012022-01Carvalheiro M, Ferreira-Silva M, Holovanchuk D, Marinho S, Moreira JN, Soares H, et al. Antagonist G-targeted liposomes for improved delivery of anticancer drugs in small cell lung carcinoma. Int J Pharmaceutics. 2022;612:121380.http://hdl.handle.net/10400.21/14382FCT_UID/Multi/00612/2019. FCT_UIDB/00100/2020. FCT_UIDP/00100/2020.Ligand-mediated targeted liposomes have the potential to increase the therapeutic efficacy of anticancer drugs. This work aimed to evaluate the ability of antagonist G, a peptide targeting agent capable of blocking the action of multiple neuropeptides, to selectivity improve targeting and internalization of liposomal formulations (long-circulating liposomes, LCL, and stabilized antisense lipid particles containing ionizable amino lipid, SALP) to H69 and H82 small cell lung carcinoma (SCLC) cell lines. Antagonist G-targeted LCL and SALP were prepared by two different methods (either by direct covalent linkage at activated PEG grafted onto the liposomal surface or by post-insertion of DSPE-PEG-antagonist-G-conjugates into pre-formed liposomes). Association of the liposomal formulations with target SCLC cells was studied by fluorescence microscopy using fluorescence-labeled liposomes and confirmed quantitatively with [3H]-CHE-labelled liposomes. An antisense oligodeoxynucleotide against the overexpressed oncogene c-myc(as(c-myc)) was efficiently loaded into SALP formulations, the encapsulation efficiency decreased due to the inclusion of the targeting ligand. Also, liposome size was affected by as(c-myc) physical-chemical properties. The amount of antagonist G linked to the surface of the liposomal formulations was dependent on the coupling method and lipid composition used. Covalent attachment of antagonist G increased liposomes' cellular association and internalization via receptor-mediated and clathrin-dependent endocytosis, as assessed in SCLC cell lines. Biodistribution studies in healthy mice revealed a preferential lung accumulation of antagonist G-targeted SALP as compared to the non-targeted counterpart. Lung levels of the former were up to 3-fold higher 24 h after administration, highlighting their potential to be used as delivery vectors for SCLC treatment.engAntineoplastic agentsTherapeutic useDrug delivery systemsLiposomesLung neoplasmsDrug therapyOligopeptidesSmall cell lung carcinomaTissue distributionFCT_UID/Multi/00612/2019FCT_UIDB/00100/2020FCT_UIDP/00100/2020journal article10.1016/j.ijpharm.2021.121380