Lipid-oligonucleotide conjugates improve cellular uptake and efficiency of TCTP-antisense in castration-resistant prostate cancer

Translationally controlled tumor protein (TCTP) has been implicated in a plethora of important cellular processes related to cell growth, cell cycle progression, malignant transformation and inhibition of apoptosis. Therefore, TCTP is now recognized as a potential therapeutic target in several cancers including prostate, breast and lung cancers. We previously showed that TCTP is overexpressed in castration-resistant prostate cancer (CRPC), and it has been implicated resistance to treatment. Recently, we developed TCTP antisense oligonucleotides (ASOs) to inhibit TCTP expression. However, the intracellular delivery and silencing activity of these oligonucleotides remains a challenge, and depend on the use of transfection agents and delivery systems. Here we show that lipid-modified ASO (LASOs) has improved penetration and efficiency in inhibiting TCTP expression in the absence of additional transfection agents, both in vitro and in vivo. Transfection with TCTP-LASO led to rapid and prolonged internalization via macropinocytosis, TCTP downregulation and significant decreased cell viability. We also show that lipid-modification led to delayed tumor progression in CRPC xenografts models, with no significant toxic effects observed.

Journal of controlled release : official journal of the Controlled Release Society. 2017 May 01 [Epub ahead of print]

Sara Karaki, Sebastien Benizri, Raquel Mejías, Virginie Baylot, Nicolas Branger, Tan Nguyen, Brune Vialet, Khalid Oumzil, Philippe Barthélémy, Palma Rocchi

Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM UMR1068, 27 Bd. Lei Roure BP30059, 13273 Marseille, France; Institut Paoli-Calmettes, 13273 Marseille, France; Aix-Marseille Université, 13284 Marseille, France; CNRS UMR7258, 13009 Marseille, France., ARNA Laboratory, University of Bordeaux, F-33076 Bordeaux, France; INSERM U1212, F-33076, Bordeaux, France; UMR CNRS 5320, F-33076, Bordeaux, France., ARNA Laboratory, University of Bordeaux, F-33076 Bordeaux, France; UMR CNRS 5320, F-33076, Bordeaux, France; UMR CNRS 5320, F-33076, Bordeaux, France., ARNA Laboratory, University of Bordeaux, F-33076 Bordeaux, France; INSERM U1212, F-33076, Bordeaux, France., Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM UMR1068, 27 Bd. Lei Roure BP30059, 13273 Marseille, France; Institut Paoli-Calmettes, 13273 Marseille, France; Aix-Marseille Université, 13284 Marseille, France; CNRS UMR7258, 13009 Marseille, France. Electronic address: .

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