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Lipid-oligonucleotide conjugates improve cellular uptake and efficiency of TCTP-antisense in castration-resistant
Sara Karaki1, Sebastien Benizri2, Raquel Mejías1
1Centre 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.
Abstract:
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.
Insights
Lipid-modified antisense oligonucleotides (ASOs) effectively inhibit translationally controlled tumor protein (TCTP) in cancer cells. This novel delivery method enhances TCTP downregulation and delays tumor progression without toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Drug Delivery
Background:
- Translationally controlled tumor protein (TCTP) is crucial for cell growth and survival, and is overexpressed in various cancers.
- TCTP overexpression is linked to treatment resistance in castration-resistant prostate cancer (CRPC).
- Antisense oligonucleotides (ASOs) targeting TCTP are promising, but face challenges in intracellular delivery and efficacy.
Purpose of the Study:
- To develop an improved delivery system for TCTP antisense oligonucleotides (ASOs).
- To evaluate the efficacy of lipid-modified ASOs (LASOs) for TCTP inhibition in vitro and in vivo.
- To assess the therapeutic potential of TCTP-LASO in preclinical models of CRPC.
Main Methods:
- Synthesis and characterization of lipid-modified antisense oligonucleotides (TCTP-LASO).
- In vitro studies assessing cellular uptake, TCTP downregulation, and cell viability.
- In vivo studies using CRPC xenograft models to evaluate tumor progression and toxicity.
Main Results:
- TCTP-LASO demonstrated enhanced cellular penetration and TCTP downregulation compared to unmodified ASOs.
- Internalization of TCTP-LASO occurred rapidly via macropinocytosis, leading to prolonged silencing.
- Treatment with TCTP-LASO significantly reduced cell viability and delayed tumor progression in CRPC xenografts with no observed toxicity.
Conclusions:
- Lipid modification significantly improves the delivery and efficacy of TCTP ASOs.
- TCTP-LASO represents a promising therapeutic strategy for CRPC and potentially other TCTP-dependent cancers.
- This approach overcomes previous delivery challenges, offering a more efficient way to target TCTP.
