Nanomolecules and cell targeting

In 2003 P. Rocchi identified Hsp27 as a highly overexpressed gene in castration resistant prostate cancer (CRPC). Hsp27 knockdown using antisense oligonucleotides (ASO) and siRNA increases apoptosis and enhances hormone- and chemo-therapy in PC. She developed a second generation ASO targeting Hsp27 that has been licensed (OGX-427, Apatorsen) and a clinical trial phase II was done in US and Canada. We hope now to understand the mechanisms leading to Hsp27 over-expression and identify the molecular switches underlying PC. We obtained an InCa-ARC-Ligue program « PAIR Prostate Program » in 2010 and started the large-scale screening of Hsp27 partner proteins using two-hybrid systems and identified Translationaly Controlled Tumor Protein (TCTP) as a novel therapeutic target driving CRPC progression. To design the antisense oligonucleotides (ASOs) targeting the entire TCTP mRNA, R software (https://cran.r-project.org) was developed in our laboratory. We then developed and patented a first generation TCTP phosphorothioate backbone ASO that downregulates mRNA and protein expression level. We then obtained an ANR Emergence project “TCTP inhibition by specific antisense oligonucleotide lipid moiety-modified as a new therapeutic strategy to restore hormone- and chemo-sensitivity for the treatment of therapy-resistant prostate cancer” to develop a second generation of TCTP ASO (TCTP-LASO) by using a lipid-conjugated oligonucleotides. This project obtained the label by Eurobiomed Competitivity Pole and started on september 1st, 2011. We demonstrated that TCTP-LASO has the ability to downregulate TCTP levels without any transfecting agent (TCTP-LASO) in prostate cancer cells, leading to restoration of the normal function of p53, a tumor suppressor protein. Interestingly, these amphiphilic LASOs were found to be able to spontaneously self-assemble into forming a hydrophobic core to encapsulate some chemical compounds and serve as nanocarriers to deliver cytotoxic chemotherpy. In order to validate this hypothesis, we obtained one SATT Sud-Est funding to use these nano-structures to encapsulate PC chemotherapy and promote its delivery. Furthermore, one of the greatest advantages of the nanoparticles technology developed in this project is the ability to generate functionalized particles from materials of diverse chemical nature, with different morphology and with a wide variety of targeting ligands. Recently, we used TCTP-LASO functionalized with targeting moieties (PMSA) for co-delivering radionuclides in order to improve anti-tumor effects molecular radiotherapy in CRPC. Radiolabeled nanoparticles will undoubtedly lead a revolution for drug delivery, therapeutics, diagnostics and multimodality imaging. This program receive the label of Aix-Marseille Université Initiative d’Excellence (Amidex Emergence et Innovation 2018 “Nucleolipid-based nanocarriers for theranostics in prostate cancer”). We will now continue to develop functional versatile and biocompatible nanocarriers for PSMA-targeted delivery of radiopharmaceutics and anticancer drugs as innovative theranostics in prostate cancer therapy.

Palma Rocchi