Development of nuclease-resistant RNA aptamer-based drugs and applications for cancer treatment

PI:

Laura Cerchia

Email:

laura.cerchia@ieos.cnr.it

Affiliation:

IEOS - Istituto per l'Endocrinologia e l'Oncologia Sperimentale" Gaetano Salvatore

ORCID:

0000-0002-7633-7932

Research activity: RNA aptamers, similarly to antibodies, form high-affinity bonds with their specific protein targets, thus representing an effective tool for active cancer targeting. However, being synthesized chemically, they are cheaper, non-immunogenic, more stable and reliable in terms of reproducibility compared to protein therapeutics.
My group has a consolidated expertise in the SELEX (Systematic Evolution of Ligands by EXponential enrichment) technology for the efficient isolation of nuclease-resistant 2’FPy-RNA aptamers and in their use for both identifying novel cancer biomarkers and targeting them by innovative therapeutic strategies. So far, by applying SELEX to different tumor types, we have generated several oncoprotein-targeting aptamers, which have been developed at preclinical level as therapeutics/theranostics. Our aptamers have been validated as tools for: 1) binding to cell surface receptors and inhibiting oncogenic signaling pathways (antagonistic therapy); 2) delivering nanoparticles loaded with therapeutic cargos (chemotherapeutics, small inhibitors, photosensitizers) specifically to target cells (targeted drug delivery); 3) causing selective gene silencing upon covalent conjugation to siRNA or siRNA-loaded nanoparticles (targeted gene therapy); 4) stimulating immune cells against cancer cells (immunotherapy). We are currently focusing on two highly aggressive tumors, glioblastoma and triple-negative breast cancer, with still limited options of targeted therapy.

Our specific goals in Spoke 6: Aim of the project “Development of nuclease-resistant RNA aptamer-based drugs and applications for cancer treatment” is the development of 2’FPy-RNA aptamers specific for new tumor-associated targets, which will be evaluated as smart anti-cancer agents. We intend to develop aptamer-functionalized nanosystems as platforms for chemotherapy, photodynamic therapy and/or gene therapy. To this aim, drug-loaded nanoparticles will be conjugated with aptamers, those already generated and validated in my lab and the newly developed aptamers, to ensure the precise delivery of their therapeutic cargo to cancer cells and tumor microenvironment components, thus improving specificity and decreasing the off-target effects.

Relevant publications

  1. Agnello L, et al. and Cerchia L. Tissue Inhibitor of Metalloproteinases-1 Overexpression Mediates Chemoresistance in Triple-Negative Breast Cancer Cells. Cells. 2023; 12(13):1809.

  2. Agnello L, et al. and Cerchia L. Aptamer-Based Strategies to Boost Immunotherapy in TNBC. Cancers (Basel). 2023;15(7):2010.

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