Title : Aptamers as therapeutic agents in human cancers and evidence for glioblastoma targeting through the blood-brain-barrier of aptamer-functionalized nanosystems
Abstract:
Highly selective compounds emerging for anti-cancer therapy are oligonucleotide aptamers that interact with their targets by recognizing a specific three-dimensional structure. Thanks to their unique properties (small size, high selectivity and sensitivity, high stability, convenient synthesis and modification, lack of immunogenicity), aptamers have been proved as a valid alternative to antibodies as targeted cancer therapeutic agents on their own or as carriers of chemotherapeutic agents, small interfering RNAs or drug-loaded nanoparticles. Although the SELEX (Systematic Evolution of Ligands by Exponential enrichment) process to isolate aptamers is typically carried out using purified target molecules, we employ whole live cells as selection targets in order to obtain aptamers against cell surface proteins in their native conformation and even in the absence of prior knowledge of biomarkers present at the cell surface. Here, we report our recent data on the tumor targeting properties and preclinical evaluation of two validated aptamers, that we previously generated by cell-SELEX as high specific ligands of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor β (PDGFRβ). Their therapeutic effects have been investigated in human glioblastoma (GBM) and triple negative breast cancers (TNBCs), heterogeneous cancers still lacking of targeted therapeutic options. Moreover, the results obtained so far on the selection of novel TNBC-specific aptamers, will be discussed as well. Polymeric nanoparticles (PNPs) offer unique possibility for in vivo delivery of diagnostics and/or therapeutics to tumor tissues, when conjugated to specific targeting agents. We will describe the preparation of drug-loaded PNPs conjugated with the anti-PDGFRβ aptamer which, in vitro, are able of high uptake into GBM cells and kill them when loaded with a PI3KmTOR inhibitor. Ultimately, in vivo, we also demonstrate the blood-brain-barrier passage and tumor accumulation in an orthotopic model of human GBM.
Takeaway Notes: The audience will know our research approach from the generation of oligonucleotide aptamers to their development as tools to: 1) identify novel biomarkers for human cancers; 2) discriminate different subtypes of heterogeneous human cancers; 3) interfere with malignant phenotype on their own and/or in combination with conventional chemotherapy; 4) deliver drug-loaded nanoparticles specifically to target cancer cells. The proposed research has the potential to lead a revolution in the development of anti-cancer drugs and should inspire other attempts to harness aptamer technology for improved cancer treatment.
