Conventional chemotherapeutics used to fight cancer promote off-target damage in cells and organs that are not affected by the disease. This major drawback may be overcome with the development of tumor-targeted therapies, in which the antitumoral drugs are selectively delivered to tumoral cells using the efficient recognition between a receptor overexpressed in these cells and its ligand, without promoting off-side effects in the rest of the body.
The group of Nanobiotechnology (NBT) from the Institut de Biotecnologia i Biomedicina (IBB-UAB), led by Prof. Antonio Villaverde, develops a new concept of pharmaceuticals based on protein nanoparticles, in close collaboration with the group of Oncogenesis and Antitumor Drugs (GOA) from the Institut d’Investigació Biomèdica Sant Pau (IIB-Sant Pau) and the group of Nucleic Acids Chemistry from the Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), respectively lead by Prof. Ramon Mangues and Prof. Ramon Eritja. This research is conducted in the frame of the Director plan of CIBER-BBN, an excellence center from the Instituto de Salud Carlos III, to which all the groups belong, being assisted by three Nanbiosis ICTS units (U1, Protein Production Platform; U18, Nanotoxicology Unit; U29, Oligonucleotide Synthesis Platform).
The generated pharmaceuticals are selective for metastatic stem cells, responsible of cancer propagation, recurrence and bad prognosis, that overexpress in their surface the CXCR4 receptor, present in 23 distinct human neoplasias. Using a precise protein engineering, we generate multi-functional protein nanoparticles that remain in the bloodstream for long times and selectively enter and destroy metastatic stem cells, thus contributing to stop cancer progression. In the last years, we have employed two main strategies in the development of antitumoral protein nanoparticles. On one side, current chemotherapeutics already used in clinics in non-targeted approaches, such as Floxuridine or Monomethyl Auristatin E, are chemically linked to targeted protein nanoparticles that serve as drug delivery systems and comprise an inert scaffold, a polyhistidine tag and a targeting peptide that directs their effect to the CXCR4-tumor. On the other side, the inert scaffold of our protein nanoparticles is replaced by toxins, venoms or other death-inducer proteins that confer the protein nanoparticle an intrinsic antitumoral activity, without the need of delivering chemical drugs. Both strategies are protected by intellectual property rights.
Recently, we have explored the possibility of combining both strategies to generate intrinsically toxic nanoparticles loaded with conventional chemotherapeutics in a single pharmacological entity. This way, we seek to potentiate their antitumoral effect and face the appearance of resistances in the tumor. In this initial step, the concept proposed has been demonstrated as fully feasible, as stable nanoparticles that contain both the toxin and the loaded chemotherapeutics were generated. Although these novel nanomaterials do not improve toxic antitumoral activities in CXCR4+ tumor cell lines, this research has been crucial to identify the main bottleneck of the technology, that is achieving a precise control of the drug-binding site in order to maintain the antitumoral activity of targeted toxins, which must act at the same time as active principle and as anchoring site for chemical drugs.
This novel platform recruits in a single pharmacological entity different therapeutic actions and may open a broad investigation field in the design of antitumoral drugs. The current results of this project have been published in the scientific journal Acta Biomaterialia and presented in the international conference NALS2022 by Eric Voltà-Durán.
By Eric Voltà-Durán
Reference article – Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles https://doi.org/10.1016/j.actbio.2020.11.018