12:00 – 12:30 Tetiana Melnyk

A polymer-based intranasal drug delivery platform as a new strategy towards pediatric gliomas treatment  

Malignant gliomas account for 75% of all brain tumors in children. Despite great achievements in other cancer treatment, poor survival rate of glioblastoma patients (12-15 months) highlights the necessity for new approaches. Unfortunately, many therapeutic strategies that have been successful with other cancers have failed in glioblastoma (GBM) as a result of immunosuppressive environment and blood-brain barrier (BBB) – the main limitation to deliver medicines effectively to the brain.  Intranasal administration is a promising non-invasive strategy that enables direct nose-to-brain delivery and bypasses the BBB and hepato-gastrointestinal metabolism. Thus, we have explored this via in order to achieve brain drug delivery by means of a polypeptide-based platform. We have selected polyglutamates (PGA) because they are excellent candidates for brain delivery due to their biodegradability and multivalency, which allows the introduction of drugs and targeting moieties to enhance mucosal permeation.  To fulfill our goal, we have accomplished three main objectives:

1) The development of an intranasal drug delivery platform, including the synthesis of targeted systems and the establishment of an ex vivo model to test their permeation capability through the mucosa,

2) The design and synthesis of polyglutamate-based conjugates with palbociclib and their physico-chemical and biological characterization.

3) The evaluation of the main candidates and the evaluation of combination therapy to enhance the efficacy of the selected treatment.

We successfully synthesized a family of star and linear PGA-palbociclib conjugates with rationally designed disulfide and peptidic linkers that specifically cleaved under redox or proteolytic conditions and then undergo self-immolation to release the intact drug. Interestingly, we observed the conformational changes in the polymeric structure of the conjugates depending on the drug loading. Correlating spectral data from circular dichroism, SAXS experiments and cell viability studies in patient-derived tumor cell lines we have demonstrated that drug loading of the conjugate affects their biological activity. In parallel, nanocarriers with efficient nose-to-brain diffusion capacity have been identified in ex vivo model and with preliminary in vivo data we confirmed that our polymers can reach the brain, proving distribution in different brain areas. Overall, in vitro and ex vivo studies have demonstrated the potential of PGA-based nanocarriers as a promising strategy for pediatric gliomas treatment.

12:30 – 13:00 Vicente Pérez García

Exploring new molecular mechanisms of placental invasion.

Introduction and brief scientific overview of one the new group at the CIPF.