Polar Star in a nutshell

Polar Star is an MSCA-IF project of the H2020 framework programme and started in June 2019. Prostate cancer (PC) is the fifth leading cause of cancer-related death worldwide. PC often presents in its Multidrug resistant form leaving the patient few survival chances. New approaches are required to overcome resistance-related problems in PC and nanomedicine holds a lot of premises to effectively contribute in this battle. In this frame POLAR STAR aims at the implementation of combination therapy to treat castrate-resistant PC. Our strategy is to exploit innovative nanotechnology to administer contemporarily different therapeutic agents that synergically exert their activity across multiple oncogenic pathways. We plan to use new mixed polymers based on biocompatible cyclodextrins as these building blocks are already FDA approved. Simple organic chemistry is pursued to implement target selectivity and in vivo tracking of the polymeric nanocarrier. The design is guided by the final goal, the future clinical application of nanocarriers to improve PC treatment, keeping in mind upgrade of the nanocarrier systems to large scale production. We will focus on the latest PC drugs suffering from side effects and emerging resistance as multiple cargo to be loaded. Full chemico-physical characterization of the systems is planned as well as assessment of the efficacy of loaded nanocarriers in cell cultures with different drug responsivity profiles. In order to reduce animal experiments POLAR STAR will take full advantage of 3D prostate tissue models for biological tests, an apporach at the forefront in drug design. We plan to reach our goal bringing together the expertise of the fellow and the supervisor supported by the private and academic teams hosting the fellow during secondments. POLAR STAR creates a multidisciplinary environment where all actors, public and private, will benefit from reciprocal transfer of knowledge. During the project the individual fellow will have the possibility to become a complete researcher improving also her complementary and soft skills.

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State-of-the-Art

Prostate cancer (PC) continues to be a major health problem in all countries independently of their Human Development Index (HDI). With about 375 000 deaths worldwide in 2020, PC is the fifth leading cause of cancer-related death in the male population. Localized PC can be successfully cured by radical surgery or radiation therapy while the advanced and metastatic PC diseases are treated mainly with androgen deprivation therapy (ADT). ADT-sensitive PC often evolves into Castration Resistant Prostate Cancer (CRPC) after two years, which currently remains incurable. Chemotherapy with docetaxel has been used in combination with ADT but provided only a small benefit to the patient with CRPC. The lack of efficacious treatments for CRPC has led to an urgent need for the development of new therapies. New therapeutic strategies will likely require personalized therapy based on combination therapy with chemotherapeutic agents targeting different metabolisms specifically operating in PC and CRPC cells. Administration of multiple therapeutics can be difficult because of unfavorable distribution in the body, rapid body clearance, limited tumor accessibility and toxicity due to high doses required. Nanotechnology for drug delivery can offer a series of advantages such as the possibility to load in a unique nanoparticle system high amounts of drugs as well as the combination of more than one therapeutic agent. Another advantage of nanoparticles for drug delivery is the selective targeting of the tumor site avoiding healthy tissues, and thus limiting toxic side effects. The tumor-specific delivery of a drug by means of a nanoparticle can be achieved in two ways: (1) passive tumor targeting is based on the principle of enhanced permeation and retention (EPR) effect and exploits both the tumor increased vascular permeability and the reduced lymphatic drainage to accumulate the nanoparticles in the tumor; (2) for active tumor targeting, instead, molecules attached to the nanoparticle are needed that bind to specific surface receptors expressed exclusively by the target cancer cells followed by nanoparticle uptake through receptor-mediated endocytosis.

Objective

The objective of the project Polar Star is the combination of known antitumoral drugs with “less known” therapeutic agents as it may open completely new roads for innovation in Castrate Resistant Prostate Cancer (CRPC) treatment. As to “less known” therapeutics, we are interested in agents able to produce cytotoxic species upon light irradiation. In particular, the idea is the administration of chemotherapeutic drugs together with a photosensitizer (PS) which upon irradiation with red light in the presence of oxygen produces Reactive Oxygen Species (ROS), mainly singlet oxygen ( 1 O 2 ); ROS start a cascade of processes finally killing the cancer cells. To implement combination therapy for CRPC, we use polymeric nanoparticles (NPs) based on cyclodextrins (CyDs) to assemble the various building blocks, ie the drugs and the photosensitizer. Our final goal is the preparation of different nanoparticles made of the CyD polymer that encapsulates the right amounts of drugs and photosensitizer ready for the application in vivo. This approach allows the contemporary administration of drugs and photosensitizer and resolves a serious of problems caused by the insolubility of many CRPC drugs in physiological fluids.

Methodology

POLAR STAR relies on four interconnected actions:

1. Synthesis of polymeric nanocarriers. The main building block of the polymeric carriers are natural cyclodextrins (CyD), water soluble, biocompatible cyclic oligosaccharides, made of α-D-glucopyranose units. We choose CyD polymers as they are able to associate drugs much more efficiently than the monomeric CyDs, to enhance drug solubility and to incorporate two or more therapeutic agents simultaneously. We will prepare water soluble CyD polymers following a CyD polycondensation method in the presence of a crosslinking bifunctional agent. If necessary, we will produce, post-condensation, positively and negatively charged polymers as well as polymers with a targeting unit promoting selective interaction with cancer cells.

2. Loading of the nanoparticles with multiple therapeutic agents: We will focus on the morecent drugs proposed for the treatment of CRPC like, for example, cabazitaxel, and enzalutamide. These drugs display serious drawbacks related with their low aqueous solubility and with the onset of severe side effects, forcing administration in tolerable doses. As drug/PS we will consider mitoxantrone, a cancer drug with light absorption spectrum extending up to 750 nm. Phase solubility diagrams will be recorded for mixed polymers loading at least two therapeutics. The drug binding constants for different polymers in solution will be measured by means of absorption, fluorescence and circular dichroism (CD). Techniques such as DLS and SEM will be used to determine the particle size of the loaded polymers organizing in NPs and to check the NP stability and possible aggregation.


3. Biological assays of the new drug loaded carriers. First, cytotoxicity of the new nanoparticles loaded with drug combinations will be tested on various prostate cell lines, normal and cancer with hormone sensitive and castrate-resistant profile in dark conditions. The quantitative and qualitative cellular uptake will be evaluated through fluorescence-activated cell sorting (FACS) analysis on various cancer cell lines in order to identify the carriers with a better profile of cell penetration.

4. Study of the drug/ nanoparticle systems in PC 3D models: 3D models and organoid cultures of normal and tumor prostate tissues have been developed to understand better key structural and functional properties of the organ compared to traditional 2D cell cultures.

Results

We studied various polymers of the α, β, and γCyDs to encapsulate three different drugs as well as the photosensitizer. In all cases the polymer of βCyDs works best and dissolves the highest amount of drug. Biological evaluation of the drug-loaded nanoparticles is currently going on.

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Elisabetta

Elisabetta Pancani

Postdoc Fellow

Elisabetta Pancani graduated with a M.Sc. in Medicinal Chemistry and Pharmaceutical Technology near the University of Torino in 2014, discussing an experimental thesis conducted during a 4 months Erasmus Placement Fellowship at Université d’Angers (France) under the joint supervision of Dr. C. Passirani and Dr. B. Stella. In 2014, she was involved in the EU Project No. 608407: FP7-PEOPLE-ITN “CyclonHit” as an Early-Stage Researcher at the Institut des Sciences Moleculaires d’Orsay in Orsay (France). Whitin this project, she obtained her PhD at Université Paris-Sud/Paris-Saclay under the supervision of Dr. R. Gref. Her PhD work aimed at the development of nanoparticles for the delivery of antimicrobial agents to fight resistance mechanisms. She focused on the co-encapsulation of drug combinations in biodegradable and biocompatible NPs based on polyesters (PLA, PLGA and PCL) or polymerized cyclodextrins and on their advanced physico-chemical characterization. In 2019, she was awarded with a H2020 MSCA-IF grant (Project No. 843014 “POLAR STAR”) and joined the Istituto per la Sintesi Organica e la Fotoreattività at CNR in Bologna. The aim of our work is to develop new mixed cyclodextrin-based nanocarriers to administer contemporarily different therapeutic agents that synergically exert their activity across multiple oncogenic pathways in castrate resistant prostate cancer. More information at ORCID.

Ilse

Ilse Manet

Coordinator

Ilse Manet graduated in Chemistry in 1992 at the Catholic University of Leuven (Belgium) discussing the thesis “Luminescence properties of lanthanide ions in supramolecular species”, supervisors Prof. N. Sabbatini and Prof. C. Görller-Walrand. In 1998 she achieved her PhD Degree in Chemical Sciences at the University of Bologna, discussing the dissertation entitled “Luminescent molecular devices”, supervisor Prof. V. Balzani. In the period 1999-2000 she collaborated with the group of prof. G. Gottarelli and G. Spada at the Faculty of Industrial Chemistry of the University of Bologna. In 2001 she became permanent researcher at the Istituto per la Sintesi Organica e la Fotoreattività (ISOF), National Research Council, Bologna (Italy). Since 2020 she is Senior Researcher near ISOF. At ISOF her research interested focused on the study of the photophysics and photochemistry of small molecules, in solution and in non covalent complexes with synthetic hosts and biomolecules using different spectroscopic optical techniques. Recently she started working in the field of confocal time-resolved fluorescence microscopy. She has published ca. 90 articles in international peer-review journals. Personal website; More information at Publons and ORCID.

Francesco

Francesco Manoli

Technician

Francesco Manoli graduated in 1991 in Pharmacy at "Università degli Studi di Padova" discussing the thesis "Phenylpentadiene tricarbonylchromium complexes: synthesis and structure". From 1982 to 1986 he was Technical Assistant near Istituto Tecnico Industriale Statale "G.Natta" of Padova, in the analytical chemistry and biological chemistry laboratories. From 1987 to 2000 he was technical Assistant near Centro di Studio sugli Stati Molecolari Radicalici ed Eccitati, National Research Council - Padova. Since 2000 he is Technical Assistant near Istituto per la Sintesi Organica e la Fotoreattività, National Research Council - Bologna, where he collaborates with Ilse Manet. More information at Publons.

CycloLab is the world's only all-round cyclodextrin service provider. Some figures: ~400 scientific papers, ~7000 citation to the papers, ~600 customer reports. CycloLab has 36 full-time employees of which 19 are R&D personnel. CycloLab's expertise and technology cover custom synthesis, drug solubilization and stabilization, controlled release, drug targeting, cyclodextrin related analytics and stability testing. CycloLab's product portfolio includes well-established cyclodextrin-based polymers, fluorescent-labeled cyclodextrin derivatives available with in-depth characterization. Website link

The Department of Diagnostic and Specialty Medicine (DIMES) is one the three Departments composing the School of Medicine of the University Alma Mater Studiorum of Bologna. The Department members carry out their research and teaching activity near the Sant’Orsola Hospital and in University Institutes. Scientific activity covers several fields of medicine; cancer research and experimental medicine are considered at the forefront of science.

The Erasmus Medical Center (EMC) is the top University Medical Research Institute in the Netherlands and ranks among the leading Medical Research Centers in the European Union. Near the Dept. of Urology Dr. W. M. van Weerden is heading a research group with national and international collaborations in the frame of EU projects. Specific research interests encompass 1. Prostate cancer modeling, with special attention to the development of novel clinically relevant patient-derived xenograft (PDX) models of CRPC, new spontaneous metastatic models, ex vivo tissue slices and novel 2D and 3D cocultivation models; 2. Mechanisms of hormone - and chemoresistance; 3. Multimodality prostate-targeted imaging using nanobodies. Her group is involved in evaluating novel (targeted) therapies and testing of compounds for pharmaceutic companies. Website link

CONTACT US

MAIL US

ilse.manet@isof.cnr.it

elisabetta.pancani89@gmail.com