Sviluppo di Nanoparticelle Polimeriche Fotoattivabili per Terapie Antitumorali Multimodali

This project aims to the design, development, characterization and potential transfer on industrial scale-up of Photoactivable Nanoparticle Polymeric Systems for Novel Multimodal Antitumoral Therapies. It is intended to develop multicargo nanocarriers encapsulating “conventional” chemotherapeutics, while simultaneously integrating photoprecursors generating Reactive Oxygen Species (ROS) and/or Reactive Nitrogen Species (RNS) as “unconventional” therapeutic agents. In particular, Nitric Oxide (NO) and/or singlet oxygen (1O2) will be generated in a selective, sequential or simultaneous fashion, exploiting the precise spatiotemporal control offered by light stimuli with biocompatible energy, absorbed by suitable photoprecursors. They will be integrated into polymeric nanocarriers through covalent and/or non-covalent approaches, together with conventional chemodrugs, with the purpose to obtain additive and/or synergistic therapeutic effects. This photo-chemo combinatory approach can, in principle, maximize the therapeutic action of the conventional antitumorals while minimizing their side-effects and overcoming drug-resistance. Nanocarriers will be produced using branched cyclodextrin polymers, well tolerated in in vivo systems. The use of FDA (Food and Drug Administration) approved polymer materials, drugs and photoprecursors, together with the development of new systems, will allow both the possibility of innovation of already existing products and the design of new potential photonanomedicines. The same polymeric scaffolds will be employed to co-assemble, stabilize and solubilize Gold (Au) nanostructures for photothermal applications. Au is able to absorb in the visible/near infrared spectral regions thanks to the localised surface plasmon resonance, and to convert the absorbed photons in the so-called “therapeutic window” into heat, with high efficiency and great photostability. This mechanism is at the basis of PTT (Photothermal Therapy), which is one of the most intriguing emerging approaches to cancer treatment and exploits temperature increase to induce cytotoxicity. Photogenerators and Au nanoparticles will be active only in the illuminated areas, overcoming the lack in site-specificity, a substantial issue of the common antitumorals. Each single therapeutic component will be designed and assembled to be excited with light at different energy, presenting fluorescence for the easy tracking in bio-systems and preserving the photochemical properties, despite the localization within the same nanocarrier (a non-trivial aspect for photoactivated processes). In this way, all the involved units will be able to operate in a parallel way under the irradiation. An insight into the photobehaviour of curcumin (CUR) is also provided. CUR is a vegetable pigment widely studied in literature for its therapeutic properties and delivered by suitable nanocarriers to enhance the very low water solubility. Its strong absorption in the blue region has encouraged the application as a phototherapeutic agent in infections and cancer treatment approaches. However, although the photobiological activities are undeniable, the mechanisms behind them are not fully understood. In this contribution, this project aims to the investigation of its photobehaviour when encapsulated within different biocompatible nanocarriers and in human serum albumin, as a representative biomolecule.  

Questo progetto mira alla progettazione, allo sviluppo, alla caratterizzazione e al potenziale trasferimento su scala industriale di sistemi polimerici di nanoparticelle fotoattivabili per nuove terapie antitumorali multimodali L'obiettivo è sviluppare nanocarrier multicargo che incapsulino chemioterapici "convenzionali", integrando contemporaneamente fotoprecursori che generino specie reattive dell'ossigeno (ROS) e/o specie reattive dell'azoto (RNS) come agenti terapeutici "non convenzionali". In particolare, l'ossido nitrico (NO) e/o l'ossigeno singoletto (1O2) saranno generati in modo selettivo, sequenziale o simultaneo, sfruttando il preciso controllo spazio-temporale offerto da stimoli luminosi con energia biocompatibile, assorbiti da opportuni fotoprecursori. I fotoprecursori saranno integrati in nanocarrier polimerici attraverso approcci covalenti e/o non covalenti, insieme a chemiofarmaci convenzionali, allo scopo di ottenere effetti terapeutici additivi e/o sinergici. Questo approccio combinatorio foto-chemioterapico può, in linea di principio, massimizzare l'azione terapeutica degli antitumorali convenzionali, minimizzandone gli effetti collaterali e superandone la farmaco-resistenza. I nanocarrier saranno prodotti utilizzando polimeri "branched" di ciclodestrine, ben tollerati nei sistemi in vivo. L'uso di materiali polimerici, farmaci e fotoprecursori approvati dalla FDA (Food and Drug Administration), insieme allo sviluppo di nuovi sistemi, consentirà sia la possibilità di innovare prodotti già esistenti, sia la progettazione di nuovi potenziali farmaci.