Hybrid injectable sol-gel systems based on thermo-sensitive polyurethane hydrogels carrying pH-sensitive mesoporous silica nanoparticles for the controlled and triggered release of therapeutic agents.

Thumbnail Image
Full text at PDC
Publication Date
Boffito, Monica
Torchio, Alessandro
Tonda-Turro, Chiara
Laurano, Rosella
Berckmann, Julia C
Cassino, Claudio
Duda, Georg
Vallet Regí, María
Advisors (or tutors)
Journal Title
Journal ISSN
Volume Title
Frontiers Media
Google Scholar
Research Projects
Organizational Units
Journal Issue
Injectable therapeutical formulations locally releasing their cargo with tunable kinetics in response to external biochemical/physical cues are gaining interest in the scientific community, with the aim to overcome the cons of traditional administration routes. In this work, we proposed an alternative solution to this challenging goal by combining thermosensitive hydrogels based on custom-made amphiphilic poly(ether urethane)s (PEUs) and mesoporous silica nanoparticles coated with a self-immolative polymer sensitive to acid pH (MSN-CS-SIP). By exploiting PEU chemical versatility, Boc-protected amino groups were introduced as PEU building block (PEU-Boc), which were then subjected to a deprotection reaction to expose pendant primary amines along the polymer backbone (PEU-NH2, 3E18 NH2/gPEU-NH2) with the aim to accelerate system response to external acid pH environment. Then, thermo-sensitive hydrogels were designed (15% w/v) showing fast gelation in physiological conditions (approximately 5 min), while no significant changes in gelation temperature and kinetics were induced by the Boc-deprotection. Conversely, free amines in PEU-NH2 effectively enhanced and accelerated acid pH transfer (pH 5) through hydrogel thickness (PEU-Boc and PEUNH2 gels covered approximately 42 and 52% of the pH delta between their initial pH and the pH of the surrounding buffer within 30 min incubation, respectively). MSN-CS-SIP carrying a fluorescent cargo as model drug (MSN-CS-SIP-Ru) were then encapsulated within the hydrogels with no significant effects on their thermo-sensitivity. Injectability and in situ gelation at 37�C were demonstrated ex vivo through sub-cutaneous injection. Hybrid Hydrogels for pH-Triggered Release in rodents. Moreover, MSN-CS-SIP-Ru-loaded gels turned out to be detectable through the skin by IVIS imaging. Cargo acid pH-triggered delivery from PEU-Boc and PEUNH2 gels was finally demonstrated through drug release tests in neutral and acid pH environments (in acid pH environment approximately 2-fold higher cargo release). Additionally, acid-triggered payload release from PEU-NH2 gels was significantly higher compared to PEU-Boc systems at 3 and 4 days incubation. The herein designed hybrid injectable formulations could thus represent a significant step forward in the development of multi-stimuli sensitive drug carriers. Indeed, being able to adapt their behavior in response to biochemical cues from the surrounding physio-pathological environment, these formulations can effectively trigger the release of their payload according to therapeutic needs.
RESEARCHER ID S-2443-2016 (Miguel Gisbert Garzarán) ORCID 0000-0001-9815-0354 (Miguel Gisbert Garzarán) RESEARCHER ID K-3719-2014 (Miguel Manzano García) ORCID 0000-0001-6238-6111 (Miguel Manzano García) RESEARCHER ID M-3378-2014 (María Vallet Regí) ORCID 0000-0002-6104-4889 (María Vallet Regí)