A novel nanoparticle-based approach for mucosal delivery of therapeutics

Biodegradable nanoparticles encapsulating drugs have the potential to make a significant impact on the treatment of many diseases, including cancer, infectious diseases and diabetes. A number of NP-based therapeutics are currently entering clinical trials or have been approved but they can only be administered by parenteral methods. An alternative and preferable approach would be mucosal administration, but this remains a challenge because transport across selective epithelial barriers is very limited. Furthermore, frequent administration is often required. As such, intranasal or oral administration is preferable due to patient convenience and compliance. Absorption of nanoparticles at mucosal surfaces is highly inefficient because of their physicochemical properties that prevent efficient transport across intestinal epithelial barriers. Thus, there is an urgent need for novel strategies that improve uptake and transcellular delivery. The easiest and most cost effective way would be self-administered mucosal delivery. A PhD student with nano-medical expertise was employed on the project, which is under the lab guidance of a postdoc. Together, they have carried out systematic studies where they have designed and produced human albumin variants with different ability to bind the receptor that is in the focus for mucosal targeting. The designed variants have been characterized in various in vitro and in vivo systems before being used to establish a number of protocols for conjugation to biodegradable nanoparticles. This has been carried out so that they retain their ability to bind pH-dependently to the receptor. Particles with different properties have been designed to be delivered over polarized epithelial cells in culture, and shown to be capable of being encapsulated with model drugs. Therapeutic effect has been shown in a new humanized mouse model, and has been published. We have also designed a new generation of nanoparticles where we utilized a unique human albumin variant with enhanced capacity to engage the receptor. These particles have been characterized by a number of different methods, and systematic experiments have been carried out in humanized mice. Here, we have verified how both the soluble albumin proteins and the designed particles behave after systemic delivery as well as after being delivered in a non-invasive manner to the lungs. There are 2 manuscripts ready for submission and we are in the process of securing additional funding to pursue the most promising results. A comprehensive overview article has also been written which sheds light on the scope of possibilities that the project has aimed to solve.

Prosjektet har bidratt til en mer omfattende forståelse av FcRn-albumin-biologi og hvordan denne biologien kan utforskes i design av strategier for målrettet levering på tvers av cellulære barrierer. Som en del av dette er det utviklet nye analyser og protokoller som vil være av betydning for prosjekter langt utover kjernefokuset i dette prosjektet. Spesielt viktighet er data som viser hvor viktig det er å forstå forskjeller i binding mellom reseptor og albumin på tvers av arter. Og i denne sammenhengen viktigheten av å skreddersy forsøkene ved bruk av en transgene musemodell i sammenheng med albuminbaserte strategier. Dette er grunnleggende viktig kunnskap for både akademia og industri i en internasjonal setting. Resultatene bør bane vei for ytterligere forbedringer av de utviklede strategiene som er anvendelige innen en rekke bruksområder. Derav er den genererte kunnskapen og teknologi utviklet av potensiell stor verdi for forskningsmiljøet med fokus på NP-design og leveransestrategier, men også for industrien i en kommersiell sammenheng.

Bio-therapeutics are usually given intramuscularly or subcutaneously, whereas the preferred route would be delivery via mucosal surfaces without the need for syringes, needles and trained health workers. Mucosal tissues form selective barriers that prevent direct delivery, however. Thus, there is an urgent need for efficient strategies for delivery across mucosal barriers. In the present project, we aim to develop novel nanoparticles (NPs) targeting the neonatal Fc receptor (FcRn), which is broadly expressed at mucosal surfaces. We have developed unique engineered albumin variants that bind favorably to FcRn, and we will site-specifically decorate NPs with such albumin variants. The NPs will be tested for transport across mucosal surfaces in vivo in a novel state-of-the-art transgenic mouse model, and delivery of encapsulated bio-therapeutics will be studied. The proposed project will pave the way for development of novel classes of NPs for targeted mucosal delivery of bio-therapeutics. As such, the project is in good agreement with the guidelines and principles in the call for proposals on health and medical technology.