Mucosal delivery of biodegradable and biocompatible nanoparticles targeting the neonatal Fc-receptor (FcRn)
1 Purpose
Drug-encapsulating nanoparticles (NPs) have the potential to make significant impacts on the treatment of various diseases. Several NP-based formulations are entering clinical trials, while some NPs have already been approved by the FDA for treatments. However, they can only be administered parenterally, that is usually invasive and requires frequent drug administration. An alternative and preferable approach would be mucosal delivery of NPs, such as oral and intranasal routes of administration, owing to patient convenience and compliance. Nonetheless, mucosal delivery remains a challenge due to the selective barrier across polarized epithelial cells at the mucosal surfaces, which hinders effective transport of NPs to the systemic circulation.
To improve the uptake and transcellular delivery of NPs following oral and intranasal administration, our study aims to develop nanoparticulate drug delivery systems targeting the neonatal Fc receptor (FcRn), which is broadly expressed at the mucosal epithelium. We have developed engineered albumin variants with altered binding affinity to FcRn that can be covalently conjugated to the surface of NPs. Based on results from in vitro studies, we will perform oral and intranasal administration of selected albumin-decorated NP formulations in transgenic mice to investigate whether the NPs may be delivered to the blood via FcRn-mediated pathway. This platform may offer a needle-free approach for the delivery of therapeutics using mucosal targeting nanocarriers.
2 Distress
Animals may experience brief fear and pain while being handled for the administration of test substances and the collection of blood. We expect no pain or suffering in animals as an outcome of the administered compounds.
3 Expected benefit
The development of NPs decorated with engineered albumin for efficient FcRn-mediated delivery of therapeutics across mucosal membranes can be translated into the next generation of nanoparticulate drug delivery systems. Oral and intranasal administration of NPs is an attractive alternative to invasive parenteral methods for improved sustained therapy and chronic delivery of therapeutics. This makes use of needles unnecessary, which will lower the risk of infections, eliminate needle sticks and disposal, and reduce patients´ pain and stress. Such a novel strategy will assuredly benefit society, especially for healthcare systems. Without the need for health workers required for providing injections, the number of patient visits to hospitals and clinics may be significantly reduced. Thus, this study will pave the way for developing novel nanocarriers for targeted mucosal delivery of therapeutics that is more efficient, cost-effective, and convenient than conventional approaches.
4 Number of animals, and what kind
The study will include 396 Tg32 mice (human FcRn transgenic) and 180 FcRn KO mice.
5 How to adhere to 3R
Highly qualified personnel will take care of the research animals, mice will have an enriched environment and we will minimize stress when handling mice. By a thorough characterization using biochemical and cellular methods, we have limited the number of NP formulations of interest, hence maintaining the animal resources needed to an absolute minimum. Yet an in vivo model is necessary to determine transepithelial transport, which depends on many factors.
9/9/2021 - Request to add participants
Drug-encapsulating nanoparticles (NPs) have the potential to make significant impacts on the treatment of various diseases. Several NP-based formulations are entering clinical trials, while some NPs have already been approved by the FDA for treatments. However, they can only be administered parenterally, that is usually invasive and requires frequent drug administration. An alternative and preferable approach would be mucosal delivery of NPs, such as oral and intranasal routes of administration, owing to patient convenience and compliance. Nonetheless, mucosal delivery remains a challenge due to the selective barrier across polarized epithelial cells at the mucosal surfaces, which hinders effective transport of NPs to the systemic circulation.
To improve the uptake and transcellular delivery of NPs following oral and intranasal administration, our study aims to develop nanoparticulate drug delivery systems targeting the neonatal Fc receptor (FcRn), which is broadly expressed at the mucosal epithelium. We have developed engineered albumin variants with altered binding affinity to FcRn that can be covalently conjugated to the surface of NPs. Based on results from in vitro studies, we will perform oral and intranasal administration of selected albumin-decorated NP formulations in transgenic mice to investigate whether the NPs may be delivered to the blood via FcRn-mediated pathway. This platform may offer a needle-free approach for the delivery of therapeutics using mucosal targeting nanocarriers.
2 Distress
Animals may experience brief fear and pain while being handled for the administration of test substances and the collection of blood. We expect no pain or suffering in animals as an outcome of the administered compounds.
3 Expected benefit
The development of NPs decorated with engineered albumin for efficient FcRn-mediated delivery of therapeutics across mucosal membranes can be translated into the next generation of nanoparticulate drug delivery systems. Oral and intranasal administration of NPs is an attractive alternative to invasive parenteral methods for improved sustained therapy and chronic delivery of therapeutics. This makes use of needles unnecessary, which will lower the risk of infections, eliminate needle sticks and disposal, and reduce patients´ pain and stress. Such a novel strategy will assuredly benefit society, especially for healthcare systems. Without the need for health workers required for providing injections, the number of patient visits to hospitals and clinics may be significantly reduced. Thus, this study will pave the way for developing novel nanocarriers for targeted mucosal delivery of therapeutics that is more efficient, cost-effective, and convenient than conventional approaches.
4 Number of animals, and what kind
The study will include 396 Tg32 mice (human FcRn transgenic) and 180 FcRn KO mice.
5 How to adhere to 3R
Highly qualified personnel will take care of the research animals, mice will have an enriched environment and we will minimize stress when handling mice. By a thorough characterization using biochemical and cellular methods, we have limited the number of NP formulations of interest, hence maintaining the animal resources needed to an absolute minimum. Yet an in vivo model is necessary to determine transepithelial transport, which depends on many factors.
9/9/2021 - Request to add participants