Mucosal delivery of biodegradable and biocompatible nanoparticles targeting the neonatal Fc-receptor (FcRn)
1 Purpose
Nanoparticles and other proteins-based therapeutics have the potential to significantly impact treatment of various diseases. Many of those are entering clinical trials or have already been approved by the FDA for treatments. However, they are usually administered parenterally, which is invasive and requires frequent drug administration. An alternative and preferable approach would be mucosal delivery, such as oral and intranasal routes, 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 drugs to the systemic circulation.
To improve the uptake and transcellular delivery of drugs following oral and intranasal administration, our study aims to develop drug delivery platforms 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 combined with the drugs. Based on results from in vitro studies, we will perform oral and intranasal administration of selected candidate in transgenic mice to investigate whether the FcRn-targeting platforms 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 platforms.
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 FcRn-targeting albumin platform for efficient FcRn-mediated delivery of therapeutics across mucosal membranes can be translated into the next generation of drug delivery systems. Oral and intranasal administration 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 drug delivery platforms 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 446 Tg32 mice (human FcRn transgenic) and 130 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 drug candidates 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.
Nanoparticles and other proteins-based therapeutics have the potential to significantly impact treatment of various diseases. Many of those are entering clinical trials or have already been approved by the FDA for treatments. However, they are usually administered parenterally, which is invasive and requires frequent drug administration. An alternative and preferable approach would be mucosal delivery, such as oral and intranasal routes, 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 drugs to the systemic circulation.
To improve the uptake and transcellular delivery of drugs following oral and intranasal administration, our study aims to develop drug delivery platforms 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 combined with the drugs. Based on results from in vitro studies, we will perform oral and intranasal administration of selected candidate in transgenic mice to investigate whether the FcRn-targeting platforms 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 platforms.
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 FcRn-targeting albumin platform for efficient FcRn-mediated delivery of therapeutics across mucosal membranes can be translated into the next generation of drug delivery systems. Oral and intranasal administration 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 drug delivery platforms 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 446 Tg32 mice (human FcRn transgenic) and 130 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 drug candidates 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.