Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 15, Pages -Publisher
MDPI
DOI: 10.3390/ijms22157987
Keywords
chitosan; hyaluronic acid; cyclodextrins; biocompatibility modulation; enzyme delivery; complement system; haemocompatibility; phenylketonuria; human phenylalanine hydroxylase; nanoparticles
Funding
- FEDER
- Fundacao para a Ciencia e a Tecnologia, I. P. [UIDB/04138/2020, UIDP/04138/2020, PTDC/QUI/64023/2006, PTDC/EBB-BIO/101237/2008, SFRH/BSAB/1210/2011, SFRH/BD/47946/2008]
- National PKU Alliance, USA
- Fundação para a Ciência e a Tecnologia [PTDC/EBB-BIO/101237/2008, SFRH/BD/47946/2008, PTDC/QUI/64023/2006, SFRH/BSAB/1210/2011] Funding Source: FCT
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This study introduces a systematic development of a delivery system based on chitosan (CS) and ionotropic gelation with tripolyphosphate (TPP) to nanoencapsulate human phenylalanine hydroxylase (hPAH) model, while maintaining protein stability and enzyme activity. By combining hyaluronic acid (HA) and cyclodextrins (CDs) as a set of biopolymers, hPAH was effectively entrapped within CS nanoparticles with improved stability and maintained activity, while achieving strict control of the formulation process. Detailed characterization showed that the lead formulations were internalized by hepatocytes, did not reveal cell toxicity, and presented a safe haemocompatible profile.
Polymeric-based nano drug delivery systems have been widely exploited to overcome protein instability during formulation. Presently, a diverse range of polymeric agents can be used, among which polysaccharides, such as chitosan (CS), hyaluronic acid (HA) and cyclodextrins (CDs), are included. Due to its unique biological and physicochemical properties, CS is one of the most used polysaccharides for development of protein delivery systems. However, CS has been described as potentially immunogenic. By envisaging a biosafe cytocompatible and haemocompatible profile, this paper reports the systematic development of a delivery system based on CS and derived with HA and CDs to nanoencapsulate the model human phenylalanine hydroxylase (hPAH) through ionotropic gelation with tripolyphosphate (TPP), while maintaining protein stability and enzyme activity. By merging the combined set of biopolymers, we were able to effectively entrap hPAH within CS nanoparticles with improvements in hPAH stability and the maintenance of functional activity, while simultaneously achieving strict control of the formulation process. Detailed characterization of the developed nanoparticulate systems showed that the lead formulations were internalized by hepatocytes (HepG2 cell line), did not reveal cell toxicity and presented a safe haemocompatible profile.
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