Abstract
In this work, we aimed to improve the encapsulation efficiency of sepiapterin (SP), the natural precursor of the essential cofactor tetrahydrobiopterin (BH4) that displays mild water-solubility and a short biological half-life, within methoxy-poly(ethylene-glycol)-poly(epsilon-caprolactone)(mPEG-PCL) nanoparticles (NPs) by means of its complexation and hydrophobization with 2,3,6-triacetyl-β-cyclodextrin (TAβCD). For this, SP/TAβCD complexes were produced by spray-drying of SP/TAβCD binary solutions in ethanol using the Nano Spray Dryer B-90 HP. Dry powders were characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and transmission and scanning electron microscopy (TEM and SEM, respectively) and compared to the pristine components and their physical mixtures (PMs). Next, SP was encapsulated within mPEG-PCL NPs by nano-precipitation of an SP/TAβCD complex/mPEG-PCL solution. In addition to the nano-encapsulation of a preformed complex within the polymeric NPs, we assessed an alternative encapsulation approach called drying with copolymer (DWC) in which pristine SP, TAβCD, and mPEG-PCL were co-dissolved in a mixture of acetone and methanol at the desired weight ratio, dried under vacuum, re-dissolved, and nano-precipitated in water. The dissolution-drying step was aimed to promote the formation of molecular hydrophobic interactions between SP, TAβCD, and the PCL blocks in the copolymer. SP-loaded mPEG-PCL NPs were characterized by dynamic light scattering (DLS) and SEM. NPs with a size of 74–75 nm and standard deviation (S.D., a measure of the peak width) of 21–22 nm were obtained when an SP:TAβCD (1:1 molar ratio) spray-dried complex was used for the nano-encapsulation and SEM analysis revealed the absence of free SP crystals. The encapsulation efficiency (%EE) and drug loading (%DL) were 85% and 2.6%, respectively, as opposed to the much lower values (14% and 0.6%, respectively) achieved with pristine SP. Moreover, the NPs sustained the SP release with relatively low burst effect of 20%. Overall, our results confirmed that spray-drying of SP/TAβCD solutions at the appropriate molar ratio leads to the hydrophobization of the relatively hydrophilic SP molecule, enabling its encapsulation within mPEG-PCL NPs and paves the way for the use of this strategy in the development of novel drug delivery systems of this vital biological precursor.
Highlights
Tetrahydrobiopterin (BH4, Figure 1a), a naturally occurring molecule, is present in most cells and tissues of higher organisms and it is a well-established as a cofactor in various essential enzymatic pathways that include the degradation of phenylalanine and the biosynthesis of neurotransmittersMolecules 2019, 24, 2715; doi:10.3390/molecules24152715 www.mdpi.com/journal/moleculesMolecules 2019, 24, 2715 such as serotonin, melatonin, dopamine, noradrenaline, and adrenaline [1,2]
Our results confirmed that spray-drying of SP/TAβCD solutions at the appropriate molar ratio leads to the hydrophobization of the relatively hydrophilic SP molecule, enabling its encapsulation within mPEG-PCL NPs and paves the way for the use of this strategy in the development of novel drug delivery systems of this vital biological precursor
Aiming to encapsulate the relatively hydrophilic SP molecule within the hydrophobic domains of methoxy-poly(ethylene-glycol)-poly(epsilon-caprolactone) NPs and sustain its release, in this work, we explored for the first time the hydrophobization of SP with TAβCD as a preamble to the nano-encapsulation stage
Summary
Tetrahydrobiopterin (BH4, Figure 1a), a naturally occurring molecule, is present in most cells and tissues of higher organisms and it is a well-established as a cofactor in various essential enzymatic pathways that include the degradation of phenylalanine and the biosynthesis of neurotransmittersMolecules 2019, 24, 2715; doi:10.3390/molecules24152715 www.mdpi.com/journal/moleculesMolecules 2019, 24, 2715 such as serotonin, melatonin, dopamine, noradrenaline, and adrenaline [1,2]. Defects in BH4 metabolism caused by mutations in specific genes encoding for enzymes involved response [1,3]. Defects (BH4 in BH4deficiency) metabolismlead caused by mutationshigh in specific genes encoding in immune its synthesis or regeneration to abnormally phenylalanine levels in for enzymes involved in its synthesis or regeneration (BH4 deficiency) lead to abnormally high the blood and the deficiency of diverse neurotransmitters in the central nervous system (CNS) [4]. Decreased levels of BH4 have been documented in neurological disorders such as Parkinson’s and nervous system (CNS) [4]. The administration of BH4 has been disorders such as Parkinson’s and Alzheimer’s disease, autism, and depression. BH4 undergoes fast aerobic degradation, administration of BH4 has been reported to improve the clinical symptoms [1,5]. The development of advanced delivery systems that improve the biological half-life of BH4 and its bioavailability in the CNS emerges as a strategy to enhance the efficacy of the current replacement therapy
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