Abstract
In this study, water-soluble chitosan lactate (CL) was reacted with lactobionic acid (LA), a disaccharide with remarkable affinity to hepatic asialoglycoprotein (ASGP) receptors, to form dual liver-targeting LA-modified-CL polymer for site-specific drug delivery to the liver. The synthesized polymer was used to encapsulate baicalin (BA), a promising bioactive flavonoid with pH-dependent solubility, into ultrahigh drug-loaded nanoparticles (NPs) via the ionic gelation method. The successful chemical conjugation of LA with CL was tested and the formulated drug-loaded LA-modified-CL-NPs were assessed in terms of particle size (PS), encapsulation efficiency (EE) and zeta potential (ZP) using full factorial design. The in vivo biodistribution and pharmacokinetics of the designed NPs were assessed using 99mTc-radiolabeled BA following oral administration to mice and results were compared to 99mTc-BA-loaded-LA-free-NPs and 99mTc-BA solution as controls. Results showed that the chemical modification of CL with LA was successfully achieved and the method of preparation of the optimized NPs was very efficient in encapsulating BA into nearly spherical particles with an extremely high EE exceeding 90%. The optimized BA-loaded-LA-modified-CL-NPs showed an average PS of 490 nm, EE of 93.7% and ZP of 48.1 mV. Oral administration of 99mTc-BA-loaded-LA-modified-CL-NPs showed a remarkable increase in BA delivery to the liver over 99mTc-BA-loaded-LA-free-CL-NPs and 99mTc-BA oral solution. The mean area under the curve (AUC0–24) estimates from liver data were determined to be 11-fold and 26-fold higher from 99mTc-BA-loaded-LA-modified-CL-NPs relative to 99mTc-BA-loaded-LA-free-CL-NPs and 99mTc-BA solution respectively. In conclusion, the outcome of this study highlights the great potential of using LA-modified-CL-NPs for the ultrahigh encapsulation of therapeutic molecules with pH-dependent/poor water-solubility and for targeting the liver.
Highlights
Baicalin (BA)—a well-known herbal medicine officially listed in the Chinese Pharmacopeia—is traditionally used to treat a wide range of diseases such as psoriasis, atopic dermatitis, asthma, bronchitis, hepatitis, nephritis, hypertension, inflammation and others [1,2]
BA-loaded-lactobionic acid (LA)-modified-chitosan lactate (CL)-NPs with extremely high EE% were prepared successfully using the above-mentioned optimized technique. This is the first study to report the successful use of CL instead of widely used chitosan to encapsulate BA in CL-NPs with a very high EE% exceeding 90%
CL in this case was very useful because BA would precipitate immediately in acidic media that must be otherwise used to solubilize chitosan during NPs formation
Summary
Baicalin (BA)—a well-known herbal medicine officially listed in the Chinese Pharmacopeia—is traditionally used to treat a wide range of diseases such as psoriasis, atopic dermatitis, asthma, bronchitis, hepatitis, nephritis, hypertension, inflammation and others [1,2]. The use of BA in the treatment of these different conditions is due to its reported antibacterial [3], antifungal [4], antiviral [5], anti-inflammatory [6], antipyretic [7], antihypertensive [8], sedative [9] and antithrombotic activity [10]. BA is classified as class II drug according to the Biopharmaceutical Classification System [15] and exhibits very poor oral bioavailability (2.2%), extremely short biological half-life (0.75 h) and complex metabolic pathway [16,17]. Several studies attempted to improve the oral bioavailability of BA through formulation using different delivery platforms such as oral chewable tablets [18,19], microemulsions [20], self-assembled nanoparticles [21], nanocrystals [22], solid dispersions [15,23], solid lipid nanoparticles [24,25,26] and thermosensitive hydrogels [27]
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