Abstract
Introduction: PCSK9 has been demonstrated to negatively influence the availability of LDL receptors (LDLR) thus predisposing to hypercholesterolemia. The plant alkaloid Berberine has been reported to enhance LDLR function while downregulating the expression of PCSK9 however this compound has limited use due to poor oral bioavailability. The nanotechnology applied to drug delivery helps improve drug pharmacokinetics and biodistribution. Aims and Objectives: In this study, we hypothesized that targeted drug delivery through enhanced intestinal M cell absorption would improve the bioavailability of Berberine Chloride and also enhance its pharmacological activity. Study Design: This study involved a first phase of optimized Nano-precipitation synthesis and characterization of the RGD functionalized drug delivery PLGA-PEG nanoparticles containing the drug Berberine Chloride along with drug entrapment efficiency and in vitro drug release studies, using Scanning/Transmission Electron Microscopy, Photon correlation Spectroscopy and UV-Spectroscopy. This is followed by a second phase, which consists of the treatment of M Cell cultures produced by co-culturing of Caco2 and Raji B cells using the previously synthesized targeted Nano-medicine. Treated cell culture samples are then analyzed for PCSK9 gene expression and Western blot studies for permeability-glycoprotein (P-gp) and PCSK-9 levels as well as IL1 and associated lipoprotein genes expressions. Results: RGD targeted Berberine Chloride encapsulating nanoparticles had a particle size range distribution of 250- 350nm determined through Photon correlation Spectroscopy. Berberine Chloride entrapment efficiency in PLGA-PEG nanoparticles was within the range of 25-50%. This was calculated from the standard curve of Berberine Chloride using UV spectroscopy. Conclusion: Favorable drug concentration levels were achieved for Berberine Chloride upon entrapment in RGD targeted PLGA-PEG nanoparticles, providing a promised opportunity that favorable pharmacokinetic and pharmacodynamics results in M cell culture models of Berberine Chloride relationship to PCSK9 levels.
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