Enhancement of scutellarin oral delivery efficacy by vitamin B12-modified amphiphilic chitosan derivatives to treat type II diabetes induced-retinopathy.

BACKGROUND: Diabetic retinopathy is the most common complication in diabetic patients relates to high expression of VEGF and microaneurysms. Scutellarin (Scu) turned out to be effective against diabetes related vascular endothelial cell dysfunction. However, its clinical applications have been limited by its low bioavailability. In this study, we formulated and characterized a novel intestinal target nanoparticle carrier based on amphiphilic chitosan derivatives (Chit-DC-VB12) loaded with scutellarin to enhance its bioavailability and then evaluated its therapeutic effect in experimental diabetic retinopathy model. RESULTS: Chit-DC-VB12 nanoparticles showed low toxicity toward the human colon adenocarcinoma (Caco-2) cells and zebra fish within concentration of 250 µg/ml, owing to good biocompatibility of chitosan. The scutellarin-loaded Chit-DC-VB12 nanoparticles (Chit-DC-VB12-Scu) were then prepared by self-assembly in aqueous solution. Scanning electron microscopy and dynamic light scattering analysis indicated that the Chit-DC-VB12-Scu nanoparticles were spherical particles in the sizes ranging from 150 to 250 nm. The Chit-DC-VB12-Scu nanoparticles exhibited high permeation in Caco-2 cell, indicated it could be beneficial to be absorbed in humans. We also found that Chit-DC-VB12 nanoparticles had a high cellular uptake. Bioavailability studies were performed in Sprague-Dawley rats, which present the area under the curve of scutellarin of Chit-DC-VB12-Scu was two to threefolds greater than that of free scutellarin alone. Further to assess the therapeutic efficacy of diabetic retinopathy, we showed Chit-DC-VB12-Scu down-regulated central retinal artery resistivity index and the expression of angiogenesis proteins (VEGF, VEGFR2, and vWF) of retinas in type II diabetic rats. CONCLUSIONS: Chit-DC-VB12 nanoparticles loaded with scutellarin have better bioavailability and cellular uptake efficiency than Scu, while Chit-DC-VB12-Scu nanoparticles alleviated the structural disorder of intraretinal neovessels in the retina induced by diabetes, and it also inhibited the retinal neovascularization via down-regulated the expression of angiogenesis proteins. In conclusion, the Chit-DC-VB12 nanoparticles enhanced scutellarin oral delivery efficacy and exhibited potential as small intestinal target promising nano-carriers for treatment of type II diabetes induced-retinopathy.

Spectroscopic investigation of a hyperbranched cationic amylopectin derivative as a multi-guest molecular host for targeted delivery of a photosensitizer to pancreatic cancer cells.

To increase pancreatic tumor-targeted phototoxicity of photosensitizers, a hyperbranched cationic amylopectin derivative conjugated with 3-(dimethylamino)-1-propylamine (DMAPA-Amp) was invevstigated as a multi-guest molecular host for the targeted delivery of a photosensitizer to human pancreatic cancer (Panc-1) cells. We selected protoporphyrin IX (PpIX) and folic acid as a photosensitizer and a tumor-targeting factor, respectively. The complexation mechanism of DMAPA-Amp with PpIX and folic acid was characterized using NMR spectroscopy including 1H NMR, two-dimensional diffusion ordered spectroscopy (2D DOSY) NMR, fluorescence and UV-vis spectroscopy. The results indicated that the DMAPA-Amp derivative could serve as a host for the encapsulation of two guests, PpIX and folic acid, through intermolecular interactions. The complex showed high phototoxicity against Panc-1 cells, and its folic-acid-mediated cancer-cell-targeting property was confirmed by laser confocal microscopy and flow cytometry analysis. We provide a method to study hyperbranched cationic polymer-based complexes containing multiple guests, which could facilitate the design of multi-functional complexes in the drug delivery field.

Preparation, complexation mechanism and properties of nano-complexes of Astragalus polysaccharide and amphiphilic chitosan derivatives.

To improve the small intestinal absorption efficacy of Astragalus polysaccharides (APS) through oral administration, amphiphilic chitosan derivatives conjugated with deoxycholic acid residues in the absence and presence of vitamin B12 residues (DA-Chit and VB12-DA-Chit, respectively) were synthesized and characterized by FTIR and NMR spectroscopy. APS and the amphiphilic chitosan derivatives formed the nano-complexes with positive zeta potentials in the size of 100-150nm observed using scanning electron microscopy. To investigate the fluorescent properties of APS, a Congo red residue-conjugated APS derivative (CR-APS) was synthesized. Fluorescence spectroscopy and resonance light scattering spectroscopy confirmed the formation of the CR-APS/DA-Chit nano-complex as a result of electrostatic interaction. The APS/DA-Chit and APS/VB12-DA-Chit nano-complexes were not toxic against the human colon adenocarcinoma (Caco-2) cells. The APS/VB12-DA-Chit nano-complex exhibited high permeation through intestinal enterocytes using the Caco-2 cell model, which could be beneficial to small intestinal absorption of humans.

One-step synthesis of amphiphilic hyperbranched amylopectin derivatives, characterization and use as functional nanovehicles.

Amylopectin is a naturally hyperbranched biopolymer with an extremely high molecular weight. Furthermore, this material is non-toxic in nature, and exhibits good biocompatibility and biodegradability properties. Herein, we describe the development of a one-step reaction strategy for the synthesis of amphiphilic high-molecular-weight hyperbranched amylopectin derivatives with hydrophobic shells and large hydrophilic cores. The chemical structures of the resulting materials were characterized using FTIR spectroscopy, solid-state (13)C cross-polarization/magic angle spinning NMR spectroscopy and gas chromatography. The results from transmission electron microscopy, fluorescence spectroscopy, and UV-vis analysis confirmed that the hyperbranched amylopectin derivatives were composed of hydrophobic shells with cholesteryl residues and hydrophilic amylopectin cores. These amylopectin derivatives exhibited high encapsulation capabilities toward water-soluble molecules, and could be used as functional nanovehicles for the controlled release of water-soluble molecules, and the in situ synthesis of metallic nanoparticles.