<p>Enhanced Cellular Uptake Of Phenamil Through Inclusion Complex With Histidine Functionalized β-Cyclodextrin As Penetrative Osteoinductive Agent</p>

Abstract

BackgroundPhenamil (PH) is a small molecule that induces bone formation through upregulation of the TRB3 gene in the bone-regeneration process. β-Cyclodextrins (βCDs) with hydrophilic surfaces and a relatively hydrophobic cavity can form inclusion complexes with primarily hydrophobic small molecules such as PH, and increase their apparent solubility and dissolution rate. The hydrophilic surface of βCDs prevents their interaction with the hydrophobic lipids of the cell membrane for penetration. Therefore, binding of penetrative groups, such as lysine, arginine, and histidine (His), to βCDs for cell penetration is required.AimThe aim of this study was to investigate the effect of His-conjugated βCD on cellular uptake of PH for bone differentiation.MethodsIn this study, His-βCDs were synthesized and used to prepare an inclusion complex of His-βCD-PH. A hydroxypropyl–βCD-PH (HP-βCD-PH) inclusion complex for increasing PH solubility without a penetrative group was prepared for comparison. 3-D geometry of βCD derivatives and PH-inclusion complexes was investigated by Fourier-transform infrared spectroscopy and molecular docking. Alizarin red staining and real-time PCR were performed to compare bone differentiation of His-βCD-PH and HP-βCD-PH.ResultsThe results suggested that the benzene ring of PH was inserted into the wide side of both His-βCD and HP-βCD. Alizarin red staining at 14 days postculture in the presence of His-βCD-PH at total concentration of 50 μM for PH showed that bone-matrix mineralization increased significantly compared with free PH and HP-βCD-PH. Real-time PCR confirmed this result, and showed gene expression increased significantly (OPN 1.84-fold, OCN 1.69-fold) when stem cells were cultured with His-βCD-PH.ConclusionThe overall results indicated that His-βCD-PH is a promising carrier for osteoinductive PH with possible penetration ability and sustained release that reduces BMP2 consumption for differentiation of mesenchymal stem cells to bone tissue.

Nanofibers from hydroxypropyl β-cyclodextrin/pantothenic acid supramolecular complexes: Physicochemical characterization and potential biomedical applications

“…This phenomenon indicated that the HP_x3b2;-CD/PA NFs inclusion complex was more easily taken up by cells, which may be caused by the specific binding between the complex and cancer cell surface. 64,65 These results were consistent with the results of the obvious in vitro cell cytotoxicity assay. It is concluded that the cyclodextrin inclusion complex drug delivery could improve the biocompatibility of the drug.…”

Cyclodextrin-Based Supramolecular Complexes of Osteoinductive Agents for Dental Tissue Regeneration

“…Similar to the inclusion complex of SV, the osteoinductive effects of other inclusion complexes containing MLT and phenamil have been demonstrated [ 79 , 80 ]. The preparation of inclusion complexes containing MLT has been reported using 2-hydroxypropyl β-CD (HP-β-CD) [ 81 , 82 , 83 , 84 ].…”

“…Jahed et al reported on the use of inclusion complexes of phenamil, a small molecule that induces bone formation through upregulation of the TRB3 gene, to improve solubility [ 80 ]. To enhance the penetration of phenamil, a histidine-conjugated β-CD derivative (His-β-CD) was synthesized for intracellular delivery.…”

Cell‐Membrane‐Targeted Drug Delivery System Based on Choline‐Phosphate‐Functionalized β‐Cyclodextrin

“…Therefore, the combination with some functional molecular may impart some new properties to the cyclodextrins derivatives. [13][14][15] Jahed et al have synthesized the histidine (His)-conjugated β-cyclodextrin (His-βCD) and prepared inclusion complexes with hydrophobic molecule phenamil (PH). His-βCD not only increased the solubility of PH but also provided cell penetration due to the cationic amino acids of histidine on His-βCD.…”

“…His-βCD not only increased the solubility of PH but also provided cell penetration due to the cationic amino acids of histidine on His-βCD. [15] A new zwitterionic molecule, choline phosphate (CP), with a reverse order of phosphate choline (PC) in cell membrane shows a unique dipole pairing between CP and PC of various cell membranes, and it can enhance the cell internalization efficiency of CP-containing molecules. [16][17][18][19] In our previous work, we have introduced the CP group on the surface of various materials to investigate their interaction with cells and proteins.…”