Abstract
The current methods for targeted drug delivery utilize ligands that must out-compete endogenous ligands in order to bind to the active site facilitating the transport. To address this limitation, we present a non-competitive active transport strategy to overcome intestinal barriers in the form of tunable nanosystems (NS) for transferrin receptor (TfR) utilizing gambogic acid (GA), a xanthanoid, as its ligand. The NS made using GA conjugated poly(lactide-co-glycolide) (PLGA) have shown non-competitive affinity to TfR evaluated in cell/cell-free systems. The fluorescent PLGA-GA NS exhibited significant intestinal transport and altered distribution profile compared to PLGA NS in vivo. The PLGA-GA NS loaded with cyclosporine A (CsA), a model peptide, upon peroral dosing to rodents led to maximum plasma concentration of CsA at 6 h as opposed to 24 h with PLGA-NS with at least 2-fold higher levels in brain at 72 h. The proposed approach offers new prospects for peroral drug delivery and beyond.
Highlights
The ligands currently in use for receptor-mediated drug delivery must out-compete endogenous ligands in order to bind to the active site facilitating the transport[6,8,10,11,12,13,19]
The mild reactions employed in the conjugation process yield high amounts of products while preserving the structural integrity of the polymer backbone, as was evident from the Gel Permeation Chromatography (GPC) and MALDI-MS data, as well as unaltered thermal properties, observed in differential scanning calorimetry (DSC)
In addition to PLGA-gambogic acid (GA), rhodamine conjugated fluorescent PLGA-Rh was prepared by coupling rhodamine-NHS to PLGA-EDA
Summary
The ligands currently in use for receptor-mediated drug delivery must out-compete endogenous ligands in order to bind to the active site facilitating the transport[6,8,10,11,12,13,19]. The degree of ligand substitution on the NS surface is critical for receptor-mediated delivery, and can be optimized by controlling the mixing ratios of ligand-functionalized polymer to non-functional polymer[23,24]. This approach, utilizing small molecule non-competitive ligand for active drug delivery, enables the development of carrier systems that have no equivalent in the world of competitive ligands
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