The Next Generation Non-competitive Active Polyester Nanosystems for Transferrin Receptor-mediated Peroral Transport Utilizing Gambogic Acid as a Ligand

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.

Double-headed nanosystems for oral drug delivery

“…While this data does not indicate if PLGA-TGA 2 nanosystems circumvent blood-retinal or blood-brain barriers, our prior studies did show that these nanosystems have the ability to permeate across these barriers. 31 In conclusion, we demonstrate a method by which higher ligand densities can be achieved for a terminal functional polyesters such as PLGA, which otherwise was not possible. Our findings suggest that the use of TREN as a linker allowed coupling of two GA molecules as opposed to one with the routinely used EDA linker.…”

“…In this study, we have used gambogic acid (GA) as a ligand specific for transferrin receptors (TfR) found in all regions of the intestinal tract. 20,31 These functional polyesters upon emulsification lead to surface active submicron sized particles encapsulating water-insoluble bioactives e.g., curcumin. These double-headed nanosystems show increase in receptor binding ex vivo and oral bioavailability of the encapsulated curcumin in vivo that is proportional to the ligand density.…”

Oral Drug Delivery Technologies—A Decade of Developments

“…While promising, the receptor-mediated drug-delivery approaches currently use endogenous ligands to modify the Oral Drug Delivery Technologies particles that can be outcompeted by the physiologic ligands that are present in high concentrations (Lundquist and Artursson, 2016). To address this limitation, our laboratory recently reported the use of gambogic acid (GA), known for its affinity to transferrin receptors, independent of transferrin binding (Kasibhatla et al, 2005), as a noncompetitive ligand for TfR present in the small intestine (Saini et al, 2016;Ganugula et al, 2017a). The GA modified poly (lactic-coglycolic acid) nanoparticles demonstrated noncompetitive transport in cellulo and improved oral bioavailability of encapsulated drugs or drug-like compounds (e.g., cyclosporine, curcumin, and insulin) in rodents (Saini et al, 2016;Ganugula et al, 2017a;Kaur et al, 2019).…”

“…To address this limitation, our laboratory recently reported the use of gambogic acid (GA), known for its affinity to transferrin receptors, independent of transferrin binding (Kasibhatla et al, 2005), as a noncompetitive ligand for TfR present in the small intestine (Saini et al, 2016;Ganugula et al, 2017a). The GA modified poly (lactic-coglycolic acid) nanoparticles demonstrated noncompetitive transport in cellulo and improved oral bioavailability of encapsulated drugs or drug-like compounds (e.g., cyclosporine, curcumin, and insulin) in rodents (Saini et al, 2016;Ganugula et al, 2017a;Kaur et al, 2019). Our laboratory also observed that the ligand-receptor stoichiometry plays an important role in receptor-mediated drug delivery.…”

Strategies for the enhanced intracellular delivery of nanomaterials

“…Thus, modifying the surface of nanomaterials with particular ligands is one way to improve their cellular uptake and endosomal escape [39]. Table 2 summarizes receptors targeted in this approach, including CD31, integrin b3 and transferrin [122], TLR2, TLR3 and TLR9 [123], avb3 integrin [119], transferrin [124], EGFR [125], CD44 [126], IGFR [127],FcRn [128], CD163 [129], biotin [130], folate [131], and vitamin B 12 [132].…”