Next Generation Precision-Polyesters Enabling Optimization of Ligand–Receptor Stoichiometry for Modular Drug Delivery

Abstract

The success of receptor-mediated drug delivery primarily depends on the ability to optimize ligand-receptor stoichiometry. Conventional polyesters such as polylactide (PLA) or its copolymer, polylactide-co-glycolide (PLGA), do not allow such optimization due to their terminal functionality. We herein report the synthesis of 12 variations of the PLA-poly(ethylene glycol) (PEG) based precision-polyester (P2s) platform, permitting 5-12 periodically spaced carboxyl functional groups on the polymer backbone. These carboxyl groups were utilized to achieve variable degrees of gambogic acid (GA) conjugation to facilitate ligand-receptor stoichiometry optimization. These P2s-GA combined with fluorescent P2s upon emulsification form nanosystems (P2Ns) of size <150 nm with GA expressed on the surface. The P2Ns outclass conventional PLGA-GA nanosystems in cellular uptake using caco-2 intestinal model cultures. The P2Ns showed a proportional increase in cellular uptake with an increase in relative surface GA density from 0 to 75%; the slight decline for 100% GA density was indicative of receptor saturation. The intracellular trafficking of P2Ns in live caco-2 cells demonstrated the involvement of endocytic pathways in cellular uptake. The P2Ns manifest transferrin receptor (TfR) colocalization in ex vivo intestinal tissue sections, despite blocking of the receptor with transferrin (Tf) noncompetitively, i.e., independently of receptor occupation by native ligand. The in vivo application of P2Ns was demonstrated using cyclosporine (CsA) as a model peptide. The P2Ns exhibited modular release in vivo, as a function of surface GA density. This approach may contribute to the development of personalized dose regimen.

Oral delivery of nanoparticle urolithin A normalizes cellular stress and improves survival in mouse model of cisplatin-induced AKI

“…(17). Use of GA-conjugated nanoparticles has significantly improved the oral bioavailability of several drugs, including cyclosporine, insulin, curcumin, and, as reported in this article, UA (17)(18)(19)46).…”

“…In brief, polymers with or without GA conjugation were first prepared. Assembly of polymers into nanoparticles and the concurrent encapsulation of UA were accomplished using the oil-in-water emulsification method (19). The amount and efficiency of UA encapsulation were determined by LC-MS. Nanoparticle particle size and shape were evaluated by dynamic light scattering and scanning electron microscopy.…”

“…We found that gambogic acid (GA), a noncompetitive ligand of TfR1, can be conjugated to traditional nanoparticles such as polylactic-coglycolic acid (PLGA) to facilitate their trafficking through the gastrointestinal barrier via TfR1 interaction (46). This discovery led to the development of next-generation precision polymer nanosystems (P2Ns) containing additional free carboxyl moieties for GA ligand conjugation (19). With increased GA density per particle, P2Ns-GA is internalized more readily than their PLGA-GA counterparts in both human cell lines and rodent models (19,46).…”

“…This discovery led to the development of next-generation precision polymer nanosystems (P2Ns) containing additional free carboxyl moieties for GA ligand conjugation (19). With increased GA density per particle, P2Ns-GA is internalized more readily than their PLGA-GA counterparts in both human cell lines and rodent models (19,46).…”

Oral Drug Delivery Technologies—A Decade of Developments

“…Our laboratory also observed that the ligand-receptor stoichiometry plays an important role in receptor-mediated drug delivery. Optimized ligand-receptor stoichiometry has been achieved through multiple coupling sites in newly formed polyester, which showed enhanced uptake and efficient drug delivery compared with benchmarking control, GA modified poly (lactic-coglycolic acid) (Ganugula, et al, 2017b). It will be interesting to see if the improved bioavailability will subsequently lead to improved clinical outcomes, in particular chronic conditions on oral dosing.…”