Double-headed nanosystems for oral drug delivery

Abstract

We demonstrate a novel strategy to engineer double-headed nanosystems by chemical modification of the carboxyl terminal polyester with a linker that offers tripodal arrangement of ligands on the particle surfaces.

Systemic anti-inflammatory therapy aided by double-headed nanoparticles in a canine model of acute intraocular inflammation

“…The literature suggests that TfR is widely expressed in the blood-ocular barriers and can potentially be useful for active delivery across these barriers ( 24 ). In addition, our ex vivo and in vivo data support the role of TfR in transport across the blood-ocular barriers ( 22 , 25 ). Here, we report the efficacy of oral CUR aided by double-headed nanoparticles in a model of lens-induced uveitis that mimics the intraocular inflammation seen after cataract surgery.…”

“…We have selected PLGA-GA 2 nanoparticles as a vehicle for the delivery of CUR because of its ability to navigate across the intestinal barriers via the TfRs in a noncompetitive manner (independent of transferrin-binding sites), resulting in improved oral bioavailability of CUR ( 21 , 22 ). The optimized synthesis protocols ( Fig, 1A ) led to scalable quantities of PLGA-GA 2 in which the GA coupling was confirmed by nuclear magnetic resonance (NMR), characterized by amide bond formation [8.01 parts per million (ppm)] and doublets at 5.7 and 6.7 ppm for GA.…”

“…Similarly, the PLGA-GA 2 -CUR nanoparticles were prepared at 1.5-g scales and freeze-dried, which led to multiple-dose canine study. Our previous studies with PLGA-GA (single head) or PLGA-GA 2 (double headed) revealed the TfR-mediated noncompetitive active transport across the intestinal barriers, leading to improved bioavailability and drug distribution ( 20 , 22 ). Our previous in silico studies also revealed the hydrophobic interaction of GA with the TfR, and such interaction is independent of transferrin binding ( 21 ).We have established the preliminary safety of PLGA-GA on repeated doses in rodents ( 21 ) that set the tone for investigating the improved versions of PLGA-GA 2 in higher-order species for preliminary safety and efficacy.…”

“…The polymers used in particle preparation were prepared according to prior optimized protocols in our laboratory (22). In brief, the linker, tris(2-aminoethyl)amine-diBoc (Di-tert-butyl dicarbonate), (TREN-diBoc) is coupled to polymer [polylactide-co-glycolide (PLGA) 50:50, Resomer 503H] using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) coupling method.…”

Oral Drug Delivery Technologies—A Decade of Developments

“…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.…”