title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Texas A&M University , TAMU Mailstop 1114, College Station, Texas 77843, United States.
authors.forename: Raghu
authors.initials: R
authors.lastname: Ganugula
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Texas A&M University , TAMU Mailstop 1114, College Station, Texas 77843, United States.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Arora
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Texas A&M University , TAMU Mailstop 1114, College Station, Texas 77843, United States.
authors.forename: Prabhjot
authors.identifier: 0000-0002-7799-7748
authors.initials: P
authors.lastname: Saini
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Texas A&M University , TAMU Mailstop 1114, College Station, Texas 77843, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Guada
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Texas A&M University , TAMU Mailstop 1114, College Station, Texas 77843, United States.
authors.forename: Majeti N V Ravi
authors.identifier: 0000-0001-5606-401X
authors.initials: MNVR
authors.lastname: Kumar
mesh_terms: D018938:Caco-2 Cells; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D006801:Humans; D019344:Lactic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D008024:Ligands; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011091:Polyesters / Q000138:chemical synthesis / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011990:Receptors, Transferrin / Q000737:chemistry*; D044004:Xanthones / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D008024:Ligands; D011091:Polyesters; D011990:Receptors, Transferrin; D044004:Xanthones; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide); C052659:gambogic acid