Optimizing Ligand Valency to Maximize Tendon Accumulation of Peptide-Targeted Nanoparticles
Year: 2024
Type: article
Abstract: In many tissues, including musculoskeletal tissues such as tendon, systemic delivery typically results in poor targeting of free drugs. Hence, we previously developed a targeted drug delivery nanoparticle (NP) system for tendon healing, leveraging a tartrate resistant acid phosphatase (TRAP) binding peptide (TBP) ligand. The greatest tendon targeting was observed with NPs functionalized with 30 000 TBP ligands per NP at day 7 during the proliferative healing phase, relative to the inflammatory (day 3) and early remodeling (day 14) phases of healing. Nevertheless, TRAP activity varies throughout healing and, therefore, may offer an opportunity for optimizing temporal therapeutic targeting through multivalent interactions. Hence, in this study, we hypothesized that the ligand density (9000-55,000 TBPs per NP) can optimize tendon accumulation on the basis of variable TRAP levels. The multivalent nanoparticles were loaded with three different fluorophores. In vitro, the ligand density and fluorophore had no effect on the physicochemical properties of the NPs, including size, charge, polydispersity index, or dye loading efficiency; however, the TRAP binding affinity correlated positively with the ligand density. In vivo, the ligand density correlated positively with NP homing and retention in the tendon, establishing opportunities to leverage ligand density for tendon targeting across the tendon healing cascade, during aging, and in other tendon pathologies, including tendinopathies.
Language: English
Subfield: Orthopedics and Sports Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Institutes of Health, National Institute on Aging, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Dental and Craniofacial Research, Division of Materials Research, National Center for Research Resources, Division of Chemical, Bioengineering, Environmental, and Transport Systems
Awards: G1766861699, G190413804, Bone-targeted polymer therapeutics for non-union fracture healing, G2880805611, G305455809, Tendon TRAP: Targeted Therapeutic Delivery to Enhance Tendon Healing, G4439917908, Engineered salivary gland tissue chips, G4923493609, s100a4 Signaling in Fibrotic Diabetic Tendon Healing, Matrix-Assisted Laser Desorption Ionization Time-of-Flight (MALDI-TOF/TOF) Mass Spectrometer, G880409603, Orchestrating Tendon Regeneration through Nanoparticle Drug Delivery
OpenAlex ID: W4404991981