Multivalent Presentation of Peptide Targeting Groups Alters Polymer Biodistribution to Target Tissues

Abstract

Drug delivery to bone is challenging, whereby drug distribution is commonly <1% of injected dose, despite development of several bone-targeted drug delivery systems specific to hydroxyapatite. These bone-targeted drug delivery systems still suffer from poor target cell localization within bone, as at any given time overall bone volume is far greater than acutely remodeled bone volume, which harbors relevant cell targets (osteoclasts or osteoblasts). Thus, there exists a need to target bone-acting drugs specifically to the cells responsible for bone remodeling. To address this need, this study synthesized oligo(ethylene glycol) copolymers based on a peptide with high affinity to tartrate-resistant acid phosphatase (TRAP), an enzyme deposited by osteoclasts during the bone resorption phase of bone remodeling, which provides greater specificity relevant for bone cell drugging. Gradient and random peptide orientations, as well as polymer molecular weights, were investigated. TRAP-targeted, high molecular weight (Mn) random copolymers exhibited superior accumulation in remodeling bone, where fracture accumulation was observed for at least one week and accounted for 14% of tissue distribution. Intermediate and low Mn random copolymer accumulation was lower, indicating residence time depends on Mn. High Mn gradient polymers were cleared, with only 2% fracture accumulation after one week, suggesting TRAP binding depends on peptide density. Peptide density and Mn are easily modified in this versatile targeting platform, which can be applied to a range of bone drug delivery applications.

Development of controlled drug delivery systems for bone fracture-targeted therapeutic delivery: A review

“…Oligopeptide (AspSerSer) 6 functionalized liposomes have shown efficient targeting to osteoblast-mediated mineralizing nodules at bone formation surfaces [196]. An oligo(ethylene glycol) copolymer system based on a peptide with high affinity to TRAP exhibited bone targeting effects, and the targeting was tuned by varying peptide orientations and polymer molecular weights [197]. The versatile system can deliver virtually any drug that maintains activity upon conjugation and/or release from the polymer.…”

Artificial exosomes for translational nanomedicine

“…Clinical failure of synthetic NPs may be attributed to the differences in the biological barriers and immune systems between human and animal models [ 22 ]. NPs could be functionalized by conjugating with polyethylene glycol (PEG) to increase circulation times [ 23 , 24 ] and by introducing antibodies or peptides [ 25 , 26 ] to the surface to enhance the targeting capacity and change biodistribution. However, modifications of NPs still can hardly simulate complex biological components.…”

Macrophage depletion increases target specificity of bone‐targeted nanoparticles

“…Peptide synthesis has been detailed previously in the following publications 18,21,22 . Briefly, tartrate‐resistant acid phosphatase (TRAP) binding peptides (TBP; sequence: TPLSYLKGLVTVG) were generated using microwave‐assisted solid‐phase peptide synthesis (CEM Corp, Liberty1 synthesizer) and Fluorenylmethyloxycarbonyl chloride (FMOC)‐protected amino acids (AAPPTec and Peptides International).…”