Nanostructured polymers for targeted and responsive drug delivery: Exploitations of RAFT and click chemistries
May 20-25, 2018
Fracture healing is a major clinical challenge, with a 10-20% impaired healing rate, resulting in prolonged hospitalizations, decreased quality of life, and substantial healthcare costs. Currently, myriad therapeutics that target various mechanisms and signalling pathways have been developed to augment fracture healing. Apart from bone morphogenic protein (BMP) implants, there are currently no FDA approved options to improve fracture healing. A major challenge to translation of bone-acting therapeutics is effective drug delivery, as systemic delivery of therapeutics is limited by short duration of action and off-target effects due to rapid clearance and poor bone biodistribution (<1% of injected dose). This motivates the development of polymer therapeutics for targeted, systemic drug delivery to bone. Design of polymeric drug conjugates and nanoparticles (NPs) decorated with bone-targeting peptides were developed to realize robust, specific bone targeting efficacy. First, poly(ethylene glycol) copolymers were synthesized with incorporation of a peptide with high affinity to tartrate-resistant acid phosphatase (TRAP) (TRAP-binding peptide, TBP), an enzyme deposited by osteoclasts during the bone resorption phase of bone remodeling, which provides high specificity relevant for bone cell drugging. Gradient and random peptide incorporation, 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 1 week and accounted for 14% of tissue distribution. Informed by these experiments, NPs were developed with high corona molecular weights with random peptide incorporation. Potent fracture-targeting efficiency was observed for this drug delivery system, and NPs accumulated at fractures for ~ 7 days (Fig. 1). NPs loaded with a small molecule bone anabolic Wnt/β-catenin agonist showed fracture site-specific upregulation of β-catenin signalling, enhanced bone mechanical properties, and faster healing rates (Fig. 1). Taken together, this drug delivery strategy developed here establish criteria for the design of next generation drug delivery systems for bone.
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Danielle Benoit, Marian Ackun-Farmmer, Yuchen Wang, and Maureen R. Newman, "Nanostructured polymers for targeted and responsive drug delivery: Exploitations of RAFT and click chemistries" in "Polymer Reaction Engineering X (PRE 10) (2018)", John Tsavalas, University of New Hampshire, USA Fouad Teymour, Illinois Institute of Technology, USA Jeffrey Stubbs, HP Inc., USA Jose R. Leiza, University of the Basque Country, Spain Eds, ECI Symposium Series, (2018). https://dc.engconfintl.org/prex/42