Nanogel‐based scaffold delivery of prostaglandin E₂ receptor–specific agonist in combination with a low dose of growth factor heals critical‐size bone defects in mice

Abstract

Objective. Regeneration of bone requires the combination of appropriate drugs and an appropriate delivery system to control cell behavior. However, the delivery of multiple drugs to heal bone is complicated by the availability of carriers. The aim of this study was to explore a new system for delivery of a selective EP4 receptor agonist (EP4A) in combination with low-dose bone morphogenetic protein 2 (BMP-2).Methods. Combined delivery of EP4A and BMP-2 was carried out with a nanogel-based scaffold in the shape of a disc, to repair critical-size circle-shaped bone defects in calvariae that otherwise did not heal spontaneously.Results. Combination treatment with EP4A and low-dose BMP-2 in nanogel efficiently activated bone cells to regenerate calvarial bone by forming both outer and inner cortical plates as well as bone marrow tissue to regenerate a structure similar to that of intact calvaria. EP4A enhanced low-dose BMP-2-induced cell differentiation and activation of transcription events in osteoblasts.Conclusion. These data indicate that combined delivery of EP4A and low-dose BMP-2 via nanogelbased hydrogel provides a new system for bone repair.

Nanogels: An overview of properties, biomedical applications and obstacles to clinical translation

“…However, the difference in pharmacokinetic and pharmacodynamic profiles among diverse drug molecules makes dosing and scheduling optimization very challenging. Combining drugs in one delivery carrier is a well-suited strategy for controlling the pharmacokinetics and co-delivery of the desired drug ratio in vivo , and a variety of nanoscale carriers, including nanogels, have been investigated in terms of their ability to deliver multiple drugs [27,83,150,151]. As highlighted in previous sections, the nanogel structure can be readily adjusted to integrate features of different materials and, thus, offer advantages for combinatorial encapsulation of drugs with varying physicochemical properties such as small molecules, proteins and nucleic acids.…”

“…Akiyoshi and colleagues evaluated nanogels based on acrylate group–modified CHP for co-delivery of prostaglandin E2 receptor–specific agonist EP4A (small molecule) in combination with bone morphogenic proteins (BMP-2) for bone regeneration [151]. In this study, EP4A-containing nanogels and BMP-2-containing nanogels were crosslinked with thiol-bearing PEG to obtain disc-like scaffolds for the implantation into large bone defects.…”

Harnessing and Modulating Inflammation in Strategies for Bone Regeneration

“…73,75 Dual delivery of BMP-2 and an EP4 agonist from a poly(ethylene glycol)-based hydrogel stimulated bone formation in a critical-sized murine cranial defect model; bone regeneration was greater with dual delivery than with delivery of either agent alone. 76 …”

Targeting polymer therapeutics to bone

“…Several studies have attempted to treat osteoporosis by either modification of PGE 2 , making it specific for EP 2 or EP 4 receptors, or by conjugation to targeting moieties [59,138,145,146]. Miller et al has attached PGE 1 via a Cat K sensitive spacer, Gly-Gly-Pro-Nle, to an HPMA copolymer (Mw 37.2 kDa), P-Asp 8 -FITC-PGE 1 .…”