Feasibility of Using a Bone-Targeted, Macromolecular Delivery System Coupled with Prostaglandin E1 to Promote Bone Formation in Aged, Estrogen-Deficient Rats

Abstract

Purpose Macromolecular delivery systems have therapeutic uses because of their ability to deliver and release drugs to specific tissues. The uptake and localization of HPMA copolymers using Asp8 as the bone-targeting moiety was determined in aged, ovariectomized (ovx) rats. PGE1 was attached via a cathepsin K-sensitive linkage to HPMA copolymer–Asp8 conjugate and was tested to determine if it could promote bone formation. Materials and Methods The uptake of FITC-labeled HPMA copolymer–Asp8 conjugate (P-Asp8-FITC) on bone surfaces was compared with the mineralization marker, tetracycline. Then a targeted PGE1-HPMA copolymer conjugate (P-Asp8-FITC-PGE1) was given as a single injection and its effects on bone formation were measured 4 weeks later. Results P-Asp8-FITC preferentially deposited on resorption surfaces, unlike tetracycline. A single injection of P-Asp8-FITC-PGE1 resulted in greater indices of bone formation in aged, ovx rats. Conclusions HPMA copolymers can be targeted to bone surfaces using Asp8, with preferential uptake on resorption surfaces. Additionally, PGE1 attached to the Asp8-targeted HPMA copolymers and given by a single injection resulted in greater bone formation measured 4 weeks later. This initial in vivo study suggests that macromolecular delivery systems targeted to bone may offer some therapeutic opportunities and advantages for the treatment of skeletal diseases.

Oriented and Ordered Biomimetic Remineralization of the Surface of Demineralized Dental Enamel Using HAP@ACP Nanoparticles Guided by Glycine

“…Therefore, ALN has been conjugated to some biological/synthetic polymers as drug carriers to endow them with the special HAP binding ability to develop bone- or tooth-targeted drug delivery systems414243444546. In this study, ALN was conjugated to CMC to form CMC-ALN; the introduction of ALN did not affect the stabilizing ability of CMC.…”

Design of polyaspartic acid peptide-poly (ethylene glycol)-poly (ε-caprolactone) nanoparticles as a carrier of hydrophobic drugs targeting cancer metastasized to bone

“…Various tetracyclines and bisphosphonates have been frequently used as bone-targeting moieties in nanotechnology-based therapy, but limitations related to these drugs remain. 15,16 Tetracycline binds mainly with less-crystalline hydroxyapatites (newly forming bone), 17 and long-term use of bisphosphonate increases the risk of osteonecrosis in the jaw. 18 A short peptide sequence of repetitive aspartic acid (4-10 amino acids) has been shown to interact exclusively with bone in vitro and in vivo.…”

Targeting polymer therapeutics to bone

“…Bringing targeting via ionic interactions full circle, Miller et al demonstrated using fluorescence microscopy that tetracycline deposits preferentially onto growing surfaces, or those with low crystallinity (Fig. 6) [59]. Application of these principles means that targeting osteoclasts should be done with AOs, which prefer absorbing surfaces, while targeting osteoblast should be done with tetracycline, which prefers growing surfaces of bone.…”

“…The unstable carbamic acid rapidly releases carbon dioxide and yields the unmodified drug [78,79]. Use of such spacers was shown in bone-targeted delivery of PGE 1 [59] and anticancer drugs to bone [80-82]. …”

“…Polymer incubation with non-skeletal and precursor cells resulted in minimal release of PGE 1 , demonstrating the specificity of this linker [93]. The specificity of the linker was also validated in vivo [59,80,81]. …”