Targeting therapeutics to bone by conjugation with bisphosphonates

Young, Robert N.; Grynpas, Marc D.

doi:10.1016/j.coph.2018.03.010

Cited by 32 publications

(28 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Over the past several years, CaP, especially HA and TCP, have attracted increasing interest as bone graft substitutes and drug‐loaded scaffolds. HA is the basis of bone matrix and has outstanding bone conductivity and high BP affinity . Loading strategies mainly include binding BPs onto HA directly to form chelation (HA‐BPs) and to add BPs to the HA manufacturing process to form a mixture (HA/BPs).…”

Section: Bp‐incorporated Composite Scaffolds For Enhanced Bone Defectmentioning

confidence: 99%

Bisphosphonate‐Functionalized Scaffolds for Enhanced Bone Regeneration

Cui

Zhu

et al. 2019

Adv Healthcare Materials

View full text Add to dashboard Cite

Bone defect healing is an intricate but methodical process that restores bone integrity and represents an intrinsic capacity of The local sustained release of bioactive substances are attracting increasing attention in bone tissue engineering, which is beneficial to bone tissue formation and helps to improve the bone ingrowth ability of a scaffold. Bisphosphonates (BPs), as a representative kind of osteoclast inhibitors, are proven to possess excellent osteogenic induction capability. Accordingly, various physical and chemical strategies are developed to functionalize bone tissue scaffolds with BPs to achieve controlled release profiles. Compared with traditional treatment modalities, local release of BPs from these composite scaffolds will contribute to continuous bone integration without the risk of many complications. This review explores the molecular mechanisms of BPs on bone metabolism and analyzes the appropriate concentrations of BPs that promote bone regeneration. The advanced BP loading strategies, implant modification technologies, and BP-loaded composite scaffolds based on different matrices are summarized. Finally, the latest advances and the future development of BP-modified scaffolds for enhanced bone regeneration are discussed. This article provides leading-edge design strategies of the BP-functionalized bone engineering scaffolds for improved bone repairability.

show abstract

Section: Bp‐incorporated Composite Scaffolds For Enhanced Bone Defectmentioning

confidence: 99%

Bisphosphonate‐Functionalized Scaffolds for Enhanced Bone Regeneration

Cui

Zhu

et al. 2019

Adv Healthcare Materials

View full text Add to dashboard Cite

show abstract

“…19 Several synthetic EP4-selective agonists have been developed to mimic the effects of PGE2. 20,21 However, the systemic administration of PGE2 and their synthetic counterparts is limited by serious side effects including nausea, diarrhea, and hypotension. 22 To avoid these systemic side-effects, the C3 and C6 conjugated drugs would be carried locally with the DBBM granules to surgically created defects and then will be released and bound locally to the bone surrounding the defect because of the strong bone targeting ability of the bisphosphonates.…”

Section: Introductionmentioning

confidence: 99%

“…Preclinical and clinical studies showed that prostaglandin E2 induces anabolic bone effects by activating the EP4 receptors found in bone tissues and other tissues 19 . Several synthetic EP4‐selective agonists have been developed to mimic the effects of PGE2 20,21 . However, the systemic administration of PGE2 and their synthetic counterparts is limited by serious side effects including nausea, diarrhea, and hypotension 22 …”

Section: Introductionmentioning

confidence: 99%

Improved bone regeneration using bone anabolic drug conjugates (C3 and C6) with deproteinized bovine bone mineral as a carrier in rat mandibular defects

Sheikh

Abdallah

Al‐Jaf

et al. 2020

Journal of Periodontology

View full text Add to dashboard Cite

Background: Deproteinized bovine bone mineral (DBBM) has been extensively studied and used for bone regeneration in oral and maxillofacial surgery. However, it lacks an osteoinductive ability. We developed two novel bone anabolic conjugated drugs, known as C3 and C6, of an inactive bisphosphonate and a bone activating synthetic prostaglandin agonist. The aim was to investigate whether these drugs prebound to DBBM granules have the potential to achieve rapid and enhanced bone regeneration. Methods: Bilateral defects (4.3 mm diameter circular through and through) were created in mandibular angles of 24 Sprague-Dawley rats were filled with DBBM Control, DBBM with C3 or DBBM with C6 (n = 8 defects per group/ each timepoint). After 2 and 4 weeks, postmortem samples were analyzed by microcomputed tomography followed by backscattering electron microscopy and histology. Results: DBBM grafts containing the C3 and C6 conjugated drugs showed significantly more bone formation than DBBM control at 2 and 4 weeks. The C6 containing DBBM demonstrated the highest percentage of new bone formation at 4 weeks. There was no significant difference in the percentage of the remaining graft between the different groups at 2 or 4 weeks. Conclusions: DBBM granules containing conjugated drugs C3 and C6 induced greater new bone volume generated and increased the bone formation rate more than the DBBM controls. This is expected to allow the development of clinical treatments that provide more predictable and improved bone regeneration for bone defect repair in oral and maxillofacial surgery.

show abstract

“…To overcome this deficit and to reduce the EP4a associated unwanted side‐effects, we have used a modified conjugate bone‐targeting approach where a synthetic, stable EP4 agonist (EP4a) is covalently linked to an inactive form of alendronate (iALN; shown as BP‐LNK in Fig. A ) to form a novel bone‐targeting conjugate prodrug C3 . The rationale is that after systemic administration, the conjugates should selectively bind to bone surface through iALN's bone targeting and binding ability, and local hydrolytic enzymes slowly liberate the EP4a component to exert anabolic effects on bone tissue in a sustained release manner (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…1A) to form a novel bonetargeting conjugate prodrug C3. (51,52) The rationale is that after systemic administration, the conjugates should selectively bind to bone surface through iALN's bone targeting and binding ability, (8) and local hydrolytic enzymes slowly liberate the EP4a component to exert anabolic effects on bone tissue in a sustained release manner ( Fig. 1B), while the iALN would be inactive (no antiresorptive effect), would remain attached to bone, and the BP-LNK bond would be stable and would not liberate active alendronate, thus allowing bone to naturally remodel.…”

mentioning

confidence: 99%

In Vivo Bone Effects of a Novel Bisphosphonate‐EP4a Conjugate Drug (C3) for Reversing Osteoporotic Bone Loss in an Ovariectomized Rat Model

et al. 2019

Self Cite

View full text Add to dashboard Cite

Pathological bone loss is a regular feature of postmenopausal osteoporosis, and the microstructural changes along with the bone loss make the individual prone to getting hip, spine, and wrist fractures. We have developed a new conjugate drug named C3, which has a synthetic, stable EP4 agonist (EP4a) covalently linked to an inactive alendronate (ALN) that binds to bone and allows physiological remodeling. After losing bone for 12 weeks, seven groups of rats were treated for 8 weeks via tail‐vein injection. The groups were: C3 conjugate at low and high doses, vehicle‐treated ovariectomy (OVX) and sham, C1 (a similar conjugate, but with active ALN at high dose), inactive ALN alone, and a mixture of unconjugated ALN and EP4a to evaluate the conjugation effects. Bone turnover was determined by dynamic and static histomorphometry; μCT was employed to determine bone microarchitecture; and bone mechanical properties were evaluated via biomechanical testing. Treatment with C3 significantly increased trabecular bone volume and vertebral BMD versus OVX controls. There was also significant improvement in the vertebral load‐bearing abilities and stimulation of bone formation in femurs after C3 treatment. This preclinical research revealed that C3 resulted in significant anabolic effects on trabecular bone, and EP4a and ALN conjugation components are vital to conjugate anabolic efficacy. A combined therapy using an EP4 selective agonist anabolic agent linked to an inactive ALN is presented here that produces significant anabolic effects, allows bone remodeling, and has the potential for treating postmenopausal osteoporosis or other diseases where bone strengthening would be beneficial. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

show abstract

Targeting therapeutics to bone by conjugation with bisphosphonates

Cited by 32 publications

References 35 publications

Bisphosphonate‐Functionalized Scaffolds for Enhanced Bone Regeneration

Bisphosphonate‐Functionalized Scaffolds for Enhanced Bone Regeneration

Improved bone regeneration using bone anabolic drug conjugates (C3 and C6) with deproteinized bovine bone mineral as a carrier in rat mandibular defects

In Vivo Bone Effects of a Novel Bisphosphonate‐EP4a Conjugate Drug (C3) for Reversing Osteoporotic Bone Loss in an Ovariectomized Rat Model

Contact Info

Product

Resources

About