Okawa Hiroko, Kondo Takeru, Hokugo Akishige, Cherian Philip, Sundberg Oskar, Campagna Jesus J, Kashemirov Boris A, John Varghese, Sun Shuting, Ebetino Frank H, McKenna Charles E, Nishimura Ichiro
Weintraub Center for Reconstructive Biotechnology, Division of Regenerative & Reconstructive Sciences, UCLA School of Dentistry, Los Angeles, CA 90095 USA.
Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Sendai, 980-8575 Japan.
Commun Med (Lond). 2022 Sep 5;2:112. doi: 10.1038/s43856-022-00172-x. eCollection 2022.
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but serious side effect of nitrogen-containing bisphosphonate drugs (N-BPs) frequently prescribed to reduce skeletal-related events in bone malignancies and osteoporosis. BRONJ is associated with abnormal oral wound healing after dentoalveolar surgery and tooth extraction. We previously found that N-BP chemisorbed to bone mineral hydroxyapatite was dissociated by secondary applied N-BP. This study investigated the effect of the surface equilibrium-based removal of N-BP from jawbone on tooth extraction wound healing of zoledronate (ZOL)-treated mice.
A pharmacologically inactive N-BP derivative (the 4-pyridyl isomer of risedronate equipped with a near-infrared 800CW fluorescent imaging dye, 800CW-pRIS) was designed and synthesized. 800CW-pRIS was intra-orally injected or topically applied in a deformable nano-scale vesicle formulation (DNV) to the palatal tissue of mice pretreated with ZOL, a potent N-BP. The female C56BL6/J mice were subjected to maxillary molar extraction and oral wound healing was compared for 800CW-pRIS/ZOL, ZOL and untreated control groups.
800CW-pRIS is confirmed to be inactive in inhibiting prenylation in cultured osteoclasts while retaining high affinity for hydroxyapatite. ZOL-injected mice exhibit delayed tooth extraction wound healing with osteonecrosis relative to the untreated controls. 800CW-pRIS applied topically to the jaw one week before tooth extraction significantly reduces gingival oral barrier inflammation, improves extraction socket bone regeneration, and prevents development of osteonecrosis in ZOL-injected mice.
Topical pre-treatment with 800CW-RIS in DNV is a promising approach to prevent the complication of abnormal oral wound healing associated with BRONJ while retaining the anti-resorptive benefit of legacy N-BP in appendicular or vertebrate bones.
双膦酸盐相关颌骨坏死（BRONJ）是一种罕见但严重的副作用，常发生于为减少骨恶性肿瘤和骨质疏松症中骨骼相关事件而频繁使用的含氮双膦酸盐药物（N-BPs）。BRONJ与牙槽外科手术和拔牙后口腔伤口愈合异常有关。我们之前发现，二次应用N-BP可使化学吸附于骨矿物质羟基磷灰石上的N-BP解离。本研究调查了基于表面平衡从颌骨去除N-BP对唑来膦酸（ZOL）治疗小鼠拔牙伤口愈合的影响。
设计并合成了一种药理惰性的N-BP衍生物（配备近红外800CW荧光成像染料的利塞膦酸4-吡啶基异构体，800CW-pRIS）。800CW-pRIS通过口腔注射或采用可变形纳米级囊泡制剂（DNV）局部应用于经强效N-BP ZOL预处理的小鼠腭组织。对雌性C56BL6/J小鼠进行上颌磨牙拔除，并比较800CW-pRIS/ZOL组、ZOL组和未治疗对照组的口腔伤口愈合情况。
证实800CW-pRIS在抑制培养破骨细胞的异戊二烯化方面无活性，同时对羟基磷灰石保持高亲和力。与未治疗的对照组相比，注射ZOL的小鼠拔牙伤口愈合延迟并伴有骨坏死。在拔牙前一周局部应用于颌骨的800CW-pRIS可显著减轻牙龈口腔屏障炎症，改善拔牙窝骨再生，并预防注射ZOL小鼠发生骨坏死。
在DNV中局部预处理800CW-RIS是一种有前景的方法，可预防与BRONJ相关的口腔伤口愈合异常并发症，同时保留传统N-BP在附属骨或椎骨中的抗吸收益处。
