Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC 27710, USA.
Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
Biomater Sci. 2022 Sep 13;10(18):5340-5355. doi: 10.1039/d2bm00843b.
Bone tissue undergoes continuous remodeling osteoclast-mediated bone resorption and osteoblast-mediated bone formation. An imbalance in this process with enhanced osteoclastic activity can lead to excessive bone resorption, resulting in bone thinning. Once activated, osteoclasts bind to the bone surface and acidify the local niche. This acidic environment could serve as a potential trigger for the delivery of therapeutic agents into the osteoporotic bone tissue. To this end, we developed a pH-responsive nanocarrier-based drug delivery system that binds to the bone tissue and delivers an osteoanabolic molecule, adenosine. Adenosine is incorporated into a hyaluronic acid (HA)-based nanocarrier through a pH-sensitive ketal group. The HA-nanocarrier is further functionalized with alendronate moieties to improve binding to the bone tissues. Systemic administration of the nanocarrier containing adenosine attenuated bone loss in ovariectomized mice and showed comparable bone qualities to that of healthy mice. Delivery of osteoanabolic small molecules that can contribute to bone formation and inhibit excessive osteoclast activity by leveraging the tissue-specific milieu could serve as viable therapeutics for osteoporosis.
骨组织不断进行重塑，即破骨细胞介导的骨吸收和成骨细胞介导的骨形成。如果这一过程失衡，破骨细胞活性增强，就会导致过度的骨吸收，从而导致骨变薄。破骨细胞一旦被激活，就会黏附在骨表面并使局部龛位酸化。这种酸性环境可能成为将治疗剂递送到骨质疏松症骨组织中的潜在触发因素。为此，我们开发了一种基于 pH 响应的纳米载体药物递送系统，该系统与骨组织结合并递送一种成骨分子，即腺苷。腺苷通过 pH 敏感的缩酮基团掺入到基于透明质酸（HA）的纳米载体中。进一步用阿仑膦酸盐修饰 HA-纳米载体以增强与骨组织的结合。载有腺苷的纳米载体的系统给药可减轻去卵巢小鼠的骨丢失，并表现出与健康小鼠相当的骨质量。通过利用组织特异性微环境输送有助于骨形成和抑制过度破骨细胞活性的成骨小分子，可能成为治疗骨质疏松症的可行疗法。
