Abstract：
Bone is one of the most prevalent sites of metastases in various epithelial malignancies, including breast cancer and this metastasis to bone often leads to severe skeletal complications in women due to its osteolytic nature. To address this, we devised a novel drug delivery approach using an Alendronate (ALN) functionalized self-assembled porous crystalsomes for concurrent targeting of Oleanolic acid (OA) and ALN (ALN + OA@NCs) to bone metastasis. Initially, the conjugation of both PEG-OA and OA-PEG-ALN with ALN and OA was achieved, and this conjugation was then self-assembled into porous crystalsomes (ALN + OA@NCs) by nanoemulsion crystallization. The reconstruction of a 3D single particle using transmission electron microscopy ensured the crystalline porous structure of ALN + OA@NCs, was well aligned with characteristic nanoparticle attributes including size distribution, polydispersity, and zeta potential. Further, ALN + OA@NCs showed enhanced efficacy in comparison to OA@NCs suggesting the cytotoxic roles of ALN towards cancer cells, followed by augmentation ROS generation (40.81%), mitochondrial membrane depolarization (57.20%), and induction of apoptosis (40.43%). We found that ALN + OA@NCs facilitated inhibiting osteoclastogenesis and bone resorption followed by inhibited osteolysis. In vivo activity of ALN + OA@NCs in the 4 T1 cell-induced tibia model rendered a reduced bone loss in the treated mice followed by restoring bone morphometric markers which were further corroborated bone-targeting effects of ALN + OA@NCs to reduce RANKL-stimulated osteoclastogenesis. Further, In vivo intravenous pharmacokinetics showed the improved therapeutic profile of the ALN + OA@NCs in comparison to the free drug, prolonging the levels of the drug in the systemic compartment by reducing the clearance culminating the higher accumulation at the tumor site. Our finding proposed that ALN + OA@NCs can effectively target and treat breast cancer metastasis to bone and its associated complications.
摘要：
骨是各种上皮恶性肿瘤中最常见的转移部位之一，包括乳腺癌和这种骨转移往往导致严重的骨骼并发症的妇女由于其溶骨的性质。为了解决这个问题，我们设计了一种新的药物递送方法,该方法使用阿仑膦酸盐(ALN)功能化的自组装多孔晶体体,用于齐墩果酸(OA)和ALN(ALN+OA@NC)同时靶向骨转移.最初，实现了PEG-OA和OA-PEG-ALN与ALN和OA的缀合，然后通过纳米乳液结晶将这种缀合物自组装成多孔晶体体(ALN+OA@NCs)。使用透射电子显微镜重建3D单个粒子，确保了ALNOA@NC的结晶多孔结构，与包括尺寸分布在内的特征纳米粒子属性很好地对齐，多分散性，和zeta电位。Further,与OA@NCs相比，ALN+OA@NCs显示出增强的功效，表明ALN对癌细胞的细胞毒性作用，其次是增加ROS产生(40.81%)，线粒体膜去极化（57.20%），诱导细胞凋亡(41.1%)。我们发现ALNOA@NC促进了破骨细胞生成和骨吸收的抑制，然后抑制了骨溶解。4T1细胞诱导的胫骨模型中ALN+OA@NC的体内活性使治疗小鼠的骨丢失减少,随后恢复骨形态测定标记,这进一步证实了ALN+OA@NC的骨靶向作用以减少RANKL刺激的破骨细胞生成。Further,与游离药物相比，体内静脉药代动力学显示ALN+OA@NC的治疗概况有所改善，通过降低肿瘤部位的清除率来延长全身隔室中的药物水平。我们的发现表明，ALN+OA@NCs可以有效地靶向和治疗乳腺癌骨转移及其相关并发症。
