Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India.
Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
J Control Release. 2024 Aug;372:331-346. doi: 10.1016/j.jconrel.2024.06.009. Epub 2024 Jun 25.
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.
骨骼是各种上皮恶性肿瘤（包括乳腺癌）中最常见的转移部位之一，这种转移到骨骼通常会由于其溶骨性而导致女性严重的骨骼并发症。为了解决这个问题，我们设计了一种新的药物输送方法，使用阿仑膦酸钠（ALN）功能化的自组装多孔晶体纳米粒来同时靶向到骨转移部位的齐墩果酸（OA）和 ALN（ALN+OA@NCs）。首先，将 PEG-OA 和 OA-PEG-ALN 与 ALN 和 OA 进行缀合，然后通过纳米乳液结晶将缀合产物自组装成多孔晶体纳米粒（ALN+OA@NCs）。使用透射电子显微镜重建 3D 单颗粒确保了 ALN+OA@NCs 的结晶多孔结构，与特征纳米颗粒属性（包括尺寸分布、多分散性和 zeta 电位）很好地对齐。此外，与 OA@NCs 相比，ALN+OA@NCs 显示出增强的疗效，表明 ALN 对癌细胞的细胞毒性作用，随后增强 ROS 生成（40.81%）、线粒体膜去极化（57.20%）和诱导细胞凋亡（40.43%）。我们发现，ALN+OA@NCs 促进抑制破骨细胞生成和骨吸收，随后抑制溶骨性。在 4T1 细胞诱导的胫骨模型中，ALN+OA@NCs 的体内活性导致治疗小鼠的骨丢失减少，随后恢复骨形态计量学标志物，这进一步证实了 ALN+OA@NCs 的骨靶向作用，以减少 RANKL 刺激的破骨细胞生成。此外，体内静脉药代动力学研究表明，与游离药物相比，ALN+OA@NCs 的治疗谱得到了改善，通过减少清除率延长了药物在全身隔室中的水平，从而导致肿瘤部位的药物积累更高。我们的研究结果表明，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。
