Alendronate-functionalized porous nano-crystalsomes mitigate osteolysis and consequent inhibition of tumor growth in a tibia-induced metastasis model

• Published in: Journal of controlled release 2024-08, Vol.372, p.331-346
• Main Authors: Shukla, Ravi Prakash, Tiwari, Pratiksha, Sardar, Anirban, Urandur, Sandeep, Gautam, Shalini, Marwaha, Disha, Tripathi, Ashish Kumar, Rai, Nikhil, Trivedi, Ritu, Mishra, Prabhat Ranjan
• Format: Article
• Language: English
• Subjects: Alendronate; Alendronate - administration & dosage; Alendronate - chemistry; Alendronate - pharmacokinetics; Animals; Bone Density Conservation Agents - administration & dosage; Bone Density Conservation Agents - pharmacokinetics; Bone Neoplasms - drug therapy; Bone Neoplasms - secondary; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Line, Tumor; Crystalsomes; Female; Humans; Mice; Mice, Inbred BALB C; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Oleanolic acid; Oleanolic Acid - administration & dosage; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - chemistry; Oleanolic Acid - pharmacokinetics; Osteoblast; Osteoclast; Osteolysis - drug therapy; Osteolysis - prevention & control; Porosity; RANKL; Tibia - drug effects; Tibia - pathology
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2024.06.009

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. [Display omitted]