Hydroxyapatite-dextran methacrylate core/shell hybrid nanocarriers for combinatorial drug therapy
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Biomaterials Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600 036, Tamil Nadu, India 2 Medical Materials Laboratory, Department of Metallurgical and Materials Engineering, Indian Institute of Technology Madras, Chennai 600 036, Tamil Nadu, India a) Address all correspondence to these authors. e-mail: [email protected]; [email protected] b) e-mail: [email protected] c) Present address: Raja Ramanna Fellow, Rajiv Gandhi Centre for Biotechnology, Jagathy, Trivandrum 695 014, Kerala, India Received: 2 April 2020; accepted: 6 July 2020
In this study, a hybrid dual drug-loaded hydroxyapatite-oxidized dextran methacrylate core–shell nanocarrier was formulated and explored for combinatorial delivery of doxorubicin (DOX) and methotrexate (MTX) to bone cancer. The synthesized nanocarrier was well characterized by different techniques. In vitro drug release studies in both acidic (pH 5) and alkaline (pH 7.4) conditions showed sequential release of MTX followed by DOX in a sustained manner for 10 days. Biocompatibility and cytotoxicity studies performed using drug-loaded nanoparticles (NPs) on fibroblast L929 cells and osteosarcoma MG63 cells (OMG63) showed that the NPs were highly biocompatible and showed concentration-dependent toxicity. Gene expression studies in OMG-63 cells exhibited the upregulation of caspase-3 and BAX which confirmed the apoptosis induced by dual drug-loaded NPs. The nanocarrier is expected to be a potential bone void filling material, as well as a platform for sequential delivery of DOX and MTX for the treatment of bone cancer.
Introduction Bone cancer is a malignant tumor which originates in the bone and destroys the healthy bone tissues. Bone cancer is a dangerous disease which can spread to distant organs easily and bone is a common site to be affected by metastatic cancer [1, 2]. Bone metastases are the main cause of morbidity and mortality in patients with advanced malignant diseases [3, 4, 5]. Among the 45 different types of bone tumors, osteosarcoma is the most common and important primary bone tumor (31.5%) followed by chondrosarcoma, Ewing’s sarcoma and chondroma [6, 7]. The treatment of bone cancer involves surgery, fixation, radiotherapy and systemic chemotherapy before and after surgery [8, 9]. Among the different types of treatment, chemotherapy is an essential requisite but repeated usage of single chemotherapeutic agents involving high doses leads to adverse effects, such as systemic toxicity and multidrug resistance. Combination therapy of multiple chemo drugs enhances treatment efficacy by acting on multiple pathways with synergistic effects [10, 11]. Nanotechnology-based combination therapy with nanocarriers, such as dendrimers, liposomes, carbon nanotubes,
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polymer drug conjugates, micelles, and polymeric, inorganic and ceramic nanoparticles (NPs) has gained considerable attention [11, 12, 13, 14, 15, 16]. Combined delivery of drugs using nanoc
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