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Publication Type : Journal Article
Thematic Areas : Nanosciences and Molecular Medicine
Publisher : Molecular Pharmaceutics
Source : Molecular Pharmaceutics, Volume 9, Number 11, p.3062-3078 (2012)
Keywords : advanced cancer, antileukemic activity, Antineoplastic Agents, apoptosis, aqueous solution, BCR ABL protein, BCR-ABL Positive, blast cell crisis, Blotting, cancer staging, cell membrane, cell proliferation, cell surface receptor, cell viability, chronic myeloid leukemia, conjugation, controlled study, correlation analysis, down regulation, Drug Carriers, drug conjugation, drug cytotoxicity, Drug Delivery Systems, drug design, Drug Resistance, flow cytometry, Fluorescence, fluorescence in situ hybridization, Fusion Proteins, gene amplification, human serum albumin, imatinib, immunoblotting, In Situ Hybridization, leukemia cell, molecular diagnosis, molecularly targeted therapy, multidrug resistance protein, mutational analysis, Myelogenous, nanoencapsulation, nanoengineering, nanomedicine, Nanoparticles, neoplasm, Niacinamide, oncogene, personalized medicine, Phenylurea Compounds, Phosphorylation, Piperazines, point mutation, protein conformation, protein domain, protein expressi
Campus : Amritapuri, Kochi
School : Center for Nanosciences, School of Engineering
Center : Amrita Center for Nanosciences and Molecular Medicine Move, Nanosciences
Department : Nanosciences and Molecular Medicine, Electronics and Communication
Year : 2012
Abstract : Deregulated protein kinases play a very critical role in tumorigenesis, metastasis, and drug resistance of cancer. Although molecularly targeted small molecule kinase inhibitors (SMI) are effective against many types of cancer, point mutations in the kinase domain impart drug resistance, a major challenge in the clinic. A classic example is chronic myeloid leukemia (CML) caused by BCR-ABL fusion protein, wherein a BCR-ABL kinase inhibitor, imatinib (IM), was highly successful in the early chronic phase of the disease, but failed in the advanced stages due to amplification of oncogene or point mutations in the drug-binding site of kinase domain. Here, by identifying critical molecular pathways responsible for the drug-resistance in refractory CML patient samples and a model cell line, we have rationally designed an endogenous protein nanomedicine targeted to both cell surface receptors and aberrantly activated secondary kinase in the oncogenic network. Molecular diagnosis revealed that, in addition to point mutations and amplification of oncogenic BCR-ABL kinase, relapsed/refractory patients exhibited significant activation of STAT5 signaling with correlative overexpression of transferrin receptors (TfR) on the cell membrane. Accordingly, we have developed a human serum albumin (HSA) based nanomedicine, loaded with STAT5 inhibitor (sorafenib), and surface conjugated the same with holo-transferrin (Tf) ligands for TfR specific delivery. This dual-targeted transferrin conjugated albumin bound sorafenib nanomedicine (Tf-nAlb-Soraf), prepared using aqueous nanoprecipitation method, displayed uniform spherical morphology with average size of ∼150 nm and drug encapsulation efficiency of ∼74%. TfR specific uptake and enhanced antileukemic activity of the nanomedicine was found maximum in the most drug resistant patient sample having the highest level of STAT5 and TfR expression, thereby confirming the accuracy of our rational design and potential of dual-targeting approach. The nanomedicine induced downregulation of key survival pathways such as pSTAT5 and antiapoptotic protein MCL-1 was demonstrated using immunoblotting. This study reveals that, by implementing molecular diagnosis, personalized nanomedicines can be rationally designed and nanoengineered by imparting therapeutic functionality to endogenous proteins to overcome clinically important challenges like molecular drug resistance. © 2012 American Chemical Society.
Cite this Research Publication : A. P. Retnakumari, Hanumanthu, P. L., Malarvizhi, G. L., Prabhu, R., Sidharthan, N., Thampi, M. V., Dr. Deepthy Menon, Mony, U., Krishnakumar N. Menon, Keechilat, P., Nair, S., and Dr. Manzoor K., “Rationally Designed Aberrant Kinase-Targeted Endogenous Protein Nanomedicine Against Oncogene Mutated/Amplified Refractory Chronic Myeloid Leukemia”, Molecular Pharmaceutics, vol. 9, pp. 3062-3078, 2012.