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High-efficiency liposomal encapsulation of a tyrosine kinase inhibitor leads to improved in vivo toxicity and tumor response profile
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Authors: Mukthavaram R, Jiang P, Saklecha R, Simberg D, Bharati IS, Nomura N, Chao Y, Pastorino S, Pingle SC, Fogal V, Wrasidlo W, Makale M, Kesari S
Published Date October 2013
Volume 2013:8(1) Pages 3991 - 4006
|Received:||23 July 2013|
|Accepted:||28 August 2013|
|Published:||21 October 2013|
1Translational Neuro-Oncology Laboratories, 2Department of Neurosciences, 3Solid Tumor Therapeutics Program, Moores Cancer Center, UC San Diego, La Jolla, CA, 4Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Denver, CO, USA
Abstract: Staurosporine (STS) is a potent pan-kinase inhibitor with marked activity against several chemotherapy-resistant tumor types in vitro. The translational progress of this compound has been hindered by poor pharmacokinetics and toxicity. We sought to determine whether liposomal encapsulation of STS would enhance antitumor efficacy and reduce toxicity, thereby supporting the feasibility of further preclinical development. We developed a novel reverse pH gradient liposomal loading method for STS, with an optimal buffer type and drug-to-lipid ratio. Our approach produced 70% loading efficiency with good retention, and we provide, for the first time, an assessment of the in vivo antitumor activity of STS. A low intravenous dose (0.8 mg/kg) inhibited U87 tumors in a murine flank model. Biodistribution showed preferential tumor accumulation, and body weight data, a sensitive index of STS toxicity, was unaffected by liposomal STS, but did decline with the free compound. In vitro experiments revealed that liposomal STS blocked Akt phosphorylation, induced poly(ADP-ribose) polymerase cleavage, and produced cell death via apoptosis. This study provides a basis to explore further the feasibility of liposomally encapsulated STS, and potentially related compounds for the management of resistant solid tumors.
Keywords: liposomes, staurosporine, glioblastoma, biodistribution, efficacy
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