title: Nanolipolee-007, a novel nanoparticle-based drug containing leelamine for the treatment of melanoma.
abstract: Malignant melanoma is a difficult cancer to treat due to the rapid development of resistance to drugs targeting single proteins. One response to this observation is to identify single pharmacologic agents that, due to a unique mechanism of action, simultaneously target multiple key pathways involved in melanoma development. Leelamine has been identified as functioning in this manner but has poor bioavailability in animals and causes lethality when administered intravenously. Therefore, a nanoliposomal-based delivery system has been developed, called Nanolipolee-007, which stably loads 60% of the compound. The nanoparticle was as effective at killing melanoma cells as leelamine dissolved in DMSO and was more effective at killing cultured melanoma compared with normal cells. Mechanistically, Nanolipolee-007 inhibited PI3K/Akt, STAT3, and MAPK signaling mediated through inhibition of cholesterol transport. Nanolipolee-007 inhibited the growth of preexisting xenografted melanoma tumors by an average of 64% by decreasing cellular proliferation, reducing tumor vascularization, and increasing cellular apoptosis, with negligible toxicity. Thus, a unique clinically viable nanoparticle-based drug has been developed containing leelamine for the treatment of melanoma that acts by inhibiting the activity of major signaling pathways regulating the development of this disease.
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. The Penn State Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Foreman Foundation for Melanoma Research, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Gowda
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: SubbaRao V
authors.initials: SV
authors.lastname: Madhunapantula
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. The Penn State Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Foreman Foundation for Melanoma Research, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Arati
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. The Penn State Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Omer F
authors.initials: OF
authors.lastname: Kuzu
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. The Penn State Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Foreman Foundation for Melanoma Research, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. gprobertson@psu.edu.
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Robertson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010766:Phosphorylation; D011897:Random Allocation; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D004224:Diterpenes; D008081:Liposomes
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