title: High-efficiency liposomal encapsulation of a tyrosine kinase inhibitor leads to improved in vivo toxicity and tumor response profile.
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.
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Mukthavaram
authors.forename: Pengfei
authors.initials: P
authors.lastname: Jiang
authors.forename: Rohit
authors.initials: R
authors.lastname: Saklecha
authors.forename: Dmitri
authors.initials: D
authors.lastname: Simberg
authors.forename: Ila Sri
authors.initials: IS
authors.lastname: Bharati
authors.forename: Natsuko
authors.initials: N
authors.lastname: Nomura
authors.forename: Ying
authors.initials: Y
authors.lastname: Chao
authors.forename: Sandra
authors.initials: S
authors.lastname: Pastorino
authors.forename: Sandeep C
authors.initials: SC
authors.lastname: Pingle
authors.forename: Valentina
authors.initials: V
authors.lastname: Fogal
authors.forename: Wolf
authors.initials: W
authors.lastname: Wrasidlo
authors.forename: Milan
authors.initials: M
authors.lastname: Makale
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004058:Diffusion; D005260:Female; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry* / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine / Q000008:administration & dosage* / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D008081:Liposomes; D053769:Nanocapsules; D011493:Protein Kinase C; D019311:Staurosporine
keywords: biodistribution; efficacy; glioblastoma; liposomes; staurosporine