title: PEG-derivatized embelin as a nanomicellar carrier for delivery of paclitaxel to breast and prostate cancers.
abstract: Paclitaxel (PTX) is one of the most effective chemotherapeutic agents for a wide spectrum of cancers, but its therapeutic benefit is often limited by severe side effects. We have developed a micelle-based PTX formulation based on a simple conjugate derived from polyethylene glycol 5000 (PEG(5K)) and embelin (EB). Embelin is a natural product and exhibits antitumor activity through blocking the activity of X-linked inhibitor of apoptosis protein (XIAP). PEG(5K)-EB₂ conjugate self-assembles to form stable micelles in aqueous solution and efficiently encapsulates hydrophobic drugs such as PTX. PEG(5K)-EB₂ micelles have a relatively low CMC of 0.002 mg/mL (0.35 μM) with sizes in the range of 20 ∼ 30 nm with or without loaded PTX. In vitro cell uptake study showed that the PEG(5K)-EB₂ micelles were efficiently taken up by tumor cells. In vitro release study showed that PTX formulated in PEG(5K)-EB₂ micelles was slowly released over 5 days with much slower release kinetics than that of Taxol formulation. PTX formulated in PEG(5K)-EB₂ micelles exhibited more potent cytotoxicity than Taxol in several cultured tumor cell lines. Total body near infrared fluorescence (NIRF) imaging showed that PEG(5K)-EB₂ micelles were selectively accumulated at tumor site with minimal uptake in major organs including liver and spleen. PTX-loaded PEG(5K)-EB₂ micelles demonstrated an excellent safety profile with a maximum tolerated dose (MTD) of 100-120 mg PTX/kg in mice, which was significantly higher than that for Taxol (15-20 mg PTX/kg). Finally, PTX formulated in PEG(5K)-EB₂ micelles showed superior antitumor activity compared to Taxol in murine models of breast and prostate cancers.
authors.affiliation: Center for Pharmacogenetics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261, USA.
authors.forename: Jianqin
authors.initials: J
authors.lastname: Lu
authors.forename: Yixian
authors.initials: Y
authors.lastname: Huang
authors.forename: Wenchen
authors.initials: W
authors.lastname: Zhao
authors.forename: Rebecca T
authors.initials: RT
authors.lastname: Marquez
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Meng
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wang
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D016227:Benzoquinones / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D017239:Paclitaxel / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D016227:Benzoquinones; D008823:Micelles; D053769:Nanocapsules; D011092:Polyethylene Glycols; D017239:Paclitaxel; C010945:embelin