PEG-derivatized embelin as a dual functional carrier for the delivery of paclitaxel.
Embelin, identified primarily from the  Embelia ribes  plant, has been shown to be a natural small molecule inhibitor of X-linked inhibitor of apoptosis protein (XIAP). It is also a potent inhibitor of NF-κB activation, which makes it a potentially effective suppressor of tumor cell survival, proliferation, invasion, angiogenesis, and inflammation. However, embelin itself is insoluble in water, which makes it unsuitable for in vivo applications. In this work, we developed a novel micelle system through conjugating embelin to a hydrophilic polymer, poly(ethylene glycol) 3500 (PEG(3.5K)) through an aspartic acid bridge. The PEG(3.5k)-embelin(2) (PEG(3.5k)-EB(2)) conjugate readily forms micelles in aqueous solutions with a CMC of 0.0205 mg/mL. Furthermore, PEG(3.5k)-EB(2) micelles effectively solubilize paclitaxel (PTX), a model hydrophobic drug used in this study. Both drug-free and drug-loaded micelles were small in size (20-30 nm) with low polydispersity indexes. In vitro cytotoxicity studies with several tumor cell lines showed that PEG(3.5k)-EB(2) is comparable to embelin in antitumor activity and synergizes with PTX at much lower doses. Our results suggest that PEG-derivatized embelin may represent a novel and dual-functional carrier to facilitate the in vivo applications of poorly water-soluble anticancer drugs such as PTX.
Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Yixian
Y
Huang
Jianqin
J
Lu
Xiang
X
Gao
Jiang
J
Li
Wenchen
W
Zhao
Ming
M
Sun
Donna Beer
DB
Stolz
Raman
R
Venkataramanan
Lisa Cencia
LC
Rohan
Song
S
Li
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008823:Micelles; D015394:Molecular Structure; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D012995:Solubility; D013329:Structure-Activity Relationship; D013499:Surface Properties; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016227:Benzoquinones; D004337:Drug Carriers; D008823:Micelles; D011092:Polyethylene Glycols; D017239:Paclitaxel; C010945:embelin