title: PEG-oligocholic acid telodendrimer micelles for the targeted delivery of doxorubicin to B-cell lymphoma.
abstract: Doxorubicin (DOX) is one of most common anti-cancer chemotherapeutic drugs, but its clinical use is associated with dose-limiting cardiotoxicity. We have recently developed a series of PEG-oligocholic acid based telodendrimers, which can efficiently encapsulate hydrophobic drugs and self-assemble to form stable micelles in aqueous condition. In the present study, two representative telodendrimers (PEG(5k)-CA(8) and PEG(2k)-CA(4)) have been applied to prepare DOX micellar formulations for the targeted delivery of DOX to lymphoma. PEG(2k)-CA(4) micelles, compared to PEG(5k)-CA(8) micelles, were found to have higher DOX loading capacity (14.8% vs. 8.2%, w/w), superior stability in physiological condition, and more sustained release profile. Both of these DOX-loaded micelles can be efficiently internalized and release the drug in Raji lymphoma cells. DOX-loaded micelles were found to exhibit similar in vitro cytotoxic activities against both T- and B-lymphoma cells as the free DOX. The maximum tolerated dose (MTD) of DOX-loaded PEG(2k)-CA(4) micelles in mice was approximately 15 mg/kg, which was 1.5-fold higher of the MTD of free DOX. Pharmacokinetics and biodistribution studies demonstrated that both DOX-loaded micelles were able to prolong the blood retention time, preferentially accumulate and penetrate in B-cell lymphomas via the enhanced permeability and retention (EPR) effect. Finally, DOX-PEG(2k)-CA(4) micelles achieved enhanced anti-cancer efficacy and prolonged survival in Raji lymphoma bearing mice, compared to free DOX and PEGylated liposomal DOX (Doxil®) at the equivalent dose. In addition, the analysis of creatine kinase (CK) and lactate dehydrogenase (LDH) serum enzymes level indicated that DOX micellar formulations significantly reduced the cardiotoxicity associated with free DOX.
authors.affiliation: Department of Biochemistry & Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA 95817, USA. iamxiaokai@hotmail.com
authors.forename: Kai
authors.initials: K
authors.lastname: Xiao
authors.forename: Juntao
authors.initials: J
authors.lastname: Luo
authors.forename: Yuanpei
authors.initials: Y
authors.lastname: Li
authors.forename: Joyce S
authors.initials: JS
authors.lastname: Lee
authors.forename: Gabriel
authors.initials: G
authors.lastname: Fung
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019826:Cholic Acid / Q000737:chemistry*; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D053208:Kaplan-Meier Estimate; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D012995:Solubility; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D050091:Dendrimers; D004337:Drug Carriers; D008823:Micelles; D011092:Polyethylene Glycols; D004317:Doxorubicin; D019826:Cholic Acid