title: Targeted delivery of Doxorubicin by folic acid-decorated dual functional nanocarrier.
abstract: Doxorubicin (DOX) is one of the most commonly used antineoplastic agents, but its clinical application is oftentimes coupled with severe side effects. Selective delivery of DOX to tumors via nanosized drug carrier represents an attractive approach to this problem. Previously, we developed a dual functional nanomicellar carrier, PEG5K-embelin2 (PEG5K-EB2), which was able to deliver paclitaxel (PTX) selectively to tumors and to achieve an enhanced therapeutic effect. In the present study, we examined the utility of PEG5K-EB2 to deliver DOX to tumors. In addition, folic acid (FA) was coupled to the surface of the PEG5K-EB2 micelles (FA-PEG5K-EB2) to further improve the selective targetability of the system. DOX-loaded PEG5K-EB2 micelles were uniformly spherical particles with a diameter of approximately 20 nm. Incorporation of FA had minimal effect on the size of the particles. The DOX loading efficiency was as high as 91.7% and 93.5% for PEG5K-EB2 and FA-PEG5K-EB2, respectively. DOX formulated in PEG5K-EB2 micelles (with or without FA decoration) demonstrated sustained kinetics of DOX release compared to free DOX. FA-PEG5K-EB2 significantly facilitated the intracellular uptake of DOX over free DOX and PEGylated liposomal DOX (Doxil) in breast cancer cells, 4T1.2, and drug resistant cells, NCI/ADR-RES. P-gp ATPase assay showed that PEG5K-EB2 significantly inhibited the function of the P-gp efflux pump. The maximum tolerated dose of DOX-loaded PEG5K-EB2 micelles was 15 mg/kg in mice, which was 1.5-fold greater than that for free DOX. Pharmacokinetics (PK) and biodistribution studies showed that both types of DOX-loaded micelles, especially FA-PEG5K-EB2, were able to significantly prolong the blood circulation time of DOX and facilitate its preferential accumulation at the tumor tissue. Finally, DOX/PEG5K-EB2 mixed micelles demonstrated significantly enhanced tumor growth inhibitory effect with minimal toxicity in comparison to free DOX and Doxil and the antitumor activity was further enhanced after the decoration by folic acid. Our data suggest that FA-PEG5K-EB2 micelles represent a promising DOX delivery system that warrants more study in the future.
authors.affiliation: Center for Pharmacogenetics, ‡Department of Pharmaceutical Sciences, School of Pharmacy, and §University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
authors.forename: Jianqin
authors.initials: J
authors.lastname: Lu
authors.forename: Wenchen
authors.initials: W
authors.lastname: Zhao
authors.forename: Yixian
authors.initials: Y
authors.lastname: Huang
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Marquez
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gibbs
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.forename: Shulin
authors.initials: S
authors.lastname: Li
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D016227:Benzoquinones / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D005260:Female; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D004337:Drug Carriers; D008823:Micelles; D011092:Polyethylene Glycols; D004317:Doxorubicin; D005492:Folic Acid; C010945:embelin
keywords: antitumor activity; doxorubicin; folic acid; multidrug resistance; nanomicelles; targeted delivery