title: Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in Ovarian Cancer Treatment.
abstract: We have developed multifunctional nanoparticles for codelivery of bortezomib and doxorubicin to synchronize their pharmacokinetic profiles and synergize their activities in solid tumor treatment, a need still unmet in the clinic. Micellar nanoparticles were formed by a spatially segregated, linear-dendritic telodendrimer containing three segments: a hydrophilic polyethylene glycol (PEG), a bortezomib-conjugating intermediate, and a dendritic doxorubicin-affinitive interior. Bortezomib-conjugated telodendrimers, together with doxorubicin, self-assembled into monodispersed micelles [NP(BTZ-DOX)] with small particle sizes (20-30 nm) for dual drug delivery. NP(BTZ-DOX) displayed excellent drug-loading capacity and stability, which minimized premature drug leakage and synchronized drug release profiles. Bortezomib release was accelerated significantly by acidic pH, facilitating drug availability in the acidic tumor microenvironment. Synergistic anticancer effects of combined bortezomib and doxorubicin were observedin vitroagainst both multiple myeloma and ovarian cancer cells. NP(BTZ-DOX) prolonged payload circulation and targeted tumorsin vivoefficiently with superior signal ratios of tumor to normal organs.In vitroandin vivoproteasome inhibition analysis and biodistribution studies revealed decreased toxicity and efficient intratumoral bortezomib and doxorubicin delivery by nanoformulation. NP(BTZ-DOX) exhibited significantly improved ovarian cancer treatment in SKOV-3 xenograft mouse models in comparison with free drugs and their combinations, including bortezomib and Doxil. In summary, tumor-targeted and synchronized delivery system elicits enhanced anticancer effects and merits further development in the clinical setting.Cancer Res; 77(12); 3293-305. ©2017 AACR.
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York.
authors.forename: Changying
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York.
authors.forename: Forrest A
authors.initials: FA
authors.lastname: Wright
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York.
authors.forename: Dandan
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Public Health and Preventive Medicine, State University of New York Upstate Medical University, Syracuse, New York.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York.|Upstate Cancer Center, State University of New York Upstate Medical University, Syracuse, New York.
authors.forename: Richard J H
authors.initials: RJH
authors.lastname: Wojcikiewicz
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York. luoj@upstate.edu.|Upstate Cancer Center, State University of New York Upstate Medical University, Syracuse, New York.
authors.forename: Juntao
authors.initials: J
authors.lastname: Luo
mesh_terms: D000818:Animals; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D004337:Drug Carriers; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D053758:Nanoparticles; D010051:Ovarian Neoplasms; D023041:Xenograft Model Antitumor Assays
chemical_list: D004337:Drug Carriers; D008823:Micelles; D000069286:Bortezomib; D004317:Doxorubicin