title: Polymer-lipid hybrid nanoparticles synchronize pharmacokinetics of co-encapsulated doxorubicin-mitomycin C and enable their spatiotemporal co-delivery and local bioavailability in breast tumor.
abstract: Effective combination chemotherapy requires the delivery of drugs of synergism to tumor sites while sparing normal tissues. Herein we investigated whether coencapsulation of doxorubicin and mitomycin C within polymer-lipid hybrid nanoparticles (DMPLN) achieved this goal via ratiometric drugs in an orthotopic murine breast tumor model with nanocarrier-modified biodistribution, pharmacokinetics, local bioavailability and toxicity. Fluorescence imaging revealed quickened and extended tumor uptake but reduced cardiac accumulation of DMPLN. Quantitative drug analysis demonstrated prolonged systemic circulation, increased tumor accumulation and sustained synergistic ratios of doxorubicin and mitomycin C delivered by DMPLN over 24h. Higher levels of tumor cell apoptosis and reduced organ toxicity were obtained with DMPLN compared to free drug cocktails. DMPLN released DOX in tumors more efficiently than that from liposomal doxorubicin, as evidenced by a higher extent of the metabolite, doxorubicinol. These findings substantiate the importance of rational design of nanoparticles for synergistic drug combination therapy.
  
  
  
  The treatment of cancer usually involves using combination chemotherapeutic agents. In adopting a nanomedicine approach, one can in theory design combination therapy consisting of drugs of synergistic activities, with the aim to target tumor specifically while minimizing systemic toxicity. The authors in this study provided evidence for this rational design by co-encapsulation of doxorubicin and mitomycin C within polymer-lipid hybrid nanoparticles (DMPLN) in a breast cancer model.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada. Electronic address: vicki.zhang@mail.utoronto.ca.
authors.forename: Rui Xue
authors.initials: RX
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada. Electronic address: ping.cai@utoronto.ca.
authors.forename: Ping
authors.initials: P
authors.lastname: Cai
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada. Electronic address: tianqq.zhang@mail.utoronto.ca.
authors.forename: Tian
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
authors.forename: King
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada. Electronic address: jason.li@utoronto.ca.
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
authors.forename: Ji
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada. Electronic address: ks.pang@utoronto.ca.
authors.forename: K Sandy
authors.initials: KS
authors.lastname: Pang
authors.affiliation: Center for Modeling Human Disease, The Lunenfeld-Tanenbaum Research Institute, Toronto Centre for Phenogenomics, Toronto, ON, Canada. Electronic address: adissu@lunenfel.ca.
authors.forename: Hibret A
authors.initials: HA
authors.lastname: Adissu
authors.affiliation: Departments of Medical Biophysics and Radiation Oncology, University of Toronto, Princess Margaret Cancer Centre, Toronto, ON, Canada. Electronic address: rauth@uhnres.utoronto.ca.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Rauth
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada. Electronic address: xywu@phm.utoronto.ca.
authors.forename: Xiao Yu
authors.initials: XY
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D008055:Lipids; D051379:Mice; D016685:Mitomycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D053758:Nanoparticles; D011108:Polymers; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D008055:Lipids; D011108:Polymers; D016685:Mitomycin; D004317:Doxorubicin
keywords: Biodistribution; Doxorubicin combination; Pharmacokinetics; Polymer–lipid nanoparticles; Ratiometric delivery