Synthesis and in vitro and in vivo evaluations of poly(ethylene glycol)-block-poly(4-vinylbenzylphosphonate) magnetic nanoparticles containing doxorubicin as a potential targeted drug delivery system.
The main challenge in antitumor chemotherapy is to enhance the curative effect and minimize the adverse effects of an anticancer drug. Administration of functionalized magnetic iron oxide nanoparticles is one of the strategies to improve sensitivity to cancer chemotherapy, and these nanoparticles are attractive materials that have been widely used in medicine for various applications, including diagnostic imaging and therapeutic applications. In this study, we describe the synthesis and characterization of drug-loaded iron oxide nanoparticles. Our aim was to obtain a biocompatible and injectable nanocarrier with anticancer activity. Iron oxide nanoparticles (IONs) were synthesized by alkali co-precipitation of iron salts followed by coating with our original surface modification agent, poly(ethylene glycol)-block-poly(4-vinylbenzylphosphonate) copolymer (PEG-PIONs). An anticancer drug doxorubicin (DOX), which clinical use is associated with cardiotoxicity, was loaded onto PEG-PIONs (PEG-PIONs/DOX), and to the best of our knowledge, this formulation showed higher drug encapsulation efficiency (drug loading capacity of the nanocarrier was 11.7%) than other formulations previously reported. PEG-PIONs/DOX had a hydrodynamic diameter of about 35nm and were stable in biological conditions over a period more than one month and showed stable and continuous in vitro drug release and antiproliferative effects on cancer cells. Fluorescent imaging indicated internalization of the PEG-PIONs/DOX in the cytoplasm of cancer cells. Biodistribution studies showed that PEG-PIONs/DOX preferentially accumulate in the tumor region via enhanced permeability and retention effect. In addition, analysis of the serum levels of enzymes indicated that PEG-PIONs/DOX reduced the cardiotoxicity associated with free DOX. These results indicate that PEG-PIONs/DOX have the potential for targeted delivery of antitumor drugs via systemic administration.
The NanoBioMedical Centre, Adam Mickiewicz University, Poznań, Poland; Division of Medical Physics, Faculty of Physics, Adam Mickiewicz University, Poznań, Poland; Department of Materials Sciences, Graduate School of Pure and Applied Sciences, University of Tsukuba, Japan.
Magdalena
M
Hałupka-Bryl
Department of Materials Sciences, Graduate School of Pure and Applied Sciences, University of Tsukuba, Japan.
Kei
K
Asai
Department of Materials Sciences, Graduate School of Pure and Applied Sciences, University of Tsukuba, Japan.
Sindhu
S
Thangavel
The NanoBioMedical Centre, Adam Mickiewicz University, Poznań, Poland; Division of Medical Physics, Faculty of Physics, Adam Mickiewicz University, Poznań, Poland; Department of Materials Sciences, Graduate School of Pure and Applied Sciences, University of Tsukuba, Japan.
Magdalena
M
Bednarowicz
The NanoBioMedical Centre, Adam Mickiewicz University, Poznań, Poland; Division of Medical Physics, Faculty of Physics, Adam Mickiewicz University, Poznań, Poland.
Ryszard
R
Krzyminiewski
Department of Materials Sciences, Graduate School of Pure and Applied Sciences, University of Tsukuba, Japan; Master's School of Medicinal Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan; International Centre for Materials Nanoarchitectonics Satellite (WPI-MANA), National Institute for Materials Sciences (NIMS) and University of Tsukuba, Japan. Electronic address: yukio@nagalabo.jp.
Yukio
Y
Nagasaki
D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001806:Blood Urea Nitrogen; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003102:Colloids; D003402:Creatine Kinase / Q000097:blood; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007770:L-Lactate Dehydrogenase / Q000097:blood; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D008297:Male; D008807:Mice, Inbred BALB C; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry*; D011145:Polyvinyls / Q000138:chemical synthesis* / Q000737:chemistry*; D014018:Tissue Distribution
D003102:Colloids; D058185:Magnetite Nanoparticles; D063065:Organophosphonates; D011145:Polyvinyls; C000594166:poly(ethylene glycol)-block-poly(4-vinylbenzylphosphonate); D011092:Polyethylene Glycols; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D003402:Creatine Kinase
Antiproliferative effect; Biodistribution; Cardiotoxicity; Intracellular drug release; Magnetic iron oxide; Targeted drug delivery