TY - JOUR
T1 - Synthesis, characterization and in vivo evaluation of a magnetic cisplatin delivery nanosystem based on PMAA-graft-PEG copolymers
AU - Voulgari, Efstathia
AU - Bakandritsos, Aristides
AU - Galtsidis, Sotiris
AU - Zoumpourlis, Vassilis
AU - Burke, Benjamin P.
AU - Clemente, Gonçalo S.
AU - Cawthorne, Christopher
AU - Archibald, Stephen J.
AU - Tuček, Jiři
AU - Zbořil, Radek
AU - Kantarelou, Vasiliki
AU - Karydas, Andreas Germanos
AU - Avgoustakis, Konstantinos
N1 - Publisher Copyright:
© 2016 Elsevier B.V.
PY - 2016/12/10
Y1 - 2016/12/10
N2 - The development of anticancer drug delivery systems which retain or enhance the cytotoxic properties of the drug to tumorous tissues, while reducing toxicity to other organs is of key importance. We investigated different poly(methacrylic acid)-g-poly(ethyleneglycol methacrylate) polymers as in situ coating agents for magnetite nanocrystallites. The obtained magnetic nano-assemblies were in turn thoroughly characterized for their structural, colloidal and physicochemical properties (drug loading capacity/release, magnetic field triggered drug release, cell uptake and localization) in order to select the best performing system. With the focus on in vivo validation of such magnetic drug delivery systems for first time, we selected cisplatin as the drug, since it is a potent anticancer agent which exhibits serious side effects due to lack of selectivity. In addition, cisplatin would offer facile determination of the metal content in the animal tissues for biodistribution studies. Alongside post-mortem Pt determination in the tissues, the biodistribution of the drug nanocarriers was also monitored in real time with PET-CT (positron emission tomography/computed tomography) with and without the presence of magnetic field gradients; using a novel chelator-free method, the nanoparticles were radiolabeled with 68Ga without having to alter their structure with chemical modifications for conjugation of radiochelators. The ability to be radiolabeled in such a straightforward but very robust way, along with their measured high MRI response, renders them attractive for dual imaging, which is an important functionality for translational investigations. Their anticancer properties were evaluated in vitro and in vivo, in a cisplatin resistant HT-29 human colon adenocarcinoma model, with and without the presence of magnetic field gradients. Enhanced anticancer efficacy and reduced toxicity was recorded for the cisplatin-loaded nanocarriers in comparison to the free cisplatin, particularly when a magnetic field gradient was applied at the tumor site. Post mortem and real-time tissue distribution studies did not reveal increased cisplatin concentration in the tumor site, suggesting that the enhanced anticancer efficacy of the cisplatin-loaded nanocarriers is driven by mechanisms other than increased cisplatin accumulation in the tumors.
AB - The development of anticancer drug delivery systems which retain or enhance the cytotoxic properties of the drug to tumorous tissues, while reducing toxicity to other organs is of key importance. We investigated different poly(methacrylic acid)-g-poly(ethyleneglycol methacrylate) polymers as in situ coating agents for magnetite nanocrystallites. The obtained magnetic nano-assemblies were in turn thoroughly characterized for their structural, colloidal and physicochemical properties (drug loading capacity/release, magnetic field triggered drug release, cell uptake and localization) in order to select the best performing system. With the focus on in vivo validation of such magnetic drug delivery systems for first time, we selected cisplatin as the drug, since it is a potent anticancer agent which exhibits serious side effects due to lack of selectivity. In addition, cisplatin would offer facile determination of the metal content in the animal tissues for biodistribution studies. Alongside post-mortem Pt determination in the tissues, the biodistribution of the drug nanocarriers was also monitored in real time with PET-CT (positron emission tomography/computed tomography) with and without the presence of magnetic field gradients; using a novel chelator-free method, the nanoparticles were radiolabeled with 68Ga without having to alter their structure with chemical modifications for conjugation of radiochelators. The ability to be radiolabeled in such a straightforward but very robust way, along with their measured high MRI response, renders them attractive for dual imaging, which is an important functionality for translational investigations. Their anticancer properties were evaluated in vitro and in vivo, in a cisplatin resistant HT-29 human colon adenocarcinoma model, with and without the presence of magnetic field gradients. Enhanced anticancer efficacy and reduced toxicity was recorded for the cisplatin-loaded nanocarriers in comparison to the free cisplatin, particularly when a magnetic field gradient was applied at the tumor site. Post mortem and real-time tissue distribution studies did not reveal increased cisplatin concentration in the tumor site, suggesting that the enhanced anticancer efficacy of the cisplatin-loaded nanocarriers is driven by mechanisms other than increased cisplatin accumulation in the tumors.
KW - Cancer therapy
KW - Cisplatin
KW - Drug delivery
KW - Magnetic targeting
KW - Nanocarriers
KW - Theranostics
UR - http://www.scopus.com/inward/record.url?scp=84996602610&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2016.10.021
DO - 10.1016/j.jconrel.2016.10.021
M3 - Article
C2 - 27793687
AN - SCOPUS:84996602610
SN - 0168-3659
VL - 243
SP - 342
EP - 356
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -
