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Synthesis, characterization and in vivo evaluation of a magnetic cisplatin delivery nanosystem based on PMAA-graft-PEG copolymers

Voulgari, Efstathia; Bakandritsos, Aristides; Galtsidis, Sotiris; Zoumpourlis, Vassilis; Burke, Benjamin P.; Clemente, Gonçalo S.; Cawthorne, Christopher; Archibald, Stephen J.; Tuček, Jiři; Zbořil, Radek; Kantarelou, Vasiliki; Karydas, Andreas Germanos; Avgoustakis, Konstantinos

Authors

Efstathia Voulgari

Aristides Bakandritsos

Sotiris Galtsidis

Vassilis Zoumpourlis

Benjamin P. Burke

Gonçalo S. Clemente

Christopher Cawthorne

Jiři Tuček

Radek Zbořil

Vasiliki Kantarelou

Andreas Germanos Karydas

Konstantinos Avgoustakis



Abstract

© 2016 Elsevier B.V. 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 68 Ga 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.

Journal Article Type Article
Publication Date Dec 10, 2016
Journal Journal of Controlled Release
Print ISSN 0168-3659
Electronic ISSN 1873-4995
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 243
Pages 342-356
APA6 Citation Voulgari, E., Bakandritsos, A., Galtsidis, S., Zoumpourlis, V., Burke, B. P., Clemente, G. S., …Avgoustakis, K. (2016). Synthesis, characterization and in vivo evaluation of a magnetic cisplatin delivery nanosystem based on PMAA-graft-PEG copolymers. Journal of controlled release : official journal of the Controlled Release Society, 243, 342-356. https://doi.org/10.1016/j.jconrel.2016.10.021
DOI https://doi.org/10.1016/j.jconrel.2016.10.021
Keywords Nanocarriers; Drug delivery; Magnetic targeting; Cisplatin; Theranostics; Cancer therapy
Publisher URL https://www.sciencedirect.com/science/article/pii/S0168365916310446?via%3Dihub
Additional Information This article is maintained by: Elsevier; Article Title: Synthesis, characterization and in vivo evaluation of a magnetic cisplatin delivery nanosystem based on PMAA-graft-PEG copolymers; Journal Title: Journal of Controlled Release; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.jconrel.2016.10.021; Content Type: article; Copyright: © 2016 Elsevier B.V. All rights reserved.