title: Synthesis, characterization and in vivo evaluation of a magnetic cisplatin delivery nanosystem based on PMAA-graft-PEG copolymers.
abstract: 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 with68Ga 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.
authors: Department of Pharmacy, University of Patras, Patras 26500, Greece.
authors: Efstathia
authors: E
authors: Voulgari
authors: Department of Materials Science, University of Patras, Patras 26500, Greece; Regional Centre for Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University in Olomouc, 17.listopadu 1192/12, 771 46 Olomouc, Czech Republic.
authors: Aristides
authors: A
authors: Bakandritsos
authors: Institute of Biology, Medicinal Chemistry & Biotechnology, NHRF, Athens, Greece.
authors: Sotiris
authors: S
authors: Galtsidis
authors: Institute of Biology, Medicinal Chemistry & Biotechnology, NHRF, Athens, Greece.
authors: Vassilis
authors: V
authors: Zoumpourlis
authors: Department of Chemistry and Positron Emission Tomography Research Centre, University of Hull, Cottingham Road, Hull HU6 7RX, UK.
authors: Benjamin P
authors: BP
authors: Burke
authors: Department of Chemistry and Positron Emission Tomography Research Centre, University of Hull, Cottingham Road, Hull HU6 7RX, UK.
authors: Gonçalo S
authors: GS
authors: Clemente
authors: Department of Chemistry and Positron Emission Tomography Research Centre, University of Hull, Cottingham Road, Hull HU6 7RX, UK.
authors: Christopher
authors: C
authors: Cawthorne
authors: Department of Chemistry and Positron Emission Tomography Research Centre, University of Hull, Cottingham Road, Hull HU6 7RX, UK.
authors: Stephen J
authors: SJ
authors: Archibald
authors: Regional Centre for Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University in Olomouc, 17.listopadu 1192/12, 771 46 Olomouc, Czech Republic.
authors: Jiři
authors: J
authors: Tuček
authors: Regional Centre for Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University in Olomouc, 17.listopadu 1192/12, 771 46 Olomouc, Czech Republic.
authors: Radek
authors: R
authors: Zbořil
authors: Institute of Nuclear and Particle Physics, NCSR "Demokritos", Athens, Greece.
authors: Vasiliki
authors: V
authors: Kantarelou
authors: Institute of Nuclear and Particle Physics, NCSR "Demokritos", Athens, Greece.
authors: Andreas Germanos
authors: AG
authors: Karydas
authors: Department of Pharmacy, University of Patras, Patras 26500, Greece. Electronic address: avgoust@upatras.gr.
authors: Konstantinos
authors: K
authors: Avgoustakis
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005260:Female; D019073:HT29 Cells; D006801:Humans; D058185:Magnetite Nanoparticles; D008689:Methacrylates / Q000737:chemistry; D008819:Mice, Nude; D016513:Mice, SCID; D011092:Polyethylene Glycols / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000737:chemistry; D000072078:Positron Emission Tomography Computed Tomography; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D058185:Magnetite Nanoparticles; D008689:Methacrylates; D011109:Polymethacrylic Acids; C524499:polyethylene glycol methacrylate; C030613:polymethacrylic acid; D011092:Polyethylene Glycols; D002945:Cisplatin
keywords: Cancer therapy; Cisplatin; Drug delivery; Magnetic targeting; Nanocarriers; Theranostics