Colloids and Surfaces B: Biointerfaces 148 (2016) 95–103 Contents lists available at ScienceDirect Colloids and Surfaces B: Biointerfaces journal homepage: www.elsevier.com/locate/colsurfb Sustained release profile of quatro stimuli nanocontainers as a multi sensitive vehicle exploiting cancer characteristics Christos Tapeinos a,b,1 , Eleni K. Efthimiadou a,∗,1 , Nikos Boukos a , George Kordas a,∗ a Sol-Gel laboratory, Institute of Nanoscience and Nanotechnology, NCSR “Demokritos”, 153 10 Aghia Paraskevi Attikis, Greece b Materials Science Department, School of Natural Sciences, University of Patras, 26 500 Patras, Greece a r t i c l e i n f o Article history: Received 3 March 2016 Received in revised form 12 August 2016 Accepted 16 August 2016 Available online 20 August 2016 Keywords: Stimuli responsive Hollow nanocontainers pH-sensitive Thermo-sensitive Redox-sensitive Magnetic nanoparticles Quatro-stimuli Radiolabelling 99 m Tc in vivo imaging Biodistribution a b s t r a c t A versatile drug delivery carrier that responds to external stimuli was synthesized via the emulsion poly- merization process. This simple two-step process was carried out by using Poly (Methyl Methacrylate) as a soft template and a series of monomers, with desired properties, as coating monomers. It is note- worthy that during shell fabrication (2nd step) an inner cavity is created inside the nanocontainers that can be used as a host for small drug molecules. The thermo-, pH- and redox sensitive monomers used in the coating procedure were Dimethyl Amino Ethyl Methacrylate (DMAEMA), Acrylic Acid (AA) and N,N ′ -(disulfanediylbis(ethane-2,1-diyl))bis(2-methylacrylamide) (Disulfide or DS), respectively. It has to be noted that DMAEMA is also pH- sensitive and acts synergistically with AA. The surface of the multi- stimuli nanocontainers was functionalized with magnetite nanoparticles in order to induce an alternating magnetic field (AMF) sensitivity. By using AMF in various strenghts and frequencies, the temperature of the final multi-stimuli nanocontainers (Q-NCs) can be increased in a controlled manner resulting in the Hyperthermia phenomenon. Loading and release studies were carried out using the anthracycline drug, Doxorubicin, aiming at the confirmation of the release mechanism. © 2016 Elsevier B.V. All rights reserved. 1. Introduction Everyday new smart Drug Delivery Systems (DDS) are fabri- cated seeking to improve cancer therapy as well as the patients’ life. The development of these systems is substantial in order to achieve more effective treatment and fewer side effects [1–12]. Conventional treatments, like chemotherapy and radiotherapy, have the disadvantage of killing normal cells and destroying neigh- boring tissues, causing toxicity. The role of DDS is to avoid these side effects by treating only cancer cells. Some of the characteristics that can be used for fabricating an intelligent DDS are: 1) temper- ature difference between cancer cells and their surrounding area, 2) vulnerability of cancer cells at 42–43 ◦ C in contrast to 45–46 ◦ C for normal cells 3) difference between intra- and extra-cellular pH with values for cancer cells around 6.0–4.5 and 6.8, respec- tively and 6.5 and 7.4, respectively for normal cells, and finally 4) ∗ Corresponding authors at: Patriarxou Grigoriou E & Neapoleos, Aghia Paraskevi, Athens, 15341, Greece. E-mail addresses: e.efthimiadou@inn.demokritos.gr, g.kordas@inn.demokritos.gr (E.K. Efthimiadou). 1 These authors contributed equally to this work. enzyme copiousness that creates reductive and oxidizing (redox) conditions. By combining all these factors [25], a smart nanocarrier can be fabricated aiming at specific targeting and drug release in a controlled manner. The idea of the aforementioned nanocarrier has been studied for the past few years and lots of ideas came to forefront. The thermo-, pH-, and redox sensitivities were used as a single property, or by combining two of the properties, for the fabrication of polymer nanocarriers [13–25]. These nanocarriers can be in the form of nanospheres, micelles, nanorods, nanopar- ticles, nanocontainers, etc. and are synthesized by monomers that have specific properties taking advantage of some unique characteristics of cancer cells. One of the many properties that are currently investigated and used for the fabrication of nanocarriers is thermo-sensitivity [26–29]. Hydroxy Propyl Methacrylamide (HPMA) and Dimethyl Amino Ethyl Methacrylate (DMAEMA) are monomers that exhibit thermo-sensitivity. Similar to thermo- sensitive monomers are, pH-sensitive monomers [30–32] like Acrylic Acid (AA) and redox-sensitive monomers [33–35] like N,N ′ -(disulfanediylbis(ethane-2,1-diyl))bis(2-methylacrylamide). An ideal combination of monomers can result to a co-polymer that integrates thermo- and pH- sensitivity, or thermo- and redox- sensitivity, or any other combination of the above properties. A http://dx.doi.org/10.1016/j.colsurfb.2016.08.019 0927-7765/© 2016 Elsevier B.V. All rights reserved.