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Nanotechnology-based approaches hold substantial potential to avoid chemoresistance and minimize side effects. In this work, we have used biocompatible iron oxide magnetic nanoparticles (MNPs) called MF66 and functionalized with the antineoplastic drug doxorubicin (DOX) against MDA-MB-231 cells. Electrostatically functionalized MNPs showed effective uptake and DOX linked to MNPs was more efficiently retained inside the cells than free DOX, leading to cell inactivation by mitotic catastrophe, senescence and apoptosis. Both effects, uptake and cytotoxicity, were demonstrated by different assays and videomicroscopy techniques. Likewise, covalently functionalized MNPs using three different linkers&mdash, disulfide (DOX-S-S-Pyr, called MF66-S-S-DOX), imine (DOX-I-Mal, called MF66-I-DOX) or both (DOX-I-S-S-Pyr, called MF66-S-S-I-DOX)&mdash, were also analysed. The highest cell death was detected using a linker sensitive to both pH and reducing environment (DOX-I-S-S-Pyr). The greatest success of this study was to detect also their activity against breast cancer stem-like cells (CSC) from MDA-MB-231 and primary breast cancer cells derived from a patient with a similar genetic profile (triple-negative breast cancer). In summary, these nanoformulations are promising tools as therapeutic agent vehicles, due to their ability to produce efficient internalization, drug delivery, and cancer cell inactivation, even in cancer stem-like cells (CSCs) from patients.

© The Author(s)., Controlled delivery of multiple chemotherapeutics can improve the effectiveness of treatments and reduce side effects and relapses. Here in, we used albumin-stabilized gold nanoclusters modified with doxorubicin and SN38 (AuNCs-DS) as combined therapy for cancer. The chemotherapeutics are conjugated to the nanostructures using linkers that release them when exposed to different internal stimuli (Glutathione and pH). This system has shown potent antitumor activity against breast and pancreatic cancer cells. Our studies indicate that the antineoplastic activity observed may be related to the reinforced DNA damage generated by the combination of the drugs. Moreover, this system presented antineoplastic activity against mammospheres, a culturing model for cancer stem cells, leading to an efficient reduction of the number of oncospheres and their size. In summary, the nanostructures reported here are promising carriers for combination therapy against cancer and particularly to cancer stem cells., his research was funded by the Spanish Ministry of Economy and Competitiveness (CTQ2016-78454-C2-2-R, SAF2014-56763-R, and SAF2017-87305-R), Comunidad de Madrid (S2013/MIT-2850), Asociación Española Contra el Cáncer, and IMDEA Nanociencia IMDEA Nanociencia acknowledges support from the ‘Severo Ochoa’ Programme for Centres of Excellence in R&D (MINECO, Grant SEV-2016-0686).

Introduction Photodynamic therapy (PDT) is a clinical-approved option in several diseases characterised by uncontrolled cell proliferation, as cancer. PDT is recognised as a minimally invasive and toxic treatment. It is based on the administration of light activatable molecule known as photosensitizer (PS). After irradiation, a photochemical reaction between the PS and molecular oxygen leads to the generation of reactive oxygen species (ROS), which results in tumour regression. Nowadays different strategies are being introduced in order to enhance PDT effectiveness, such as combination of PDT with chemotherapy or improvement of PS features. Material and methods A new combined PDT-chemotherapy comprising two drugs widespread in clinical research -the hydrophobic Zinc(II)-phthalocyanine (ZnPc) as PS and the common chemotherapeutic agent doxorubicin (DOX)- was tested in tumour cell lines and primary cells from patients affected by metastatic breast cancer. ZnPc was incorporated into nanoliposomes to increase its solubility and uptake into tumoral cells. This dual-therapy was also assayed in vivo (intravenously administrated) in a breast cancer xenograft model following tumour growth by luciferase activity. Results and discussions MTT cytotoxicity assay showed that combination of both therapies remarkably increases the effectiveness of the treatment by inducing a synergistic cell death effect when compared to DOX or ZnPc monotherapy. In addition, annexin-V detection by flow cytometry, analysis of active caspase-3 and cytochrome c by immunofluorescence and time-lapse videomicroscopy corroborated a fine-tunable effect depending on light dose, leading to apoptotic or necrotic mechanism of cell death. Subcellular location visualised by fluorescence microscopy confirmed internalisation of both drugs. Using DCFH-DA probe, we demonstrate that a significant higher ROS generation into cells was the main cause of the synergistic effect of this combined treatment. Further, mammosphere formation efficiency assay (MFE) showed a reduced breast cancer stem cell activity in established cell line and primary cells obtained from patients, even using DOX at much lower concentration than clinical level. Finally, studies in human breast cancer xenografts indicated a high efficiency also in vivo. Conclusion All these results provide novel and valuable information that contribute to consider chemophototherapy as a promising tool in current antitumoral treatments, potentially overcoming resistance to cancer chemotherapy and targeting cancer stem cells.

Introduction Tumor cells can effectively be killed by heat, e.g. by using magnetic hyperthermia. The main challenge in the field, however, is the generation of therapeutic temperatures selectively in the whole tumor region. We aimed to improve magnetic hyperthermia of breast cancer by using innovative nanoparticles which display a high heating potential and are functionalized with a cell internalization and a chemotherapeutic agent to increase cell death. Methods The superparamagnetic iron oxide nanoparticles (MF66) were electrostatically functionalized with either Nucant multivalent pseudopeptide (N6L; MF66-N6L), doxorubicin (DOX; MF66-DOX) or both (MF66-N6LDOX). Their cytotoxic potential was assessed in a breast adenocarcinoma cell line MDA-MB-231. Therapeutic efficacy was analyzed on subcutaneous MDA-MB-231 tumor bearing female athymic nude mice. Results All nanoparticle variants showed an excellent heating potential around 500 W/g Fe in the alternating magnetic field (AMF, conditions: H = 15.4 kA/m, f = 435 kHz). We could show a gradual inter- and intracellular release of the ligands, and nanoparticle uptake in cells was increased by the N6L functionalization. MF66-DOX and MF66-N6LDOX in combination with hyperthermia were more cytotoxic to breast cancer cells than the respective free ligands. We observed a substantial tumor growth inhibition (to 40% of the initial tumor volume, complete tumor regression in many cases) after intratumoral injection of the nanoparticles in vivo. The proliferative activity of the remaining tumor tissue was distinctly reduced. Conclusion The therapeutic effects of breast cancer magnetic hyperthermia could be strongly enhanced by the combination of MF66 functionalized with N6L and DOX and magnetic hyperthermia. Our approach combines two ways of tumor cell killing (magnetic hyperthermia and chemotherapy) and represents a straightforward strategy for translation into the clinical practice when injecting nanoparticles intratumorally. Electronic supplementary material The online version of this article (doi:10.1186/s13058-015-0576-1) contains supplementary material, which is available to authorized users.