Doxorubicin-Loaded Gold Nanoarchitectures as a Therapeutic Strategy against Diffuse Intrinsic Pontine Glioma.

Diffuse Intrinsic Pontine Gliomas (DIPGs) are highly aggressive paediatric brain tumours. Currently, irradiation is the only standard treatment, but is palliative in nature and most patients die within 12 months of diagnosis. Novel therapeutic approaches are urgently needed for the treatment of this devastating disease. We have developed non-persistent gold nano-architectures (NAs) functionalised with human serum albumin (HSA) for the delivery of doxorubicin. Doxorubicin has been previously reported to be cytotoxic in DIPG cells. In this study, we have preclinically evaluated the cytotoxic efficacy of doxorubicin delivered through gold nanoarchitectures (NAs-HSA-Dox). We found that DIPG neurospheres were equally sensitive to doxorubicin and doxorubicin-loaded NAs. Colony formation assays demonstrated greater potency of NAs-HSA-Dox on colony formation compared to doxorubicin. Western blot analysis indicated increased apoptotic markers cleaved Parp, cleaved caspase 3 and phosphorylated H2AX in NAs-HSA-Dox treated DIPG neurospheres. Live cell content and confocal imaging demonstrated significantly higher uptake of NAs-HSA-Dox into DIPG neurospheres compared to doxorubicin alone. Despite the potency of the NAs in vitro, treatment of an orthotopic model of DIPG showed no antitumour effect. This disparate outcome may be due to the integrity of the blood-brain barrier and highlights the need to develop therapies to enhance penetration of drugs into DIPG.

Functionalized Carbon Nanostructures Versus Drug Resistance: Promising Scenarios in Cancer Treatment.

Carbon nanostructures (CN) are emerging valuable materials for the assembly of highly engineered multifunctional nanovehicles for cancer therapy, in particular for counteracting the insurgence of multi-drug resistance (MDR). In this regard, carbon nanotubes (CNT), graphene oxide (GO), and fullerenes (F) have been proposed as promising materials due to their superior physical, chemical, and biological features. The possibility to easily modify their surface, conferring tailored properties, allows different CN derivatives to be synthesized. Although many studies have explored this topic, a comprehensive review evaluating the beneficial use of functionalized CNT vs G or F is still missing. Within this paper, the most relevant examples of CN-based nanosystems proposed for MDR reversal are reviewed, taking into consideration the functionalization routes, as well as the biological mechanisms involved and the possible toxicity concerns. The main aim is to understand which functional CN represents the most promising strategy to be further investigated for overcoming MDR in cancer.

Dextran-Curcumin Nanoparticles as a Methotrexate Delivery Vehicle: A Step Forward in Breast Cancer Combination Therapy.

With the aim to effectively deliver methotrexate (MTX) to breast cancer cells, we designed a nanocarrier system (DC) derived from the self-assembly of a dextran-curcumin conjugate prepared via enzyme chemistry with immobilized laccase acting as a solid biocatalyst. Nanoparticles consisted of homogeneously dispersed nanospheres with a mean diameter of 290 nm, as characterized by combined transmission electron microscopy and dynamic light scattering investigations. DC was able to control the MTX release overtime (t1/2 value of 310 min), with cell internalization studies proving its presence inside MCF-7 cytoplasm. Finally, improved MTX efficacy was obtained in viability assays, and attributed to the synergy of curcumin moieties and loaded MTX as underlined by a combination index (CI) < 1.

When polymers meet carbon nanostructures: expanding horizons in cancer therapy.

The development of hybrid materials, which combine inorganic with organic materials, is receiving increasing attention by researchers. As a consequence of carbon nanostructures high chemical versatility, they exhibit enormous potential for new highly engineered multifunctional nanotherapeutic agents for cancer therapy. Whereas many groups are working on drug delivery systems for chemotherapy, the use of carbon nanohybrids for radiotherapy is rarely applied. Thus, nanotechnology offers a wide range of solutions to overcome the current obstacles of conventional chemo- and/or radiotherapies. Within this review, the structure and properties of carbon nanostructures (carbon nanotubes, nanographene oxide) functionalized preferentially with different types of polymers (synthetic, natural) are discussed. In short, synthesis approaches, toxicity investigations and anticancer efficacy of different carbon nanohybrids are described.

Combining Carbon Nanotubes and Chitosan for the Vectorization of Methotrexate to Lung Cancer Cells.

A hybrid system composed of multi-walled carbon nanotubes coated with chitosan was proposed as a pH-responsive carrier for the vectorization of methotrexate to lung cancer. The effective coating of the carbon nanostructure by chitosan, quantified (20% by weight) by thermogravimetric analysis, was assessed by combined scanning and transmission electron microscopy, and X-ray photoelectron spectroscopy (N1s signal), respectively. Furthermore, Raman spectroscopy was used to characterize the interaction between polysaccharide and carbon counterparts. Methotrexate was physically loaded onto the nanohybrid and the release profiles showed a pH-responsive behavior with higher and faster release in acidic (pH 5.0) vs. neutral (pH 7.4) environments. Empty nanoparticles were found to be highly biocompatible in either healthy (MRC-5) or cancerous (H1299) cells, with the nanocarrier being effective in reducing the drug toxicity on MRC-5 while enhancing the anticancer activity on H1299.

Magnetic Graphene Oxide Nanocarrier for Targeted Delivery of Cisplatin: A Perspective for Glioblastoma Treatment.

Selective vectorization of Cisplatin (CisPt) to Glioblastoma U87 cells was exploited by the fabrication of a hybrid nanocarrier composed of magnetic γ-Fe2O3 nanoparticles and nanographene oxide (NGO). The magnetic component, obtained by annealing magnetite Fe3O4 and characterized by XRD measurements, was combined with NGO sheets prepared via a modified Hummer's method. The morphological and thermogravimetric analysis proved the effective binding of γ-Fe2O3 nanoparticles onto NGO layers. The magnetization measured under magnetic fields up to 7 Tesla at room temperature revealed superparamagnetic-like behavior with a maximum value of MS = 15 emu/g and coercivity HC ≈ 0 Oe within experimental error. The nanohybrid was found to possess high affinity towards CisPt, and a rather slow fractional release profile of 80% after 250 h. Negligible toxicity was observed for empty nanoparticles, while the retainment of CisPt anticancer activity upon loading into the carrier was observed, together with the possibility to spatially control the drug delivery at a target site.

Graphene Oxide Functional Nanohybrids with Magnetic Nanoparticles for Improved Vectorization of Doxorubicin to Neuroblastoma Cells.

With the aim to obtain a site-specific doxorubicin (DOX) delivery in neuroblastoma SH-SY5Y cells, we designed an hybrid nanocarrier combining graphene oxide (GO) and magnetic iron oxide nanoparticles (MNPs), acting as core elements, and a curcumin⁻human serum albumin conjugate as functional coating. The nanohybrid, synthesized by redox reaction between the MNPs@GO system and albumin bioconjugate, consisted of MNPs@GO nanosheets homogeneously coated by the bioconjugate as verified by SEM investigations. Drug release experiments showed a pH-responsive behavior with higher release amounts in acidic (45% at pH 5.0) vs. neutral (28% at pH 7.4) environments. Cell internalization studies proved the presence of nanohybrid inside SH-SY5Y cytoplasm. The improved efficacy obtained in viability assays is given by the synergy of functional coating and MNPs constituting the nanohybrids: while curcumin moieties were able to keep low DOX cytotoxicity levels (at concentrations of 0.44⁻0.88 µM), the presence of MNPs allowed remote actuation on the nanohybrid by a magnetic field, increasing the dose delivered at the target site.

Electro-responsive graphene oxide hydrogels for skin bandages: The outcome of gelatin and trypsin immobilization.

A free radical polymerization method was adopted for the fabrication of hybrid hydrogel films based on acrylamide and polyethylene glycol dimethacrylate as plasticizing and crosslinking agents, respectively, to be employed as smart skin bandages. Electro-sensitivity, biocompatibility and proteolytic properties were conferred to the final polymer networks by introducing graphene oxide (0.5% w/w), gelatin or trypsin (10% w/w) in the polymerization feed. The physical chemical and mechanical characterization of hybrid materials was performed by means of determination of protein content, Raman spectroscopy, thermogravimetric analysis and measurement of tensile strength. The evaluation of both water affinity and curcumin release profiles (analyzed by suitable mathematical modelling) upon application of an external electric stimulation in the 0-48 voltage range, confirmed the possibility to modulate the release kinetics. Proper proteolytic tests showed that the trypsin enzymatic activity was retained by 80% upon immobilization. Moreover, for all samples, we observed a viability higher than 94% in normal human fibroblast cells (MRC-5), while a reduction of methicillin-resistant Staphylococcus aureus CFU mL-1 (90%) was obtained with curcumin loaded samples.