The objective of this study was to synthesize a nanocomposite, aptamer-gold nanoparticle-hybridized graphene oxide (Apt-AuNP-GO), to facilitate targeted treatment of tumor cells by near-infrared (NIR) light-activatable photothermal therapy. We also investigated whether Apt-AuNP-GO with NIR illumination modulates heat shock proteins (HSPs) expression leading to therapeutic response in human breast cancer cells. These findings can provide strategies for improving the photothermal therapy efficacy of cancer. The self-assembled Apt-AuNP-GO nanocomposite could selectively target MUC1-positive human breast cancer cells (MCF-7) due to the specific interaction between the MUC1-binding-aptamer and the MUC1 (type I transmembrane mucin glycoprotein) on cell membrane. In addition, Apt-AuNP-GO has a high light-to-heat conversion capability for photoabsorption of NIR light, and it is able to exert therapeutic effects on MCF-7 cells at an ultralow concentration without inducing adverse effects in healthy cells. The Apt-AuNP-GO nanocomposites combine the advantages of GOs, AuNPs, and Apts, possess specific targeting capability, excellent biocompatibility, and tumor cell destruction ability, suggesting great potential for application in the photothermal therapy of breast cancer. Under NIR illumination, Apt-AuNP-GO induced transient increase in HSP70 expression, which decreased thereafter. This phenomenon may cause irreversible damage to Apt-AuNP-GO-treated MCF-7 cell under NIR illumination. We also demonstrated that the combination therapy of heat and HSP70 inhibitor could synergistically generate marked tumoricidal effects against breast cancer. These results suggest that the degree and duration of HSP70 protein expression are correlated with therapeutic effects against breast cancer for Apt-AuNP-GO-assisted photothermal therapy. We believe that such a nanocomposite can be readily extended to the construction of HSP70 inhibitors-loaded Apt-AuNP-GO, which could deliver both heat and HSP70 inhibitors to tumorigenic regions for the chemo-photothermal therapy.

maozuguo@hit.edu.cn; d.r.westhead@leeds.ac.uk.

Recent investigations reveal that lactate is not a waste product but a major energy source for cells, especially in the mitochondria, which can support cellular survival under glucose shortage. Accordingly, the new understanding of lactate prompts to target it together with glucose to pursue a more efficient cancer starvation therapy. Herein, zeolitic imidazolate framework-8 (ZIF-8) nanoplatforms are used to co-deliver -cyano-4-hydroxycinnamate (CHC) and glucose oxidase (GOx) and fulfill the task of simultaneous depriving of lactate and glucose, resulting in a new nanomedicine CHC/GOx@ZIF-8. The synthesis conditions are carefully optimized in order to yield monodisperse and uniform nanomedicines, which will ensure reliable and steady therapeutic properties. Compared with the strategies aiming at a single carbon source, improved starvation therapy efficacy is observed. Besides, more than boosting the energy shortage, CHC/GOx@ZIF-8 can block the lactate-fueled respiration and relieve solid tumor hypoxia, which will enhance GOx catalysis activity, depleting extra glucose, and producing more cytotoxic H 2 O 2 . By the synergistically enhanced anti-tumor effect, both in vitro and in vivo cancer-killing efficacies of CHC/GOx@ZIF-8 show twice enhancements than the GOx mediated therapy. The results demonstrate that the dual-depriving of lactate and glucose is a more advanced strategy for strengthening cancer starvation therapy.

Functional nucleic acids, which can target cancer cells and realize stimuli-responsive drug delivery in tumor microenvironment, have been widely applied for anticancer chemotherapy. At present, high cost, unsatisfactory biostability, and complicated fabrication process are the main limits for the development of DNA-based drug-delivery nanocarriers. Here, a doxorubicin (Dox)-delivery nanoparticle for tumor-targeting chemotherapy is developed taking advantage of rolling circle amplification (RCA) technique, by which a high quantity of functional DNAs can be efficiently collected. Furthermore, Mg, a major electrolyte in human body showing superior biocompatibility, can sufficiently condense the very long sequence of an RCA product and better preserve its functions. The resultant DNA nanoparticle exhibits a high biostability, making it a safe and ideal nanomaterial for in vivo application. Through cellular and in vivo experiments, we thoroughly demonstrate that this kind of Mg-stabilized multifunctional DNA nanoparticles can successfully realize tumor-targeted Dox delivery. Overall, exploiting RCA technique and Mg condensation, this new strategy can fabricate nanoparticles with a nontoxic composition through a simple fabrication process and provides a good way to preserve and promote DNA functions, which will show a broad application potential in the biomedical field.

Oligonucleotide-stabilized silver nanoclusters (AgNCs) show promising applications in bioimaging and bio-/chemo-sensing. However, their unsatisfactory photostability limits their practical applications. In this work, fluorescent AgNCs were synthesized in situ in a DNA hydrogel, consisting of cross-linked enzymatically amplified polymeric DNAs with cytosine-rich sequences in the presence of Ag. The fluorescence property of the resultant AgNCs was optimized by a rational design of the DNA sequences to cover a broad spectrum with comparable green and red emissions. Under the protection of the DNA hydrogel, the AgNCs showed significantly improved photostability in an ambient oxygen environment, as well as low cytotoxicity even at a high concentration. Therefore, these properties show the rolling-circle-amplification-stabilized AgNCs to be a promising possible fluorescent probe for the detection of reactive oxygen/nitrogen species (ROS/RNS) in live cells because red-emitting species are susceptible to oxidation and consequently convert to green-emitting species. Finally, the as-prepared AgNCs were demonstrated to be a sensitive and specific probe for cellular imaging and the monitoring of ROS/RNS levels, which broadens the applications of AgNCs and provides a new tool for related biological investigations.

No abstract

Despite tremendous efforts toward developing novel near-infrared (NIR)-absorbing nanomaterials, improvement in therapeutic efficiency remains a formidable challenge in photothermal cancer therapy. This study aims to synthesize a specific peptide conjugated polydopamine-modified reduced graphene oxide (pDA/rGO) nanocomposite that promotes the bystander effect to facilitate cancer treatment using NIR-activated photothermal therapy. To prepare a nanoplatform capable of promoting the bystander effect in cancer cells, we immobilized antiarrhythmic peptide 10 (AAP10) on the surface of dopamine-modified rGO (AAP10-pDA/rGO). Our AAP10-pDA/rGO could promote the bystander effect by increasing the expression of connexin 43 protein in MCF-7 breast-cancer cells. Because of its tremendous ability to absorb NIR absorption, AAP10-pDA/rGO offers a high photothermal effect under NIR irradiation. This leads to a massive death of MCF-7 cells via the bystander effect. Using tumor-bearing mice as the model, it is found that NIR radiation effectively ablates breast tumor in the presence of AAP10-pDA/rGO and inhibits tumor growth by ≈100%. Therefore, this research integrates the bystander and photothermal effects into a single nanoplatform in order to facilitate an efficient photothermal therapy. Furthermore, our AAP10-pDA/rGO, which exhibits both hyperthermia and the bystander effect, can prevent breast-cancer recurrence and, therefore, has great potential for future clinical and research applications.

The interaction between graphene oxide (GO) and DNA is very sensitive to the environment. For example, under acidic conditions, the affinity of GO for DNA is enhanced, weakening the capability of GO to distinguish DNAs with different conformations. This effect has impeded the development of sensitive pH biosensors based on GO-DNA nanosystems. In this work, we systematically studied the affinity between GO and i-motif forming oligonucleotides (IFOs) at different pH values and developed a herring sperm DNA (HSD) treatment method. Using this method, HSD occupies the surface of GO, compromising the attractive force of GO that is significantly enhanced under acidic conditions. As a result, the ability of GO to distinguish between "open" and "closed" IFOs is successfully generalized to a wider pH range. Finally, a pH-sensitive GO-IFO nanosystem was fabricated that showed excellent sensing ability both in vitro and for intracellular pH detection. Because the interaction between GO and DNA is the basis for constructing GO-DNA biosensors, the strategy developed in this work shows great potential to be applied in a variety of other GO-DNA sensing systems.