Graphene Oxide‐Cyclic R10 Peptide Nuclear Translocation Nanoplatforms for the Surmounting of Multiple‐Drug Resistance

Multidrug resistance resulting from a variety of defensive pathways in cancer has become a global concern with a considerable impact on the mortality associated with the failure of traditional chemotherapy. Therefore, further research and new therapies are required to overcome this challenge. In this work, a cyclic R10 peptide (cR10) is conjugated to polyglycerol-covered nanographene oxide to engineer a nanoplatform for the surmounting of multidrug resistance. The nuclear translocation of the nanoplatform, facilitated by cR10 peptide, and subsequently, a laser-triggered release of the loaded doxorubicin result in efficient anticancer activity confirmed by both in vitro and in vivo experiments. The synthesized nanoplatform with a combination of different features, including active nucleus-targeting, high-loading capacity, controlled release of cargo, and photothermal property, provides a new strategy for circumventing multidrug resistant cancers.National Natural Science Foundation of China http://dx.doi.org/10.13039/501100001809Natural Science Foundation of Jiangsu Province http://dx.doi.org/10.13039/501100004608Fundamental Research Funds for the Central Universities http://dx.doi.org/10.13039/501100012226Iran Science Elites Federation and China Scholarship CouncilPeer Reviewe

Graphene Oxide‐Cyclic R10 Peptide Nuclear Translocation Nanoplatforms for the Surmounting of Multiple‐Drug Resistance

Multidrug resistance resulting from a variety of defensive pathways in cancer has become a global concern with a considerable impact on the mortality associated with the failure of traditional chemotherapy. Therefore, further research and new therapies are required to overcome this challenge. In this work, a cyclic R10 peptide (cR10) is conjugated to polyglycerol‐covered nanographene oxide to engineer a nanoplatform for the surmounting of multidrug resistance. The nuclear translocation of the nanoplatform, facilitated by cR10 peptide, and subsequently, a laser‐triggered release of the loaded doxorubicin result in efficient anticancer activity confirmed by both in vitro and in vivo experiments. The synthesized nanoplatform with a combination of different features, including active nucleus‐targeting, high‐loading capacity, controlled release of cargo, and photothermal property, provides a new strategy for circumventing multidrug resistant cancers

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Funktionaliserte Graphenschichten als multivalente 2D Platformen und ihre antitumorale Anwendung

In this thesis, functionalized graphene sheets were synthesized and their cellular uptake features, drug release properties, and anti-MDR ability were investigated and some significant conclusions were obtained. Hyperbranched polyglycerol (hPG) was successfully conjugated to the graphene backbone that was functionalized by nitrene through a [2+1] cycloaddition reaction. The resulting hPG-coating graphene sheets showed high polymer coverage, controllable size, good water dispersibility, excellent biocompatibility and can be easily post-functionalized. Amination and sulfation was applied to obtain positively charged and negatively charged graphene sheets, respectively. Furthermore, functionalized graphene sheets could be broken down into smaller sizes by horn sonication with corresponding time frames. In my first project, the cellular uptake characteristics of these graphene derivatives with similar polymer content, but different size and surface charges were investigated. It was found that large functionalized graphene sheets (1 μm) were preferable taken up via a phagocytic pathway, regardless of their surface charges. However, surface charge is a dominant factor for their small analogs (200 nm size). Small graphene sheets with positive charges mainly entered into the cells through clathrin-mediated endocytosis (CME), while this pathway did not play a significant role for the small ones with negative charge. Because of the surface charge, the negatively charged and positively charged graphene derivatives displayed size-independent and sizedependent uptake efficacy. Moreover, our results also revealed the cellular internalization of hPG-conjugated graphene sheets is negligible for all the sizes, which is attributed to the protein-resistant feature of hPG and low nonspecific interactions with biointerfaces. In the next project, we prepared graphene sheets with similar polymer content, size (around 150 nm), but different functionalities and surface charges according to our established protocol of the first project. The hydrophobic anticancer drug, DOX, was loaded onto these graphene derivatives and a pH-sensitive dye was connected onto their surface and employed as an antenna to receive strong signals from the acidic cell compartments. It was found that these functionalized graphene sheets with different functionalities underwent the same cellular uptake and acidification process, while their intracellular release properties were fundamentally different. The protonation of DOX in acidic conditions decreased their hydrophobic and π-π stacking interaction with graphene backbone and facilitated its release from both sheets with different surface charges. However, protonated DOX was positively charged and exhibited attractive and repulsive electrostatic interactions with negatively charged and positively charged hPG-conjugated graphene derivatives, respectively. While the release of DOX was accelerated by repulsive electrostatic force in the case of positive sheets, many of them were trapped on the surface of negative sheets via attractive electrostatic interactions. Therefore, the overall release rate and therapeutic effect was much higher in the first case. This study revealed that intracellular location and release features of the therapeutic agents are a function of their hydrophobic and electrostatic interactions with the graphene-based nanocarriers. In the third project, a graphene-based delivery nanoplatforms was introduced to overcome the newly-emerging MDR in tumor cells. Triphenylphosphonium and 2,3- dimethylmaleic anhydride were conjugated onto the hPG-covered nanographene sheets to achieve mitochondria targeting and charge-convention properties. The average size of these functionalized nanographene sheets were around 75 nm with a narrow sizedistribution, which was favorable for their accumulation in tumor site owning to the widely confirmed EPR effect. After internalization, these nanosheets targeted the mitochondria and finally disrupted them under laser irradiation, leading to the plunge of adenosine triphosphate (ATP) synthesis. Without enough “biological fuel,” the P-gP lost its function and the MDR was successfully reversed. Both of the in vitro and in vivo antitumor results confirmed these functionalized graphene sheets could effectively surmount the troublesome MDR tumors and remarkably promote the synergic antitumor theranostic efficacy. Moreover, serious side effects caused by chemotherapy agents could also be avoided with these graphene-based nanocarriers. During the doctoral studies, my work focused on the biological behavior of graphene derivatives and their potential application for antitumor therapy. Many promising results were obtained and several critical problems were addressed, including the cellular uptake properties, intracellular release features, and anti-MDR theranostic. These outcomes revealed that the biological behaviors of functionalized graphene sheets could be adjusted by their physiochemical characteristics and MDR reversal therapy could be achieved though the rational design of graphene-based nanoplatforms, which is of great significance for the future development of graphene-based nanomaterials for bioapplications

Bio-Inspired Supramolecular Hybrid Dendrimers Self-Assembled from Low-Generation Peptide Dendrons for Highly Efficient Gene Delivery and Biological Tracking

Currently, supramolecular self-assembly of dendrons and dendrimers emerges as a powerful and challenging strategy for developing sophisticated nanostructures with excellent performances. Here we report a supramolecular hybrid strategy to fabricate a bio-inspired dendritic system as a versatile delivery nanoplatform. With a rational design, dual-functionalized low-generation peptide dendrons (PDs) self-assemble onto inorganic nanoparticles <i>via</i> coordination interactions to generate multifunctional supramolecular hybrid dendrimers (SHDs). These SHDs exhibit well-defined nanostructure, arginine-rich peptide corona, and fluorescent signaling properties. As expected, our bio-inspired supramolecular hybrid strategy largely enhances the gene transfection efficiency of SHDs approximately 50 000-fold as compared to single PDs at the same R/P ratio. Meanwhile the bio-inspired SHDs also (i) provide low cytotoxicity and serum resistance in gene delivery; (ii) provide inherent fluorescence for tracking intracellular pathways including cellular uptake, endosomal escape, and gene release; and (iii) work as an alternative reference for monitoring desired protein expression. More importantly, <i>in vivo</i> animal experiments demonstrate that SHDs offer considerable gene transfection efficiency (in muscular tissue and in HepG2 tumor xenografts) and real-time bioimaging capabilities. These SHDs will likely stimulate studies on bio-inspired supramolecular hybrid dendritic systems for biomedical applications both <i>in vitro</i> and <i>in vivo</i>

Mechanistic Understanding of the Interactions between Nano-Objects with Different Surface Properties and α-Synuclein

Aggregation of the natively unfolded protein α-synuclein (α-syn) is key to the development of Parkinson's disease (PD). Some nanoparticles (NPs) can inhibit this process and in turn be used for treatment of PD. Using simulation strategies, we show here that α-syn self-assembly is electrostatically driven. Dimerization by head-to-head monomer contact is triggered by dipole-dipole interactions and subsequently stabilized by van der Waals interactions and hydrogen bonds. Therefore, we hypothesized that charged nano-objects could interfere with this process and thus prevent α-syn fibrillation. In our simulations, positively and negatively charged graphene sheets or superparamagnetic iron oxide NPs first interacted with α-syn's N/C terminally charged residues and then with hydrophobic residues in the non-amyloid-β component (61-95) region. In the experimental setup, we demonstrated that the charged nano-objects have the capacity not only to strongly inhibit α-syn fibrillation (both nucleation and elongation) but also to disaggregate the mature fibrils. Through the α-syn fibrillation process, the charged nano-objects induced the formation of off-pathway oligomers

Multifunctional Cationic Hyperbranched Polyaminoglycosides that Target Multiple Mediators for Severe Abdominal Trauma Management

Abstract Trauma and its associated complications, including dysregulated inflammatory responses, severe infection, and disseminated intravascular coagulation (DIC), continue to pose lethal threats worldwide. Following injury, cell‐free nucleic acids (cfNAs), categorized as damage‐associated molecular patterns (DAMPs), are released from dying or dead cells, triggering local and systemic inflammatory responses and coagulation abnormalities that worsen disease progression. Harnessing cfNA scavenging strategies with biomaterials has emerged as a promising approach for treating posttrauma systemic inflammation. In this study, the effectiveness of cationic hyperbranched polyaminoglycosides derived from tobramycin (HPT) and disulfide‐included HPT (ss‐HPT) in scavenging cfNAs to mitigate posttrauma inflammation and hypercoagulation is investigated. Both cationic polymers demonstrate the ability to suppress DAMP‐induced toll‐like receptor (TLR) activation, inflammatory cytokine secretion, and hypercoagulation by efficiently scavenging cfNAs. Additionally, HPT and ss‐HPT exhibit potent antibacterial efficacy attributed to the presence of tobramycin in their chemical composition. Furthermore, HPT and ss‐HPT exhibit favorable modulatory effects on inflammation and therapeutic outcomes in a cecal ligation puncture (CLP) mouse abdominal trauma model. Notably, in vivo studies reveal that ss‐HPT displayed high accumulation and retention in injured organs of traumatized mice while maintaining a higher biodegradation rate in healthy mice, contrasting with findings for HPT. Thus, functionalized ss‐HPT, a bioreducible polyaminoglycoside, holds promise as an effective option to enhance therapeutic outcomes for trauma patients by alleviating posttrauma inflammation and coagulation complications