Nanoemulsion carriers of porous γ-alumina modified by polyvinylpyrrolidone and carboxymethyl cellulose for pH-sensitive delivery of 5-fluorouracil.

5-Fluorouracil (5-FU) is a cytotoxic drug with a low half-life. These features can cause some problems such as burst drug release and numerous side effects. In the present study, a pH-sensitive nanocomposite of polyvinylpyrrolidone (PVP)/carboxymethyl cellulose (CMC)/γ-alumina developed by using water in oil in water (W/O/W) double emulsion method. The fabricated emulsion has been employed as the 5-FU carrier to investigate its effects on drug half-life, side effects, drug loading efficiency (DLE), and drug entrapment efficiency (DEE). Analyzing the FTIR and XRD indicated the successful loading of 5-FU into the nanocarrier and affirmed the synthesized nanocomposite's chemical bonding and crystalline features. Furthermore, by using DLS and Zeta potential assessment, size and undersize distribution, as well as the stability of the drug-loaded nanocomposite were determined, which demonstrated the monodisperse and stable nanoparticles. Moreover, the nanocomposites with spherical shapes and homogeneous surfaces were shown in FE-SEM, which indicated good compatibility for the constituents of the nanocomposites. Moreover, by employing BET analysis the porosity has been investigated. Drug release pattern was studied, which indicated a controlled drug release behavior with above 96 h drug retention. Besides, the loading and entrapment efficiencies were obtained 44 % and 86 %, respectively. Furthermore, the curve fitting technique has been employed and the predominant release mechanism has been determined to evaluate the best-fitted kinetic models. MTT assay and flow cytometry assessment has been carried out to investigate the cytotoxic effects of the fabricated drug-loaded nanocomposite on MCF-7 and normal cells. The results showed enhanced cytotoxicity and late apoptosis for the PVP/CMC/γ-alumina/5-FU. Based on the MTT assay outcomes on normal cell lines (L929), which indicated above 90 % cell viability, the biocompatibility and biosafety of the synthesized nanocarrier have been confirmed. Moreover, due to the porosity of the PVP/CMC/γ-alumina, this nanocarrier can exploit from high specific surface area and be more sensitive to environmental conditions such as pH. These outcomes propose that the novel pH-sensitive PVP/CMC/γ-alumina nanocomposite can be a potential candidate for drug delivery applications, especially for cancer therapy.

ROS-generating, pH-responsive and highly tunable reduced graphene oxide-embedded microbeads showing intrinsic anticancer properties and multi-drug co-delivery capacity for combination cancer therapy.

The development of effective carriers enabling combination cancer therapy is of practical importance due to its potential to enhance the effectiveness of cancer treatment. However, most of the reported carriers are monofunctional in nature. The carriers that can be applied to concomitantly mediate multiple treatment modalities are highly deficient. This study fills this gap by reporting the design and fabrication of ROS-generating carbohydrate-based pH-responsive beads with intrinsic anticancer therapy and multidrug co-delivery capacity for combination cancer therapy. Sodium alginate (SA) microspheres and reduced graphene oxide (rGO)-embedded chitosan (CS) beads are developed via emulsion-templated ionic gelation for a combination therapy involving co-delivery of curcumin (CUR) and 5-fluororacil (5-FU). Drug-encapsulated microbeads are characterized by FTIR, DSC, TGA, XRD, and SEM. 5-FU and CUR-encapsulated microbeads are subjected to in vitro drug release studies at pH 6.8 and 1.2 at 37 °C. Various release kinetic parameters are evaluated. The results show that the Korsmeyer-Peppas model and non-Fickian release kinetics are best suited. The microspheres and microbeads are found to effectively act against MCF7 cells and show intrinsic anticancer capacity. These results indicate the promising performance of our beads in mediating combination drug therapy to improve the effectiveness of cancer treatment.

Synthesis and characterization of a novel pH-responsive drug-releasing nanocomposite hydrogel for skin cancer therapy and wound healing.

Local skin cancer recurrence occurs in ∼12% of the patients post-surgery due to persistent growth of residual cancer cells. Wound infection is another significant complication following surgery. We report a novel in situ-forming nanocomposite hydrogel (NCH) containing PLGA-carboxymethyl chitosan nanoparticles (186 nm) for localized pH-responsive skin cancer therapy and wound healing. This injectable hydrogel, comprising of a citric acid-derived polymer backbone, gelled within 5 minutes, and demonstrated excellent swelling (283% of dry weight) and compressive strengths (∼5.34 MPa). Nanoparticle incorporation did not significantly affect hydrogel properties. The NCH effluents were cytocompatible with human dermal fibroblasts at 500 µg ml-1 concentration and demonstrated pH-dependent drug release and promising therapeutic efficacy against A431 and G361 skin cancer cells in vitro. Significant zones of inhibition were observed in S. aureus and E. coli cultures on NCH treatment, confirming its antibacterial properties. Our studies show that the pH-responsive NCH can be potentially used for adjuvant skin cancer treatment and wound healing.

Fabrication of self-healing pectin/chitosan hybrid hydrogel via Diels-Alder reactions for drug delivery with high swelling property, pH-responsiveness, and cytocompatibility.

Self-healing hydrogels with pH-responsiveness could protect loaded drugs from being destroyed till it arrives to the target. The pectin-based hydrogel is a candidate due to the health benefit, anti-inflammation, antineoplastic activity, nontoxicity, and biospecific degradation, et al. However, the abundant existence of water-soluble branched heteropolysaccharide chains influenced its performance resulting in limitation of the potential. In the present study, we prepared a series of self-healing pectin/chitosan hydrogels via the Diels-Alder reaction. Moreover, pectin/chitosan composite hydrogel was prepared as a contrast. By comparison, it can be seen that the Diels-Alder reaction greatly improved the cross-linking density of hydrogels. The self-healing experiments showed excellent self-healing performance. In different swelling mediums, significant transformation in the swelling ratio was shown, indicating well-swelling property, pH- and thermo-responsiveness. The drug loading and release studies presented high loading efficiency and sustained release performance. The cytotoxicity assay that showed a high cell proliferation ratio manifested great cytocompatibility.

Insight into the Sorption of 5-Fluorouracil and Methotrexate onto Soil-pH, Ionic Strength, and Co-Contaminant Influence.

Nowadays anticancer drugs (ADs), like other pharmaceuticals, are recognized as new emerging pollutants, meaning that they are not commonly monitored in the environment; however, they have great potential to enter the environment and cause adverse effects there. The current scientific literature highlights the problem of their presence in the aquatic environment by publishing more and more results on their analytics and ecotoxicological evaluation. In order to properly assess the risk associated with the presence of ADs in the environment, it is also necessary to investigate the processes that are important in understanding the environmental fate of these compounds. However, the state of knowledge on mobility of ADs in the environment is still very limited. Therefore, the main aim of our study was to investigate the sorption potential of two anticancer drugs, 5-fluorouracil (5-FU) and methotrexate (MTX), onto different soils. Special attention was paid to the determination of the influence of pH and ionic strength as well as presence of co-contaminants (cadmium (Cd2+) and another pharmaceutical-metoprolol (MET)) on the sorption of 5-FU and MTX onto soil. The obtained distribution coefficient values (Kd) ranged from 2.52 to 6.36 L·kg-1 and from 6.79 to 12.94 L·kg-1 for 5-FU and MTX, respectively. Investigated compounds may be classified as slightly or low mobile in the soil matrix (depending on soil). 5-FU may be recognized as more mobile in comparison to MET. It was proved that presence of other soil contaminants may strongly influence their mobility in soil structures. The investigated co-contaminant (MET) caused around 25-fold increased sorption of 5-FU, whereas diminished sorption of MTX. Moreover, the influence of environmental conditions such as pH and ionic strength on their sorption has been clearly demonstrated.

Tragacanth gum-based multifunctional hydrogels and green synthesis of their silver nanocomposites for drug delivery and inactivation of multidrug resistant bacteria.

This study investigated natural polymer-based stimuli-responsive hydrogels (TGIAVE) and their silver nanocomposites (TGIAVE-Ag). The hydrogels were composed of tragacanth gum, N-isopropyl acrylamide, and 2-(vinlyoxy) ethanol and were prepared via simple redox polymerization using N,N'-methylene-bis-acrylamide as a crosslinker and potassium persulfate as an initiator. The TGIAVE-Ag were synthesized via a green method involving an aqueous extract of Terminalia bellirica seeds. Structural, thermal, crystallinity, morphology, and size characteristics of the TGIAVE and TGIAVE-Ag were investigated by FTIR, UV-Vis, XRD, DSC, SEM, EDS, DLS, and TEM. To understand the physicochemical interaction and diffusion characteristics of TGIAVEs, network parameters such as zero-order, first-order, Hixson-Crowell, Higuchi, and Korsmeyer-Peppas values were calculated by assessing swelling data. TGIAVE hydrogels at pH 1.2 and 7.4 and temperatures of 25 and 37 °C may be used for time-dependent controlled release of 5-fluorouracil, an anticancer drug, TGIAVE-Ag may be applied for the inactivation of multidrug resistant (MDR) bacteria.

Mass spectrometry in the study of molecular complexes between 5-fluorouracil and catechins.

5-Fluorouracil (5FU) is a widely employed antineoplastic agent that acts as antimetabolite. However, 5FU activity is strongly reduced against a subset of cancer cells called cancer stem cells (CSCs), which are believed to be responsible for chemoresistance and tumour recurrence. It was found that epigallocatechin-3-gallate (EGCG), the most abundant catechin present in green tea extract, suppresses CSCs grown in various cancers. This chemosensitizing effect of EGCG was investigated in 5FU-resistant (5FUR) CRC cells, showing that EGCG enhances 5FU-induced cytotoxicity. However, the real mechanism of an improved 5FU chemosensitivity in the presence of EGCG was not evaluated. Considering the capability of catechins to form bimolecular noncovalent complexes, in the present study, the interaction of catechins and 5FU was studied by different mass spectrometric approaches. The ESI(+) and ESI(-) spectra of [5FU-catechin] mixtures were studied, showing the formation of protonated and deprotonated bimolecular complexes, whose nature was confirmed by MS/MS experiments (product and precursor ion scans). To exclude the possible origin of these species as ESI artefacts, a further series of experiments were performed by high-resolution liquid chromatography-mass spectrometry. By this approach, bimolecular complexes have been detected at retention times different from those of free 5FU and catechins, proving their presence in the original solution. Analogous studies were performed on 5FU-green tea extract mixtures, showing that 5FU leads to complexes not only with EGCG but also with other catechins. These molecular species, differently to free 5FU drug alone, would in principle possess a new biological activity and could be an explanation of the described activity cited above.

Synergistic Antitumor Effect of 5-Fluorouracil Combined with Constituents from Pleurospermum lindleyanum in Hepatocellular Carcinoma SMMC-7721 Cells.

BACKGROUND: A Chinese folk medicine plant Pleurospermum lindleyanum possesses pharmacological activities of heat-clearing, detoxifying and preventing from hepatopathy, coronary heart disease, hypertension, and high altitude sickness. We isolated and characterized its constituents to investigate its synergistic effects against human hepatoma SMMC-7721 cells. OBJECTIVE: The aim of this study was to explore the synergistic anti-cancer activities of isolates from P. lindleyanum with 5-FU on hepatoma SMMC-7721 cells in vitro and their primary mechanisms. METHODS: Sequential chromatographic techniques were conducted for the isolation studies. The isolate's structures were established by spectroscopic analysis as well as X-ray crystallographic diffraction. Growth inhibition was detected by MTT assay. The isobologram method was used to assess the effect of drug combinations. Flow cytometry and western blot were used to examine apoptosis and protein expression. RESULTS: A new coumarin (16), along with sixteen known compounds, were isolated from the whole plant of P. lindleyanum and their structures were elucidated by spectroscopic methods. Four coumarins (2, 3, 5, and 16), two flavonoids (8 and 9) and three phytosterols and triterpenes (12-14) were found to synergistically enhance the inhibitory effect of 5-FU against SMMC-7721 cells. Among them, compounds 3 and 16 exhibited the best synergistic effects with IC50 of 5-FU reduced by 16-fold and 22-fold possessing the minimum Combination Index (CI) 0.34 and 0.27. The mechanism of action of combinations might be through synergistic arresting for the cell cycle at G1 phases and the induction of apoptosis. Moreover, western blotting and molecular docking revealed that compounds 3 or 5 might promote 5-FU-induced apoptosis by regulating the expression of Caspase 9 and PARP. CONCLUSION: Constituents from P. lindleyanum may improve the treatment effectiveness of 5-FU against hepatocellular carcinoma cells.

Thermosensitive hydrogels for local delivery of 5-fluorouracil as neoadjuvant or adjuvant therapy in colorectal cancer.

Spurred by high risk for local tumor recurrence and non-specific toxicity of systemic chemotherapy, clinicians have recently granted a growing interest to locoregional therapeutic strategies. In this perspective, we recently developed a multipurpose thermosensitive hydrogel based on reversible thermogelling properties of poloxamers P407 and P188, a bioadhesive excipient and antineoplastic effect of 5-fluorouracil (5-FU) for the local treatment of colorectal cancer (CRC) in ectopic CT26 murine models. Antitumor efficacy was assessed in mice following intratumoral (IT) injection mimicking neoadjuvant therapy and subcutaneous (SC) application after tumor excision simulating adjuvant therapy. Rheological characterization disclosed that P407/P188/alginate 20/2/1% w/v thermosensitive hydrogel is an injectable free-flowing solution at ambient temperature that undergoes a SOL-GEL transition at 26.0 °C ± 0.6 °C and thereby forms in situ a non-flowing gel at physiological temperature. The generated gel presented an elastic behavior and responded according to a shear-thinning fluid upon shear rate. Although delayed by the addition of alginate 1% w/v, 5-FU is released mainly by diffusion mechanism. The local delivery of 5-FU from P407/P188/alginate/5-FU 20/2/1/0.5% w/v hydrogel in the preclinical tumor models led to a significant tumor growth delay. These results demonstrated that poloxamer-based thermosensitive hydrogels provide a simple and efficient means for local chemotherapeutics delivery.

Design of polysaccharidic nano-in-micro soft agglomerates as primary oral drug delivery vehicle for colon-specific targeting.

Microencapsulation of polysaccharidic nanoparticles is met with nanoscale and biological performance changes. This study designs soft agglomerates as nanoparticle vehicle without nanoparticles undergoing physical processes that alter their geometry. The nanoparticles were made of high molecular weight chitosan/pectin with covalent 5-fluorouracil/folate. Nanoparticle aggregation vehicle was prepared from low molecular weight chitosan. The nanoparticles and aggregation vehicle were blended in specific weight ratios to produce soft agglomerates. Nanoparticles alone are unable to agglomerate. Adding aggregation vehicle (< 2 µm) promoted soft agglomeration with nanoparticles deposited onto its surfaces with minimal binary coalescence. The large and rough-surfaced aggregation vehicle promoted nanoparticles deposition and agglomeration. A rounder vehicle allowed assembly of nanoparticles-on-aggregation vehicle into agglomerates through interspersing smaller between larger populations. Soft agglomeration reduced early drug release, and was responsive to intracapsular sodium alginate coat to further sustain drug release. The soft agglomerates can serve as a primary oral colon-specific vehicle.

Recent Advances in Polymer Nanomaterials for Drug Delivery of Adjuvants in Colorectal Cancer Treatment: A Scientific-Technological Analysis and Review.

Colorectal cancer (CRC) is the type with the second highest morbidity. Recently, a great number of bioactive compounds and encapsulation techniques have been developed. Thus, this paper aims to review the drug delivery strategies for chemotherapy adjuvant treatments for CRC, including an initial scientific-technological analysis of the papers and patents related to cancer, CRC, and adjuvant treatments. For 2018, a total of 167,366 cancer-related papers and 306,240 patents were found. Adjuvant treatments represented 39.3% of the total CRC patents, indicating the importance of adjuvants in the prognosis of patients. Chemotherapy adjuvants can be divided into two groups, natural and synthetic (5-fluorouracil and derivatives). Both groups can be encapsulated using polymers. Polymer-based drug delivery systems can be classified according to polymer nature. From those, anionic polymers have garnered the most attention, because they are pH responsive. The use of polymers tailors the desorption profile, improving drug bioavailability and enhancing the local treatment of CRC via oral administration. Finally, it can be concluded that antioxidants are emerging compounds that can complement today's chemotherapy treatments. In the long term, encapsulated antioxidants will replace synthetic drugs and will play an important role in curing CRC.

A novel and simple oral colon-specific drug delivery system based on the pectin/modified nano-carbon sphere nanocomposite gel films.

The 3-aminopropyltriethoxysilane modified nano-carbon sphere (MNCS) was added into pectin-Ca2+ film to improve the controlled release properties of the pectin-based oral colon-specific drug delivery system (OCDDS). The FT-IR measurements indicated the successful modification of nano-carbon sphere via silylation reaction and the electrostatic interaction between the pectin molecules and MNCS in the composite film. The FE-SEM showed the pore structure when the MNCS was mingled with the pectin. The 5-fluorouracil (5-FU) was employed as the drug model and the controlled release properties of the corresponding OCDDSs were determined. The values of the encapsulation efficiency ranged from 30.1% to 52.6%. All composite film based OCDDSs presented higher encapsulation efficiency than single pectin-Ca2+ based OCDDS. The drug release studies emerged that almost all the OCDDSs from composite films presented better release properties than single pectin-Ca2+ based OCDDS. The sample C revealed best release performance with the cumulative release rate of 32.17%, 22.77% and 63.89% in the simulated gastric fluid, small intestinal fluid and colon fluid, respectively. In addition, the kinetics studies were performed to analyze the release data. The cytotoxicity assay indicated good biocompatibility of the composite carriers.

Theoretical analyses and experimental validation of the effects caused by the fluorinated substituent modification of DNA.

Halogen-modified nucleic acid molecules, such as trifluorothymidine (FTD) and 5-fluorouracil, are widely used in medical science and clinical site. These compounds have a very similar nucleobase structure. It is reported that both of these compounds could be incorporated into DNA. The incorporation of FTD produces highly anti-tumor effect. However, it is not known whether to occur a significant effect by the incorporation of 5-fluorouracil. Nobody knows why such a difference will occur. To understand the reason why there is large differences between trifluorothymidine and 5-fluorouracil, we have performed the molecular dynamics simulations and molecular orbital calculations. Although the active interaction energy between Halogen-modified nucleic acids or and complementary adenine was increased, in only FTD incorporated DNA, more strongly dispersion force interactions with an adjacent base were detected in many thermodynamic DNA conformations. As the results, the conformational changes occur even if it is in internal body temperature. Then the break of hydrogen bonding between FTD and complementary adenine base occur more frequently. The double helix structural destabilization of DNA with FTD is resulted from autoagglutination caused by the bonding via halogen orbitals such as halogen bonding and the general van der Waals interactions such as CH-[Formula: see text], lone pair (LP)-[Formula: see text], and [Formula: see text]-[Formula: see text] interactions. Therefore, it is strongly speculated that such structural changes caused by trifluoromethyl group is important for the anti-tumor effect of FTD alone.

Sequential delivery of synergistic drugs by silica nanocarriers for enhanced tumour treatment.

Herein hybrid silica nanoparticles have been engineered to direct the sequential delivery of multiple chemotherapeutic drugs in response to external stimuli such as variations in pH. The nanocarriers consist of conventional MCM-41-type nanoparticles, which have been functionalised with an organic ligand (or stalk) grafted onto the external surface. The stalk is designed to "recognise" a complementary molecule, which serves as a "cap" to block the pores of the nanoparticles. First, camptothecin is introduced into the pores by diffusion prior to capping the pore apertures via molecular recognition. The cap, which is a derivative of 5-fluorouracil, serves as a second cytotoxic drug for synergistic chemotherapy. In vitro tests revealed that negligible release of the drugs occurred at pH 7.4, thus avoiding toxic side effects in the blood stream. In contrast, the stalk/cap complex is destabilised within the endolysosomal compartment (pH 5.5) of cancer cells, where release of the drugs was demonstrated. Furthermore, this environmentally responsive system exhibited a synergistic effect of the two drugs, where the pH-triggered release of the cytotoxic cap followed by diffusion-controlled release of the drug cargo within the pores led to essentially complete elimination of breast cancer cells.

A New Strategy for Identifying Mechanisms of Drug-drug Interaction Using Transcriptome Analysis: Compound Kushen Injection as a Proof of Principle.

Drug-drug interactions (DDIs), especially with herbal medicines, are complex, making it difficult to identify potential molecular mechanisms and targets. We introduce a workflow to carry out DDI research using transcriptome analysis and interactions of a complex herbal mixture, Compound Kushen Injection (CKI), with cancer chemotherapy drugs, as a proof of principle. Using CKI combined with doxorubicin or 5-Fu on cancer cells as a model, we found that CKI enhanced the cytotoxic effects of doxorubicin on A431 cells while protecting MDA-MB-231 cells treated with 5-Fu. We generated and analysed transcriptome data from cells treated with single treatments or combined treatments and our analysis showed that opposite directions of regulation for pathways related to DNA synthesis and metabolism which appeared to be the main reason for different effects of CKI when used in combination with chemotherapy drugs. We also found that pathways related to organic biosynthetic and metabolic processes might be potential targets for CKI when interacting with doxorubicin and 5-Fu. Through co-expression analysis correlated with phenotype results, we selected the MYD88 gene as a candidate major regulator for validation as a proof of concept for our approach. Inhibition of MYD88 reduced antagonistic cytotoxic effects between CKI and 5-Fu, indicating that MYD88 is an important gene in the DDI mechanism between CKI and chemotherapy drugs. These findings demonstrate that our pipeline is effective for the application of transcriptome analysis to the study of DDIs in order to identify candidate mechanisms and potential targets.

Electrospun oral formulations for combined photo-chemotherapy of colon cancer.

In this work, we report new formulations for the combined photo-chemotherapy of colon cancer. Fibers were fabricated via coaxial-electrospinning with the intent of targeting delivery of the anti-cancer drug carmofur (CAR) and the photosensitizer rose bengal (RB) selectively to the colon site. The fibers comprised a hydroxypropyl methylcellulose (HPMC) core loaded with the active ingredients, and a pH-sensitive Eudragit L100-55 shell. The fibers were found to be homogeneous and cylindrical and have visible core-shell structures. X-ray diffraction and differential scanning calorimetry demonstrated that both CAR and RB were present in the fibers in the amorphous physical form. In vitro drug release studies showed that the fibers have the potential to selectively deliver drugs to the colon, with only 10-15 % release noted in the acidic conditions of the stomach but sustained release at pH 7.4. Cytotoxicity studies were undertaken on human dermal fibroblast (HDF) and colon cancer (Caco-2) cells, and the influence of light on cell death was also explored. The fibers loaded with CAR alone showed obvious toxicity to both cell lines, with and without the application of light. The RB-loaded fibers led to high viability (ca. 80% for both cell types) in the absence of light, but much greater toxicity was noted (30-50%) with light. The same trends were observed with the formulation containing both CAR and RB, but with lower viabilities. The RB and RB/CAR loaded systems show clear selectivity for cancerous over non-cancerous cells. Finally, mucoadhesion studies revealed there were strong adhesive forces between the rat colonic mucosa and the fibers after they had passed through an acidic environment. Such electrospun fibers thus could have potential in the development of oral therapies for colon cancer.

An easy access to topical gels of an anti-cancer prodrug (5-fluorouracil acetic acid) for self-drug-delivery applications.

An easy access to topical gels (both hydro- and organogels) derived from an anti-cancer prodrug namely 5-fluorouracil acetic acid (5-FuA) achieved by exploiting a simple salt formation strategy is reported for the first time. Nearly 85% of the salts synthesized were gelators. Single crystal structures of some of the gelator salts revealed an intriguing hydrogen bonding network including double stranded 1D chains stabilized through uracil-uracil complementary interactions and the crystal structures of the gelator salts corroborated well with the hypothesis based on which the gelators were designed. Studies indicated that both the hydrogel and the methyl salicylate gel of the gelator salt FuA-15 were suitable for self-drug-delivery application.

Highly Uniform Synthesis of Selenium Nanoparticles with EGFR Targeting and Tumor Microenvironment-Responsive Ability for Simultaneous Diagnosis and Therapy of Nasopharyngeal Carcinoma.

Rational design of multifunctional and smart drug-delivered nanoplatforms is a promising strategy to achieve simultaneous diagnosis, real-time monitoring, and therapy of cancers. Herein, highly uniform and stable selenium nanoparticles with epidermal growth factor receptor (EGFR) targeting and tumor microenvironment-responsive ability (Se-5Fu-Gd-P(Cet/YI-12)) were designed and synthesized by using EGFR as the targeting molecule, gadolinium chelate as the magnetic resonance imaging contrast agent, 5-fluorouracil (5Fu) and cetuximab as drug payloads, polyamidoamine (PAMAM) and 3,3'-dithiobis (sulfosuccinimidyl propionate) as the response agents of intratumoral glutathione, and pH for the treatment and diagnosis of nasopharyngeal carcinoma (NPC). This Se nanoplatform showed excellent magnetic resonance imaging capability and has the potential for its clinical application as a diagnostic agent for tumor tissue specimens. Additionally, in vitro cellular experiments showed that by means of introducing clinical targeted drugs and peptides not only validly increased the intracellular uptake of the Se nanoplatform in NPC cells but also enhanced its penetration ability toward CNE tumor spheroids, resulting in simultaneous inhibition of CNE cell growth, invasion, and migration. In addition, the sequentially triggered bioresponsive property of the nanoplatform in a tumor microenvironment effectively improved the targeting delivery and anticancer efficiency of payloads. Overall, this study not only provides a strategy for facile synthesis of highly uniform and stable nanomedicines and tailing of the bioresponsive property but also sheds light on its application in targeting theranosis of NPC.

Engineered Targeted Hyaluronic Acid-Glutathione-Stabilized Gold Nanoclusters/Graphene Oxide-5-Fluorouracil as a Smart Theranostic Platform for Stimulus-Controlled Fluorescence Imaging-Assisted Synergetic Chemo/Phototherapy.

A theranostic platform with integrated diagnostic and therapeutic functions as well as specific targeted and controlled combination therapy to enhance treatment efficacy is of great importance for a wide range of biomedical applications. Here, we first attempted to develop biocompatible hyaluronic acid (HA)-glutathione (GSH) conjugate stabilized gold nanoclusters (GNCs) combined with graphene oxide (GO), accompanied by loading 5-fluorouracil (5FU), as a novel theranostic platform (HG-GNCs/GO-5FU, HG refers to HA-GSH). Multifunctional HG-GNCs possessed excellent fluorescence, photosensitivity and specific targeting ability to the cancer cells while their fluorescence and singlet oxygen generation could be strongly inhibited by GO and then effectively restored by lysosomal hyaluronidase in tumor cells. The sustained and complete release of 5FU from HG-GNCs/GO could also be stimulated successively by enzymatic degradation of HA and light-induced heat effect of GO under laser irradiation so that turn-on cell imaging-assisted synergistic therapeutic strategies associated with triple enzyme/light-controlled chemo/photothermal/photodynamic therapy could be achieved at the same time, reducing greatly the side effects of materials to normal cells. Our study presents a novel strategy to combine targeting and bioimaging with triple therapies to enhance the antitumor effect.

α-methylation and α-fluorination electronic effects on the regioselectivity of carbonyl groups of uracil by H and triel bonds in the interaction of U, T and 5FU with HCl and TrH3 (Tr = B, Al).

Quantum chemical calculations at the ωB97XD/6-311++G(d,p) level of theory have been executed to investigate the effect of substituents via hydrogen-bonded and triel-bonded complexes between uracil (U), thymine (T) and 5-fluorouracil (5FU) with HCl for the former complexes, and with BH3 and AlH3 for the latter complexes. These calculations are supported by single-point energy calculations at MP2/6-311++G(d,p) and CCSD/6-31 + G(d,p) levels of theory, Natural Bond Orbital (NBO) and Molecular Electrostatic Potentials (MEPs) analyses, and global/local reactivity descriptors. The results reveal that triel-bonded complexes are strongly bounded than hydrogen-bonded ones, and Al-containing dimers stronger than B-containing ones. In addition, as the central triel atom grows in size, B-containing dimers (B-O triel bond) are accompanied by weak B-H⋯O unconventional H-bonds. According to local reactivity descriptors, the B-O triel bond is hard-hard interaction that indicates that the association is primarily charge controlled, while the Al-O triel bond is soft-soft interaction that is primarily orbital controlled. In both Hydrogen as well as triel-bonded complexes, the α-methylation slightly overestimates the binding strength of U, while the α-fluorination exerts the opposite role by underestimating the binding strength of U. In overall, the effect of substituents on the bond strength and thus on the regioselectivity is very small, suggesting a competition between the two carbonyl groups in terms of structures and binding energies.