Biodegradable nanocarrier of gemcitabine and tocopherol succinate synergistically ameliorates anti-proliferative response in MIA PaCa-2 cells.

Gemcitabine (GEM) is an important chemotherapeutic agent used alone or in combination with other anticancer agents for the treatment of various solid tumors. In this study, the potential of a dietary supplement, α-tocopherol succinate (TOS) was investigated in combination with GEM by utilizing human serum albumin-based nanoparticles (HSA NPs). The developed nanoparticles were characterized using DLS, SEM and FTIR and evaluated in a panel of cell lines to inspect cytotoxic efficacy. The ratio metric selected combination of the NPs was further investigated in human pancreatic cancer cell line (MIA PaCa-2 cells) to assess the cellular death mechanism via a myriad of biochemical and bio-analytical assays including nuclear morphometric analysis by DAPI staining, ROS generation, MMP loss, intracellular calcium release, in vitro clonogenic assay, cell migration assay, cell cycle analysis, immunocytochemical staining followed by western blotting, Annexin V-FITC and cellular uptake studies. The desolvation-crosslinking method was used to prepare the NPs. The average size of TOS-HSA NPs and GEM-HSA NPs was found to be 189.47 ± 5 nm and 143.42 ± 7.4 nm, respectively. In combination, the developed nanoparticles exhibited synergism by enhancing cytotoxicity in a fixed molar ratio. The selected combination also significantly triggered ROS generation and mitochondrial destabilization, alleviated cell migration potential and clonogenic cell survival in MIA PaCa-2 cells. Further, cell cycle analysis, Annexin-V FITC assay and caspase-3 activation, up regulation of Bax and down regulation of Bcl-2 protein confirmed the occurrence of apoptotic event coupled with the G0/G1 phase arrest. Nanocarriers based this combination also offered approximately 14-folds dose reduction of GEM. Overall, the combined administration of TOS-HSA NPs and GEM-HSA NPs showed synergistic cytotoxicity accompanied with dose reduction of the gemcitabine. These encouraging findings could have implication in designing micronutrient based-combination therapy with gemcitabine and demands further investigation.

Liposomal nanostructures for Gemcitabine and Paclitaxel delivery in pancreatic cancer.

Pancreatic cancer (PC) is an incurable disease with a high death rate in the world nowadays. Gemcitabine (GEM) and Paclitaxel (PTX) are considered as references of chemotherapeutic treatments and are commonly used in clinical applications. Factors related to the tumor microenvironment such as insufficient tumor penetration, toxicity, and drug resistance can limit the effectiveness of these therapeutic anticancer drugs. The use of different liposomal nanostructures is a way that can optimize the drug's effectiveness and reduce toxicity. Given the development of PC therapy, this review focuses on advances in Nano-formulation, characterization, and delivery systems of loaded GEM and PTX liposomes using chemotherapy, nucleic acid delivery, and stroma remodeling therapy. As a result, the review covers the literature dealing with the applications of liposomes in PC therapy.

Direct Observation of Excitation Wavelength-Dependent Ultrafast Intersystem Crossing in Cytosine Nucleoside Solution.

A triplet excited state can lead to different DNA photolesions, especially in cytosine and its nucleoside/nucleotide as they are hotspots for DNA mutations. However, the triplet state generation mechanism is in controversy, and experimental evidence of ultrafast intersystem crossing (ISC) has not been registered in these molecules. In this work, ultrafast ISC is directly observed in 2'-deoxycytidine (dCyd) solution by using femtosecond transient absorption spectroscopy. Surprisingly, we demonstrate that ISC in dCyd is sensitive to the excitation wavelength, and a spin-vibronic ISC mechanism is proposed. This finding is the last piece of the dCyd excited-state deactivation mechanism puzzle and sets the base for further investigation of triplet state-involved photophysics and photochemistry in dCyd-containing DNA.

8-Furylimidazolo-2'-deoxycytidine: crystal structure, packing, atropisomerism and fluorescence.

8-Furylimidazolo-2'-deoxycytidine (furImidC), C14H14N4O5, is a fluorescent analogue of 2'-deoxycytidine, also displaying the same recognition face. As a constituent of DNA, furImidC forms extraordinarily strong silver-mediated self-pairs. Crystal structure determination revealed that furImidC adopts two types of disordered residues: the sugar unit and the furyl moiety. The disorder of the sugar residue amounts to an 87:13 split. The disorder of the furyl ring results from axial chirality at the C8-C2'' bond connecting the nucleobase to the heterocycle. The two atropisomers are present in unequal proportions [occupancies of 0.69 (2) and 0.31 (2)], and the nucleobase and the furyl moiety are coplanar. Considering the atomic sites with predominant occupancy, an anti conformation with χ = - 147.2 (7)° was found at the glycosylic bond and the 2'-deoxyribosyl moiety shows a C2'-endo (S, 2T1) conformation, with P = 160.0°. A 1H NMR-based conformational analysis of the furanose puckering revealed that the S conformation predominates also in solution. In the solid state, two neighbouring furImidC molecules are arranged in a head-to-tail fashion, but with a notable tilt of the molecules with respect to each other. Consequently, one N-H...N hydrogen bond is found for neighbouring molecules within one layer, while a second N-H...N hydrogen bond is formed to a molecule of an adjacent layer. In addition, hydrogen bonding is observed between the nucleobase and the sugar residue. A Hirshfeld surface analysis was performed to visualize the intermolecular interactions observed in the X-ray study. In addition, the fluorescence spectra of furImidC were measured in solvents of different polarity and viscosity. furImidC responds to microenvironmental changes (polarity and viscosity), which is explained by a hindered rotation of the furyl residue in solvents of high viscosity.

Two Possible Strategies for Drug Modification of Gemcitabine and Future Contributions to Personalized Medicine.

Drug repurposing is an emerging strategy, which uses already approved drugs for new medical indications. One such drug is gemcitabine, an anticancer drug that only works at high doses since a portion is deactivated in the serum, which causes toxicity. In this review, two methods were discussed that could improve the anticancer effect of gemcitabine. The first is a chemical modification by conjugation with cell-penetrating peptides, namely penetratin, pVEC, and different kinds of CPP6, which mostly all showed an increased anticancer effect. The other method is combining gemcitabine with repurposed drugs, namely itraconazole, which also showed great cancer cell inhibition growth. Besides these two strategies, physiologically based pharmacokinetic models (PBPK models) are also the key for predicting drug distribution based on physiological data, which is very important for personalized medicine, so that the correct drug and dosage regimen can be administered according to each patient's physiology. Taking all of this into consideration, it is believed that gemcitabine can be repurposed to have better anticancer effects.

Self-Delivery Janus-Prodrug for Precise Immuno-Chemotherapy of Colitis-Associated Colorectal Cancer.

Aromatized thioketal (ATK) linked the immunoregulatory molecule (budesonide, Bud) and the cytotoxic molecule (gemcitabine, Gem) to construct a ROS-activated Janus-prodrug, termed as BAG. Benefiting from the hydrogen bonding, π-π stacking, and other intermolecular interactions, BAG could self-assemble into nanoaggregates (BAG NA) with a well-defined spherical shape and uniform size distribution. Compared to the carrier-based drug delivery system, BAG NA have ultrahigh drug loading content and ROS concentration-dependent drug release. Colitis-associated colorectal cancer (CAC) is a typical disease in which chronic inflammation transforms into tumors. BAG NA can be internalized by colon cancer C26 cells and then triggered by excessive intracellular ROS to release nearly 100% of the drugs. Based on this, BAG NA showed a stronger pro-apoptotic effect than free Bud combined with free Gem. What is gratifying is that orally administered BAG NA can precisely accumulate in the diseased colon tissues of CAC mice induced by AOM/DSS and simultaneously release Bud and Gem. Bud can regulate the tumor immune microenvironment to restore and enhance the cytotoxicity of Gem. Therefore, BAG NA maximizes the synergistic therapeutic effect through co-delivery of Bud and Gem. This work provided a cutting-edge method for constructing self-delivery Janus-prodrug based on ATK and confirmed its potential application in inflammation-related carcinogenesis.

Integrin-Mediated Targeted Cancer Therapy Using c(RGDyK)-Based Conjugates of Gemcitabine.

c(RGDyK)-based conjugates of gemcitabine (GEM) with the carbonate and carbamate linkages in the 6-OH group of GEM were synthesized for the targeted delivery of GEM to integrin αvß3, overexpressing cancer cells to increase the stability as well as the tumor delivery of GEM and minimize common side effects associated with GEM treatment. Competitive cell uptake experiments demonstrated that conjugate TC113 could be internalized by A549 cells through integrin αvß3. Among the synthesized conjugates, TC113 bearing the carbamate linker was stable in human plasma and was further assessed in an in vivo pharmacokinetic study. TC113 appeared to be relatively stable, releasing GEM slowly into blood, while it showed potent antiproliferative properties against WM266.4 and A549 cells. The encouraging data presented in this study with respect to TC113 provide a promising keystone for further investigation of this GEM conjugate with potential future clinical applications.

Fabrication of dopamine conjugated with protein @metal organic framework for targeted drug delivery: A biocompatible pH-Responsive nanocarrier for gemcitabine release on MCF­7 human breast cancer cells.

Metal-organic structures (MOF), modern extremely proliferous materials consisting of metal ions and organic coordinating molecules, has become a promising biomedical material because of its unusual features, including great surface area, wide pore volume, flexible functionality and superior performance for drug loading. In the current investigation, Gemcitabine Hydrochloride (Gem), an anticancer drug, and Amygdalin (Amy) were loaded into a nanocomposite structure formed from bovine serum albumin (BSA) as a center and zeolytic imidazolate framework-8 (ZIF-8) as a pH sensitive protective coating. The formed BSA-Gem@ZIF-8 and BSA-Gem-Amy@ZIF-8 were successively coated by polydopamine, chelated by Au3+ and conjugated via gallic acid (GA), acquired ZIF-8 structure as a multifunctional nanocarrier at the end. It was confirmed by different characterization methods that the nanocarrier was successfully produced. Due to the nature of ZIF-8, pH dependent releases of BSA-Gem@ZIF-8/Dopa/GA and BSA-Gem-Amy@ZIF-8/Dopa/GA were observed in in vitro studies. Cytotoxicity and apoptotic effects of these nanocarriers were evaluated using WST-1 and acridine orange staining in MCF-7 human breast cancer and HUVEC control cell lines. In-vitro cytotoxicity studies showed that both BSA-Gem@ZIF-8/Dopa/GA and BSA-Gem-Amy@ZIF-8/Dopa/GA were more effective than gemcitabine alone in MCF-7 cells with less toxicity in HUVEC cells. Additionally, both pH-responsive nanocarriers induced more apoptotic cell death in MCF-7 cells. We therefore believe that the built multifunctional nanocarrier based on ZIF-8 could be an alternative therapeutic strategy the use of gemcitabine for cancer therapy.

The Cisplatin, 5-fluorouracil, Irinotecan, and Gemcitabine Treatment in Resistant 2D and 3D Model Triple Negative Breast Cancer Cell Line: ABCG2 Expression Data.

BACKGROUND: Chemotherapeutics have been commonly used in cancer treatment. OBJECTIVE: In this study, the effects of Cisplatin, 5-fluorouracil, Irinotecan, and Gemcitabine have been evaluated on two-dimensional (2D) (sensitive and resistance) cell lines and three dimensional (3D) spheroid structure of MDA-MB- 231. The 2D cell culture lacks a natural tissue-like structural so, using 3D cell culture has an important role in the development of effective drug testing models. Furthermore, we analyzed the ATP Binding Cassette Subfamily G Member 2 (ABCG2) gene and protein expression profile in this study. We aimed to establish a 3D breast cancer model that can mimic the in vivo 3D breast cancer microenvironment. METHODS: The 3D spheroid structures were multiplied (globally) using the three-dimensional hanging drop method. The cultures of the parental cell line MDA-MB-231 served as the controls. After adding the drugs in different amounts, we observed a clear and well-differentiated spheroid formation for 24 h. The viability and proliferation capacity of 2D (sensitive and resistant) cell lines and 3D spheroid cell treatment were assessed by the XTT assay. RESULTS: Cisplatin, Irinotecan, 5-Fu, and Gemcitabine-resistant MDA-MB-231 cells were observed to begin to disintegrate in a three-dimensional clustered structure at 24 hours. Additionally, RT-PCR and protein assay showed overexpression of ABCG2 when compared to the parental cell line. Moreover, MDA-MB-231 cells grown in 3D showed decreased sensitivity to chemotherapeutics treatment. CONCLUSION: More resistance to chemotherapeutics and altered gene expression profile were shown in 3D cell cultures when compared with the 2D cells. These results might play an important role to evaluate the efficacy of anticancer drugs to explore the mechanisms of MDR in the 3D spheroid forms.

Unified Description of Ultrafast Excited State Decay Processes in Epigenetic Deoxycytidine Derivatives.

Epigenetic DNA modifications play a fundamental role in modulating gene expression and regulating cellular and developmental biological processes, thereby forming a second layer of information in DNA. The epigenetic 2'-deoxycytidine modification 5-methyl-2'-deoxycytidine, together with its enzymatic oxidation products (5-hydroxymethyl-2'-deoxycytidine, 5-formyl-2'-deoxycytidine, and 5-carboxyl-2'-deoxycytidine), are closely related to deactivation and reactivation of DNA transcription. Here, we combine sub-30-fs transient absorption spectroscopy with high-level correlated multiconfigurational CASPT2/MM computational methods, explicitly including the solvent, to obtain a unified picture of the photophysics of deoxycytidine-derived epigenetic DNA nucleosides. We assign all the observed time constants and identify the excited state relaxation pathways, including the competition of intersystem crossing and internal conversion for 5-formyl-2'-deoxycytidine and ballistic decay to the ground state for 5-carboxy-2'-deoxycytidine. Our work contributes to shed light on the role of epigenetic derivatives in DNA photodamage as well as on their possible therapeutic use.

Uric Acid as a Photosensitizer in the Reaction of Deoxyribonucleosides with UV Light of Wavelength Longer than 300 nm: Identification of Products from 2'-Deoxycytidine.

DNA reacts directly with UV light with a wavelength shorter than 300 nm. Although ground surface sunlight includes little of this short-wavelength UV light due to its almost complete absorption by the atmosphere, sunlight is the primary cause of skin cancer. Photosensitization by endogenous substances must therefore be involved in skin cancer development mechanisms. Uric acid is the final metabolic product of purines in humans, and is present at relatively high concentrations in cells and fluids. When a neutral mixed solution of 2'-deoxycytidine, 2'-deoxyguanosine, thymidine, and 2'-deoxyadenosine was irradiated with UV light with a wavelength longer than 300 nm in the presence of uric acid, all the nucleosides were consumed in a uric acid dose-dependent manner. These reactions were inhibited by the addition of radical scavengers, ethanol and sodium azide. Two products from 2'-deoxycytidine were isolated and identified as N4-hydroxy-2'-deoxycytidine and N4,5-cyclic amide-2'-deoxycytidine, formed by cycloaddition of an amide group from uric acid. A 15N-labeled uric acid, uric acid-1,3-15N2, having two 14N and two 15N atoms per molecule, produced N4,5-cyclic amide-2'-deoxycytidine containing both 14N and 15N atoms from uric acid-1,3-15N2. Singlet oxygen, hydroxyl radical, peroxynitrous acid, hypochlorous acid, and hypobromous acid generated neither N4-hydroxy-2'-deoxycytidine nor N4,5-cyclic amide-2'-deoxycytidine in the presence of uric acid. These results indicate that uric acid is a photosensitizer for the reaction of nucleosides by UV light with a wavelength longer than 300 nm, and that an unidentified radical derived from uric acid with a delocalized unpaired electron may be generated.

Supramolecular Organization of Polymer Prodrug Nanoparticles Revealed by Coarse-Grained Simulations.

Drug-polymer conjugates that can self-assemble into nanoparticles are promising drug delivery systems that improve the drug bioavailability and allow their controlled release. However, despite the possibility of reaching high drug loadings, the efficiency of the drug release, mediated by cleavage of the drug-polymer linker, is a key parameter to obtain significant anticancer activity. To overcome the limitations of experimental characterizations and to gain a better understanding of such systems, we conducted a coarse-grained molecular dynamics simulation study on four representative drug-polymer conjugates obtained by the "drug-initiated" method and studied their supramolecular organization upon self-assembly. The prodrugs were composed of either a gemcitabine or a paclitaxel anticancer drug, either a propanoate or a diglycolate linker, and a polyisoprene chain. Our simulations gave crucial information concerning the spatial organization of the different components (e.g., drug, linker, polymer, etc.) into the nanoparticles and revealed that the linkers are not fully accessible to the solvent. Notably, some cleavage sites were either poorly hydrated or partially solvated. These observations might account for the low efficiency of drug release from the nanoparticles, particularly when the linker is too short and/or not hydrophilic/solvated enough. We believe that our theoretical study could be adapted to other types of polymer prodrugs and could guide the design of new polymer prodrug nanoparticles with improved drug release efficiency.

Decoration of Squalenoyl-Gemcitabine Nanoparticles with Squalenyl-Hydroxybisphosphonate for the Treatment of Bone Tumors.

Therapeutic perspectives of bone tumors such as osteosarcoma remain restricted due to the inefficacy of current treatments. We propose here the construction of a novel anticancer squalene-based nanomedicine with bone affinity and retention capacity. A squalenyl-hydroxybisphosphonate molecule was synthetized by chemical conjugation of a 1-hydroxyl-1,1-bisphosphonate moiety to the squalene chain. This amphiphilic compound was inserted onto squalenoyl-gemcitabine nanoparticles using the nanoprecipitation method. The co-assembly led to nanoconstructs of 75 nm, with different morphology and colloidal properties. The presence of squalenyl-hydroxybisphosphonate enhanced the nanoparticles binding affinity for hydroxyapatite, a mineral present in the bone. Moreover, the in vitro anticancer activity was preserved when tested in commercial and patient-treated derived pediatric osteosarcoma cells. Further in vivo studies will shed light on the potential of these nanomedicines for the treatment of bone sarcomas.

Cell-specific activation of gemcitabine by endogenous H2S stimulation and tracking through simultaneous fluorescence turn-on.

The endogenous H2S-driven theranostic H2S-Gem has been invented. The theranostic prodrug H2S-Gem is selectively activated in cancer cells, releasing active gemcitabine with a simultaneous fluorescence turn-on. H2S-Gem selectively inhibited cancer cell growth compared to the mother chemotherapeutic gemcitabine. Overall, it is a unique protocol for tracking and transporting chemotherapeutic agents to tumor areas without the guidance of tumor-directive ligands.

Reactivity and DNA Damage by Independently Generated 2'-Deoxycytidin-N4-yl Radical.

Oxidative stress produces a variety of radicals in DNA, including pyrimidine nucleobase radicals. The nitrogen-centered DNA radical 2'-deoxycytidin-N4-yl radical (dC·) plays a role in DNA damage mediated by one electron oxidants, such as HOCl and ionizing radiation. However, the reactivity of dC· is not well understood. To reduce this knowledge gap, we photochemically generated dC· from a nitrophenyl oxime nucleoside and within chemically synthesized oligonucleotides from the same precursor. dC· formation is confirmed by transient UV-absorption spectroscopy in laser flash photolysis (LFP) experiments. LFP and duplex DNA cleavage experiments indicate that dC· oxidizes dG. Transient formation of the dG radical cation (dG+•) is observed in LFP experiments. Oxidation of the opposing dG in DNA results in hole transfer when the opposing dG is part of a dGGG sequence. The sequence dependence is attributed to a competition between rapid proton transfer from dG+• to the opposing dC anion formed and hole transfer. Enhanced hole transfer when less acidic O6-methyl-2'-deoxyguanosine is opposite dC· supports this proposal. dC· produces tandem lesions in sequences containing thymidine at the 5'-position by abstracting a hydrogen atom from the thymine methyl group. The corresponding thymidine peroxyl radical completes tandem lesion formation by reacting with the 5'-adjacent nucleotide. As dC· is reduced to dC, its role in the process is traceless and is only detectable because of the ability to independently generate it from a stable precursor. These experiments reveal that dC· oxidizes neighboring nucleotides, resulting in deleterious tandem lesions and hole transfer in appropriate sequences.

N-trimethyl chitosan coated nano-complexes enhance the oral bioavailability and chemotherapeutic effects of gemcitabine.

N-trimethyl chitosan (TMC) is a multifunctional polymer that can be used in various nanoparticle forms in the pharmaceutical, nutraceutical and biomedical fields. In this study, TMC was used as a mucoadhesive adjuvant to enhance the oral bioavailability and hence antitumour effects of gemcitabine formulated into nanocomplexes composed of poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) conjugated with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). A central composite design was applied to achieve the optimal formulation. Cellular uptake and drug transportation studies revealed the nanocomplexes permeate over the intestinal cells via adsorptive-mediated and caveolae-mediated endocytosis. Pharmacokinetic studies demonstrated the oral drug bioavailability of the nanocomplexes was increased 5.1-fold compared with drug solution. In pharmacodynamic studies, the formulation reduced tumour size 3.1-fold compared with the drug solution. The data demonstrates that TMC modified nanocomplexes can enhance gemcitabine oral bioavailability and promote the anticancer efficacy.

Intragenomic Decarboxylation of 5-Carboxy-2'-deoxycytidine.

Cellular DNA is composed of four canonical nucleosides (dA, dC, dG and T), which form two Watson-Crick base pairs. In addition, 5-methylcytosine (mdC) may be present. The methylation of dC to mdC is known to regulate transcriptional activity. Next to these five nucleosides, the genome, particularly of stem cells, contains three additional dC derivatives, which are formed by stepwise oxidation of the methyl group of mdC with the help of Tet enzymes. These are 5-hydroxymethyl-dC (hmdC), 5-formyl-dC (fdC), and 5-carboxy-dC (cadC). It is believed that fdC and cadC are converted back into dC, which establishes an epigenetic control cycle that starts with methylation of dC to mdC, followed by oxidation and removal of fdC and cadC. While fdC was shown to undergo intragenomic deformylation to give dC directly, a similar decarboxylation of cadC was postulated but not yet observed on the genomic level. By using metabolic labelling, we show here that cadC decarboxylates in several cell types, which confirms that both fdC and cadC are nucleosides that are directly converted back to dC within the genome by C-C bond cleavage.

Development and evaluation of a multi-functional organic-inorganic nanotheranostic hybrid for pancreatic cancer therapy.

Pancreatic cancer is a highly invasive disease with low survival rates. The high death rates associated with pancreatic cancer are due to multiple factors including late stage diagnosis, multi-drug resistance, invasive nature and restricted access of the therapeutic moiety to the cancer cells due to the stroma. Smart multifunctional nanocarriers that deliver the therapeutic agent in to the cancer tissue as well as enable imaging of the tissue represent an emerging paradigm in cancer therapy. Accurate and reliable detection of cancerous lesions in pancreas is essential for designing appropriate therapeutic strategy to annihilate the highly aggressive pancreatic cancer. A combination of imaging modalities can enhance the reliability of cancer detection. In this context, we report here a hybrid iron oxide-gold nanoparticle with dual contrast enhancing ability for both magnetic resonance imaging (MRI) and micro-computed tomography (micro-CT) that is co-encapsulated with the nucleotide analogue gemcitabine in a chitosan matrix. The theranostic system displayed enhanced cytotoxicity against PanC-1 pancreatic cancer cells when compared to normal cells over 48 h due to differences in cell internalization. The iron oxide-gold hybrid enabled visualization of the theranostic nanoparticle by MRI as well as micro-CT. Further, the magnetocaloric effect of the iron oxide enabled faster release of the chemotherapeutic agent as well as augmented the cytotoxicity by inducing hyperthermia. This system holds promise for further exploration as an integrated diagnostic and therapeutic platform for pancreatic cancer.

The α-D-anomer of 2'-deoxycytidine: crystal structure, nucleoside conformation and Hirshfeld surface analysis.

ß-2'-Deoxyribonucleosides are the constituents of nucleic acids, whereas their anomeric α-analogues are rarely found in nature. Moreover, not much information is available on the structural and conformational parameters of α-2'-deoxyribonucleosides. This study reports on the single-crystal X-ray structure of α-2'-deoxycytidine, C9H13N3O4 (1), and the conformational parameters characterizing 1 were determined. The conformation at the glycosylic bond is anti, with χ = 173.4 (2)°, and the sugar residue adopts an almost symmetrical C2'-endo-C3'-exo twist (23T; S-type), with P = 179.7°. Both values lie outside the conformational range usually preferred by α-nucleosides. In addition, the amino group at the nucleobase shows partial double-bond character. This is supported by two separated signals for the amino protons in the 1H NMR spectrum, indicating a hindered rotation around the C4-N4 bond and a relatively short C-N bond in the solid state. Crystal packing is controlled by N-H...O and O-H...O contacts between the nucleobase and sugar moieties. Moreover, two weak C-H...N contacts (C1'-H1' and C3'-H3'A) are observed. A Hirshfeld surface analysis was carried out and the results support the intermolecular interactions observed by the X-ray analysis.

PEG-PEI-modified gated N-doped mesoporous carbon nanospheres for pH/NIR light-triggered drug release and cancer phototherapy.

A novel hybrid drug carrier has been designed, taking N-doped mesoporous carbon (NMCS) as the core and PEG-PEI as the outer shell. NMCS was functionalized with a photocleavable nitrobenzyl-based linker following a click reaction. Gemcitabine was loaded into NMCS prior to the functionalization via π-π stacking interactions. NIR and the pH-responsive behavior of NMCS-linker-PEG-PEI bestow the multifunctional drug carrier with the controlled release of gemcitabine triggered by dual stimuli. The NMCS core upconverts NIR light to UV, which is absorbed by a photosensitive molecular gate and results in its cleavage and drug release. Further, NMCS converts NIR to heat, which deforms the outside polymer shell, thus triggering the drug release process. The release can be promptly arrested if the NIR source is switched off. A promising gemcitabine release of 75% has been achieved within 24 h under the dual stimuli of pH and temperature. NMCS-linker-PEG-PEI produced reactive oxygen species (ROS), which were verified in FaDu cells using flow cytometry. In vitro experiments showed that the NMCS-linker-PEG-PEI-GEM hybrid particle can induce synergistic therapeutic effects in FADU cells when exposed to the NIR light.