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Carbon Dots (CDs) have recently attracted a considerable amount of attention thanks to their well-documented biocompatibility, tunable photoluminescence, and excellent water solubility. However, CDs need further analysis before their potential use in clinical trials. Previously, we reported a new type of carbon nitride dot (CND) that displayed selective cancer uptake traits attributed to structural resemblances between CNDs and glutamine. Here, the effects of surface structural differences on the cellular uptake of CNDs are further investigated to understand their selective cancer cell uptake trend. Beyond enhanced drug loading on modified CNDs, our cytotoxicity, western blotting and bioimaging studies proposed that modified CNDs’ cellular uptake mechanism is thoroughly linked with ASCT2 and LAT1 transporters. Therefore, CNDs have a promising trait of selective cancer cell targeting by utilizing highly expressed transporters on cancer cells. Additionally, drug loaded CNDs exhibited improved anti-cancer efficacies towards cancer cells along with good non-tumor biocompatibilities. 

Tumor microenvironment responsive drug delivery systems are potential approaches to reduce the acute toxicity caused by high-dose cancer chemotherapy. Notwithstanding the conventional nano-drug delivery systems, the redox and pH stimuli drug delivery systems are currently gaining attention. Therefore, the current study was designed to compare three different covalent carbon dots (C-dots) systems based on doxorubicin (dox) release profiles and cancer cell viability efficacy under acidic and physiological conditions. The C-dots nanosystems that were examined in this study are directly conjugated (C-dots-dox), pH triggered (C-dots-HBA-dox), and the redox stimuli (C-dots-S–S-dox) conjugates. The drug loading content (DLC%) of the C-dots-S–S-dox, C-dots-HBA-dox, and C-dots-dox was 34.2 ± 0.4, 60.0 ± 0.3, and 70.0 ± 0.2%, respectively, that examined by UV-vis spectral analysis. The dox release paradigms were emphasized that all three conjugates were promisingly released the dox from C-dots faster in acidic pH than in physiological pH. The displayed highest dox released percentage in the acidic medium was 74.6 ± 0.8% obtained by the pH stimuli, C-dots-HBA-dox conjugate. When introducing the redox inducer, dithiothreitol (DTT), preferentially, the redox stimuli C-dot-S–S-dox conjugate demonstrated a faster dox release at acidic pH than in the pH 7.4. The SJGBM2 cell viability experiments revealed that the pH stimuli, C-dots-HBA-dox conjugate, displayed a significant cell viability drop in the artificially acidified pH 6.4 medium. However, in the physiological pH, the redox stimuli, C-dots-S–S-dox conjugate, was promising over the pH stimuli C-dots-HBA-dox, exhibiting cell viability of 60%, though its’ efficacy dropped slightly in the artificially acidified pH 6.4 medium. Moreover, the current study illustrates the stimuli conjugates’ remarkable efficacy on sustain drug release than direct amide linkage. 

Pediatric glioblastomas are known to be one of the most dangerous and life-threatening cancers among many others regardless of the low number of cases reported. The major obstacles in the treatment of these tumors can be identified as the lack of prognosis data and the therapeutic requirement to be able to cross the blood–brain barrier (BBB). Due to this lack of data and techniques, pediatric patients could face drastic side effects over a long-time span even after survival. Therefore, in this study, the capability of non-toxic carbon nitride dots (CNDs) to selectively target pediatric glioblastoma cells was studied in vitro . Furthermore, the nanocarrier capability and efficiency of CNDs were also investigated through conjugation of a chemotherapeutic agent and transferrin (T f ) protein. Gemcitabine (GM) was introduced into the system as a chemotherapeutic agent, which has never been successfully used for the treatment of any central nervous system (CNS) cancer. More than 95% of selective damage of SJGBM2 glioma cells was observed at 1 μM of CN–GM conjugate with almost 100% viability of non-cancerous HEK293 cells, although this ability was diminished at lower concentrations. However, further conjugation of T f to obtain CN–GM–T f allowed the achievement of selective targeting and prominent anti-cancer activity at a 100-fold lower concentration of 10 nM. Furthermore, both conjugates were capable of effectively damaging several other brain tumor cells, which were not well responsive towards the single treatment of GM. The capability of BBB penetration of the conjugates was observed using a zebrafish model, which confirms the CNDs’ competence as an excellent nanocarrier to the CNS. 

Most of the dual nano drug delivery systems fail to enter malignant brain tumors due to a lack of proper targeting systems and the size increase of the nanoparticles after drug conjugation. Therefore, a triple conjugated system was developed with carbon dots (C-dots), which have an average particle size of 1.5–1.7 nm. C-dots were conjugated with transferrin (the targeted ligand) and two anti-cancer drugs, epirubicin and temozolomide, to build the triple conjugated system in which the average particle size was increased only up to 3.5 nm. In vitro studies were performed with glioblastoma brain tumor cell lines SJGBM2, CHLA266, CHLA200 (pediatric) and U87 (adult). The efficacy of the triple conjugated system (dual drug conjugation along with transferrin) was compared to those of dual conjugated systems (single drug conjugation along with transferrin), non-transferrin C-dots–drugs, and free drug combinations. Transferrin conjugated samples displayed the lowest cell viability even at a lower concentration. Among the transferrin conjugated samples, the triple conjugated system (C-dots-trans-temo-epi (C-DT)) was more strongly cytotoxic to brain tumor cell lines than dual conjugated systems (C-dots-trans-temo (C-TT) and C-dots-trans-epi (C-ET)). C-DT increased the cytotoxicity to 86% in SJGBM2 at 0.01 μM while C-ET and C-TT reduced it only to 33 and 8%, respectively. Not only did triple conjugated C-DT increase the cytotoxicity, but also the two-drug combination in C-DT displayed a synergistic effect. 

Glioblastoma (GBM) has a dismal prognosis and successful elimination of GBM stem cells (GSCs) is a high-priority as these cells are responsible for tumor regrowth following therapy and ultimately patient relapse. Natural products and their derivatives continue to be a source for the development of effective anticancer drugs and have been shown to effectively target pathways necessary for cancer stem cell self-renewal and proliferation. We generated a series of curcumin inspired bis-chalcones and examined their effect in multiple patient-derived GSC lines. Of the 19 compounds synthesized, four analogs robustly induced GSC death in six separate GSC lines, with a half maximal inhibitory concentration (IC50) ranging from 2.7–5.8 μM and significantly reduced GSC neurosphere formation at sub-cytotoxic levels. Structural analysis indicated that the presence of a methoxy group at position 3 of the lateral phenylic appendages was important for activity. Pathway and drug connectivity analysis of gene expression changes in response to treatment with the most active bis-chalcone 4j (the 3,4,5 trimethoxy substituted analog) suggested that the mechanism of action was the induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) mediated cell death. This was confirmed by Western blot analysis in which 4j induced robust increases in CHOP, p-jun and caspase 12. The UPR is believed to play a significant role in GBM pathogenesis and resistance to therapy and as such represents a promising therapeutic target.