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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. 

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.