pH-Responsive Delivery of Hydrophobic Anticancer Drugs Using Boron and Nitrogen Co-Doped Carbon Dots as Fluorescent Nanocarriers

pH-Responsive Delivery of Hydrophobic Anticancer Drugs Using Boron and Nitrogen Co-Doped Carbon Dots as Fluorescent Nanocarriers | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article pH-Responsive Delivery of Hydrophobic Anticancer Drugs Using Boron and Nitrogen Co-Doped Carbon Dots as Fluorescent Nanocarriers Seyed Mostafa Jafari, Saeed Masoum, Elahe Seyed Hosseini This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7731800/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 15 You are reading this latest preprint version Abstract In recent years, carbon dots have attracted a lot of attention among the nanocarbon family, due to their remarkable benefits and interesting properties like solubility, biocompatibility, tunable photoluminescence, and so forth. We can also design and synthesize carbon dots according to the capabilities that we expect from them (such as sensors, biosensors or drug delivery systems). In the current study, nitrogen and boron co-doped carbon dots (which is abbreviated as "NBCDs") were successfully used as efficient highly fluorescent nanocarrier to load two types of hydrophobic anticancer drugs including curcumin (CUR) and paclitaxel (PTX). The NBCDs were studied before and after conjugation with CUR and PTX drugs by spectroscopic techniques. After calculating drug loading capacity (LC%) and adsorption efficiency (AE%) for NBCDs nanocarriers, the drug release behavior from NBCDs was studied against two buffers (pH 5.0 and pH 7.4) as release media by dialysis bag method for 72 h. Finally, the pH-dependent release behavior of drugs was studied using several kinetic models. Biological sciences/Biochemistry Biological sciences/Biotechnology Biological sciences/Cancer Physical sciences/Chemistry Biological sciences/Drug discovery Physical sciences/Materials science Physical sciences/Nanoscience and technology Carbon dots Nanocarrier Anticancer drug Curcumin Paclitaxel Drug release models Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Cancer is one of the most devastating diseases and prevailing threat in human owing to its high incidence, severe mortality and low survival rate, while development of nanotechnology offers promising methods to improve cancer diagnosis and therapy [ 1 ]. However, chemotherapeutic agents have been used to treat of cancers, yet. Among them, curcumin (CUR) and paclitaxel (PTX) as the most effective anticancer drug models, were used for variety of cancers. CUR as a polyphenolic and bioactive natural compound has numerous properties such as antioxidant, anticancerous, anti-inflammatory, antiviral, antifungal immunomodulatory, antiangiogenic, neuroprotective, antimicrobial, proliferation of cancer cells [ 2 , 3 ] and also, as a potential therapeutic agent for treating Alzheimer's [ 4 ] and Parkinson's [ 5 ] diseases. Also it was used to wound healing [ 6 ] and drug delivery systems [ 7 , 8 ]. In addition, PTX has been used as a potent anticancer drug to treat a wide range of tumors, including colon [ 9 ], primary epithelial ovarian [ 10 ], non-small cell lung [ 11 ], breast cancer [ 12 ], prostate cancer [ 13 ]. The most anticancer drugs are hydrophobic properties with low water solubility and thus suffer from unfavorable pharmacokinetics, rapid metabolism and poorly bioavailability [ 8 , 14 ]. By using alternative formulation systems, such as liposomes, micelles and nanoparticles, the numerous attempts are being made to increase water-solubility of these drugs. The conventional and commercial approaches for solubilizing hydrophobic anticancer drugs is recommended by using surfactants and organic solvents. For instance, in the paclitaxel injection formulation (Taxol®) uses considerable amount of cremophor EL and dehydrated ethanol to improve its solubility. But, cremophor EL is poisonous to the human body and use of Taxol® in cancer treatment associated with some side effects as peripheral neuropathy, hypersensitivity reactions, and hyperlipidemia [ 15 , 16 ]. In recent years to improve the water-solubility and bioavailability of CUR and PTX, as hydrophobic anticancer drug models, nanoparticles have been used as promising nanocarriers in nano-sized drug delivery systems. Among the nanoparticles that have been synthesized so far, the fluorescent carbon dots have attracted tremendous attention, owing to their attractive properties including excellent biocompatible, low toxicity, multiple functional groups, excitation-dependent emission, high resistance to photobleaching and excellent photostability [ 17 ]. These fascinating materials are nanoparticles with particle size within several nanometers. [ 18 , 19 ] According to previous literatures, carbon dots were used as a desirable platform for the design of novel drug delivery systems therapeutic agents [ 20 , 21 ]. So far, many methods have been proposed to enhance the targeting and bioavailability of CUR and PTX such as the use of nanocarriers [ 8 , 22 ]. Thereby, nano-based drug delivery systems can be improved the overall anticancer activity of CUR [ 23 ]. Anticancer effect is ascribed to its free-radical scavenging and antioxidant properties [ 24 ]. In the selection of drug delivery vehicles for cancer therapy, nanoparticles size, shape, charge and surface chemistry play a key role [ 25 ]. In the present work, we synthesized N/B co-doped CDs (NBCDs) using citric acid (as carbon source) and ethylenediamine / boric acid (as Nitrogen and Boron source) with high quantum yield by hydrothermal method, according to previous literatures [ 26 , 27 ]. In the following, we developed a desirable nanocarrier system to improve the water solubility and bioavailability of PTX and CUR. In the final step, CUR and PTX release kinetics behavior from the NBCDs-CUR and NBCDs-PTX conjugations, were studied at two different pH (7.4 as physiological and 5.0 as tumor cells conditions) using the release kinetics models over the time course of 72 h by KinetDS3.0 software. Based on the obtained drug release pattern, the drug release behavior from the surface of NBCDs is a pH-dependent process. EXPERIMENTAL SECTION Synthesis of NBCDs. In our study, NBCDs were synthesized using the citric acid, boric acid and ethylenediamine as precursors by hydrothermal method [ 26 ]. The brown solution as hydrothermal product was purified with a dialysis membrane against of DI water. The purified solution was dried at room temperature and then the collected powder was homogenized and stored in a closed container for future uses. To characterization of prepared NBCDs, the UV-Vis absorption spectrophotometry, fluorescence spectroscopy, FT-IR, TEM, EDS, XPS, DLS and zeta potential methods were applied. Drug Loading Studies. Both the conjugation and maximum ratio between NBCDs and drug, was investigated by titration method. In this state, the different concentrations of NBCDs were separately added to fixed concentration of methanolic CUR or PTX (1:1 w/v) and the complex formation process between NBCDs to these drugs was followed by recording the absorption spectra. After obtaining the ratio between drug and nanocarrier, a dispersed mixture of them was subjected to ultrasound and stirred for 24 h at room temperature in the dark condition. Then, the solvent was evaporated and the residual dried at ~ 50°C using an oven. Then, it again was dispersed in 10 mL of DI water and centrifuged (5000 rpm, 10 min) and the supernatant collected. The pellet was dissolved in a known amount of methanol and the free drug concentration was determined using UV-Vis spectrophotometer and calibration curve for each drug. Thus, the loading capacity or adsorption efficiency of drug onto the carrier is calculable. According to the definition, adsorption efficiency (AE) is defined as the amount of drug adsorbed/entrapped onto the NBCDs to the total amount of drug added (Eq. 1), whereas about the loading capacity (LC) of drug, it can be expressed as the amount of drug loaded per unit weight of the NBCDs as nanocarriers (Eq. 2), as shown below [ 28 ]: AE (%) = \(\:\:\:\frac{TDA-FDS}{TDA}\times\:100\) (1) LC (%) = \(\:\frac{\text{w}\text{e}\text{i}\text{g}\text{h}\text{t}\:\text{o}\text{f}\:\text{d}\text{r}\text{u}\text{g}\:\text{l}\text{o}\text{a}\text{d}\text{e}\text{d}\:\text{o}\text{n}\text{t}\text{o}\:\text{C}\text{D}\text{s}}{\text{w}\text{e}\text{i}\text{g}\text{h}\text{t}\:\text{o}\text{f}\:\text{C}\text{D}\text{s}}\:\times\:100\) (2) where AE, LC, TDA, FDS are corresponded to adsorption efficiency, loading capacity, total drug added and free drug in solution, respectively. Briefly, for preparation of NBCDs-CUR, 50 mL of methanolic CUR solution (1:1 w/v) was added dropwise to 25 mL of NBCDs solution (2 mg/mL in PBS, 0.1 M and pH 7.4), while the mixture was stirred (500 rpm) for 30 min at room temperature. After sonication of mixture in a water bath (for ~ 30 min), the stirring of mixture was continued for another 24 h at room temperature in dark conditions. In the next step, the methanol solvent was evaporated in an electrical oven. Eventually, to purify the prepared nanoconjugate (as a drug delivery system), it was transferred to a dialysis bag before being immersed in 50 mL of deionized water in a flask and 5 mL of methanol as a co-solvent. Indeed, the purification step was performed using dialysis method (for 2 h) to remove untreated materials (such as the free CUR). The orange-color residue was dried using an oven at 50°C and it was dissolved again in 10 mL of deionized water with helping from a magnetic stirrer. In the final step, the aqueous mixture was centrifuged at 5000 rpm for 10 min and the supernatant (including NBCDs-CUR) was collected. Likewise, for loading of PTX onto the carbon dots surface, a saturated solution of PTX in methanol (~ 20 mg/mL) was prepared. Then, the PTX solution was gradually added to the NBCDs solution (60 mg/mL in PBS 0.1 M and pH 7.4) and the resulted solution was sonicated for ~ 5 min and stirred (500 rpm) for 24 h at room temperature and dark conditions. Similar to above-mention section, the desired volume from the PTX methanolic solution was added to NBCDs solution (2 mg/mL in PBS 0.1 M and pH 7.4). Indeed, PTX drug was added to NBCDs at 3:1 w/w ratio. After mixing NBCDs with PTX solution, the methanol was evaporated in an electrical oven and the dried mixture was again dissolved in the appropriate amount of deionized water after stirring of mixture for ~ 30 min. Then, the centrifugation (5000 rpm) of mixture was carried out for 10 min. Eventually, to purify the prepared mixture (as a drug delivery system), it was transferred to a dialysis bag before being immersed in 50 mL of deionized water in a flask containing 5 mL of methanol as a co-solvent. In fact, purification of the prepared mixture was performed using the dialysis bag method (for 2 h) to remove the untreated materials (such as the free PTX). Finally, the purified product was dried at 50°C and the homogenized powder was stored. In Vitro Drug Release Studies. The study of drug release pattern from drug delivery systems is one of the main analyses to investigate the efficiency of drug delivery systems. In this study, the in vitro drug release profile was investigated at the two different pHs (5.0 and 7.4) based on physiological environment in cancer and normal cells, respectively. Then, the amount of drug release (% cumulative drug) from NBCDs was estimated over the time by calibration curve of drug in buffer. The percentage of drug release was calculated by using of Eq. (3), which is shown below [ 29 ]: Drug release (%) = \(\:\frac{\:\text{D}\text{r}\text{u}\text{g}\:\text{r}\text{e}\text{l}\text{e}\text{a}\text{s}\text{e}\:\text{c}\text{o}\text{n}\text{c}\text{e}\text{n}\text{t}\text{r}\text{a}\text{t}\text{i}\text{o}\text{n}\:\:}{\text{D}\text{r}\text{u}\text{g}\:\text{l}\text{o}\text{a}\text{d}\text{i}\text{n}\text{g}\:\text{c}\text{o}\text{n}\text{c}\text{e}\text{n}\text{t}\text{r}\text{a}\text{t}\text{i}\text{o}\text{n}\:}\times\:100\) (3) Owing to the lactic acid metabolism pathway, cancer cells possess a weak acid environment. In this study, the drug release was carried out by dialysis method. Briefly, the desired amount from each dried drug-loaded NBCDs was weighted and dispersed in phosphate-buffered saline (PBS) solution with 2% (v/v) tween 80 and infused to the dialysis bag before immersing in proper volume of PBS containing 0.5% (v/v) tween 80, as release medium [ 30 ]. Then, 2 mL of release medium were taken and replaced with 2 mL of the same fresh buffer and the absorbance value of released drug was obtained at the maximum absorption wavelength (λ max ) of each drug by UV-Vis spectrophotometer. Concentrations of released drug were calculated from the drug standard curve. In detail, 8.38 mg of dried NBCDs-CUR was dispersed in 1 mL PBS with 2% (v/v) tween 80 and infused into a dialysis bag (the weighted amount for NBCDs-PTX was 7.73 mg). Then, the dialysis bag was immersed into a flask containing PBS (30 mL) + 0.5% (v/v) tween 80 as release medium and solution stirred at 37 ºC under a constant rotation speed (200 rpm) by a hot plate equipped with a magnetic stirrer. The sampling of drug release medium was performed as follow: at different time intervals (up to 72 h), 2 mL from release medium was taken, and the absorbance of the released drug measured by drawing the calibration curve of CUR or PTX in PBS + 0.5% (v/v) tween 80 as release medium at 425 nm (λ max of CUR) and 225 nm (λ max of PTX). After sampling of release buffer, 2 mL of fresh medium was replaced into the flask. As such, the drug release mechanism from NBCDs-drug nanoconjugate was investigated by fitting the data to various release models [ 31 ]. Kinetic Release Study. In general, mathematical models are useful tools to optimize the design of novel pharmaceutical formulations and evaluate (in vitro/ in vivo) drug release processes [ 32 , 33 ]. These models help to understand mechanisms of release. Some of the main-release kinetics models were used to predict the release process. Well-known mathematical models including: zero-order, first-order, Korsmeyer-Peppas, Hill, Weibull, Hixson-Crowell and Higuchi, which used in most of literatures [ 34 ]. RESULTS AND DISCUSSION Characterization of NBCDs and Drug-Loaded NBCDs. To study the absorption properties of NBCDs, CUR, NBCDs-CUR, PTX and NBCDs-PTX samples, the absorption spectra of them were recorded by UV-Vis spectrophotometer (see Fig. 1). According to Fig. 1A, the absorption spectra of NBCDs indicated two original peaks at 215 nm that is assigned to the C = C bond or aromatic π orbitals from the carbon core (π-π * transitions), and another peak at 350 nm that is due to n-π * transitions of C = O or C = N bond involving functional groups with electron lone- pair [ 28 , 35 ]. In addition to the absorption peak at 215 nm, another shoulder peak is appeared around 230 nm. Typically, these absorption peaks are due to aromatic π system with extended conjugation as in the carbon dots structure. Thus, the peak around 230 nm can be related to π-π* transitions [ 36 ]. As a result of trapping excited state energy at the surface states, the latter peak can be commonly attributed to in the highly fluorescent carbon dots [ 27 , 37 ]. With respect to the existence of different groups on carbon dots surfaces, it can be suggested that each of these functional groups creates an energy level gap between the LUMO and HOMO orbitals. The water-soluble synthesized NBCDs were brownish and bright blue in color (inset in Fig. 1A) under day-light (left side) and UV-light (right side), respectively. The UV-Vis spectrum of CUR (dissolved in methanol, Fig. 1B) shows a weak peak at ~ 240 nm corresponding to π-π * and a strong peak (as original peak) at ~ 425 nm corresponding to n-π* transitions [ 38 ]. According to Fig. 1B, the UV-Vis spectrum of NBCDs-CUR depicts two peaks at 215 and 340 nm with increased intensity compared to its corresponding peaks in carbon dots. Meanwhile, a blue-shift ~ 10 nm (350→340 nm) can be seen in the UV-Vis spectrum of NBCDs-CUR with respect to bare NBCDs spectrum (at 350 nm). Based on these spectra, a new additional peak was created at ~ 275 nm at absorption spectrum of NBCDs-CUR. Thus, the changes in absorption peaks of NBCDs nanocarrier before and after loading with CUR drug were observed. These changes in the absorption spectra of carbon dots should be observed due to their interactions with CUR. In Fig. 1C, the PTX in methanol exhibit a strong peak at 225 nm that is due to π-π * transitions. So, the NBCDs-PTX conjugation exhibit two peaks at 215 nm and 340 nm.. With respect to Fig. 1C, the absorption peak of the NBCDs-PTX conjugate exhibits a 10 nm blue shift (225→215 nm) and a decrease in intensity compared to the PTX spectrum. This is likely due to π-π stacking interactions between the π-groups of PTX and NBCDs. Additionally, an intense peak is observed compared to the NBCDs spectrum, accompanied by a 10 nm blue shift (350 → 340 nm). This shift may result from interactions between electron lone pairs in PTX (e.g., the N in the -NH group) and functional groups of NBCDs (e.g., the B in the –B(OH)₂ group), as well as their involvement in bond formation. Following PTX loading onto NBCDs and the formation of NBCDs-PTX, the shoulder peak at 230 nm (present in the NBCDs spectrum) disappears. The absorption spectra confirm that NBCDs could be successfully conjugated to both drugs. Also, the photoluminescence emitted spectra (Fig. 1D) of NBCDs were recorded at different excitation wavelengths (with 10 nm increment). The photoluminescence of NBCDs showed a maximum fluorescence intensity of NBCDs at 440 nm under an excitation wavelength of 360 nm. According to the previous studies, the emissive behavior of the carbon dots is immensely dependent on their surface functionalities [ 39 ]. The fluorescence quantum yield (QY) of NBCDs and NBCDs-drug were measured by gradient method, according to Figures S1 A and S1B. The QY of NBCDs, NBCDs-CUR and NBCDs-PTX were obtained ~ 60%, ~ 21% and ~ 57%, respectively. The fluorescence quenching of NBCDs can be explained by the spectral overlap between the absorption spectrum of the drug (CUR or PTX) with the excitation or emission spectra of NBCDs (Figure S2). The FT-IR spectra related to drugs and NBCDs and drug-loaded NBCDs were demonstrated in Figs. 2 A and 2 B. The FT-IR results of NBCDs, CUR, PTX and their conjugated products were listed in Table S1 and Table S2. Some of the prominent bands for NBCDs were existed in both drug-loaded carbon dots. The peak located at 1747 cm − 1 can be corresponded to C = O stretching vibration. The IR bands at 1081 cm − 1 and 1342 cm − 1 are assigned the C–B and B–O stretching vibration modes, respectively [ 40 ]. The bonding of B–O–C or B–O–H deformation vibration or C–O stretching vibration are supported by the absorption peak at around 1020 cm − 1 [ 40 ]. The IR band at around 1237 cm − 1 is related to C–N stretching vibration, showing that N atoms were successfully doped into NBCDs [ 41 , 42 ]. The band at around 1554 cm − 1 is corresponded to N–H bending vibration of amide groups. The peaks at around 3000 cm − 1 are related to ArC-H/ N–H stretching vibration [ 42 ]. In detail, the presence of a broad peak at around 3185 cm − 1 and a peak at 798 cm − 1 can be a confirmation of the existence of primary amide groups on the carbon dots surface. Also, two peaks at 3185 and 3386 cm − 1 are indicated B-OH / -NH 2 and O-H groups, respectively. The excellent aqueous stability and hydrophilicity of NBCDs in water is due to many polar functional groups [ 43 , 44 ]. The FT-IR spectrum of CUR (in Fig. 2 A) was indicated absorption bands at 963 cm − 1 (benzoate trans-CH vibration / C = C stretching benzene ring / O-H enolic in-plane bending), 1028 cm − 1 (C–O), 1274 cm − 1 (C–O–C), 1433 and 1585 cm − 1 (C = C stretching vibration), 2932 cm − 1 (C–H stretching, methyl ring), 3506 cm − 1 (–OH (phenolic) stretching) [ 45 ]. After adding CUR to NBCDs, the B atom in the -B-OH functional groups on the surface of carbon dots can be conjugated to the enol / keto of the CUR, due to empty orbital of B atom. So, the bending vibration peak at 1183 cm − 1 (B–O–H in carbon dot) and 1274 cm − 1 (enol stretching in CUR) were disappeared after forming the six-membered in ring (Scheme S1). Also, after NBCDs-CUR formation (according to Fig. 2 A), the peaks at 1554, 1081 cm − 1 (aromatic moiety of CUR) and 931 cm − 1 (of NBCDs), were shifted to 1589, 1087 and 937 cm − 1 , respectively. The removal of peaks at 1507, 1433 and 1274 cm − 1 related to CUR, after conjugating to carbon dots and existence of peak at 1399 cm − 1 (as a sign for C = C stretching) in CUR and NBCDs can be a reason for conjugation between two parts. Indeed, after loading of CUR onto the NBCDs, we can see that peak at 1183 cm − 1 (related to carbon dots) is disappeared, due to formation of NBCDs-CUR, that is due to removing B–O–H absorbance peak of carbon dots. Obviously, the 3386 cm − 1 peak of NBCDs is shifted to 3419 cm − 1 in NBCDs-CUR system, that it is again proved hydrogen bonding between CUR and NBCDs. In Fig. 2 B, for PTX drug, several characteristic peaks is observed at 3390 cm − 1 (stretching of O-H), 2486 cm − 1 (stretching of –N-H), 2927 cm − 1 (stretching of C-H), 1736 cm − 1 and 1703 cm − 1 (stretching of C = O carbonyl ketone), 1639 cm − 1 (C = O amide stretching), 1432 cm − 1 (CH2 scissoring mode), 1081 cm − 1 (aromatic moiety or C-O stretching) and 614 cm − 1 (bending of aromatic C-H bond) [ 46 , 47 ]. After PTX loading onto NBCDs, the following peaks are indicated in FT-IR spectra of NBCDs-PTX: O-H and N-H stretching vibrations at 3442 cm − 1 , -NH group of PTX at 2537 cm − 1 and several peaks at 1641, 1441, 1408, 1102 and 609 cm − 1 were due to C = O stretching of NBCDs and PTX, CH 2 scissoring mode of PTX, C = C stretching, overlapping C-N stretching vibration of NBCDs with aromatic moiety vibration of PTX, respectively. So, these peaks confirm the successful loading of PTX on the NBCDs. XRD analysis of NBCDs powder was also carried out. As observed in Fig. 2 C, a broad amorphous peak was observed at 2θ = 15°-27° in the XRD pattern for the prepared NBCDs, which confirms its graphitic nature and was consistent with previous reports. The presence of a sharp and high-intensity reflection at 2θ = 28° along with several weak-intensity reflection, can possibly be related to the presence of nitrogen and cubic B 2 O 3 according to the JCPDS card number 00-006-0297, in the peak list of Fig. 2 C. The inset in Fig. 2 C, shows the reaction of B 2 O 3 formation from the boric acid at high pressure and temperature inside the autoclave. Based on the previous reports, carbon dots due to possess distinct optical and chemical properties allow us to (1) have optical properties compatible with living cells, (2) modify with suitable exogenous chemicals, and (3) be biocompatible and nontoxic [ 48 ]. Likewise, the high and stable fluorescent carbon dots can be a significant benefit for development of drug delivery systems. To study of photostability of the NBCDs, the fluorescence intensity of carbon dots was recorded at λ max = 360 nm (as excitation wavelength) and different time intervals. When NBCDs are used as a fluorescent nanocarrier, the stability index is an important factor for these purposes. According to Figure S3, it can be clearly seen that the fluorescence intensity or optical stability of carbon dots and drug-loaded carbon dots remains almost constant in different time intervals, after several weeks or with a slight decrease after several months. The decreased fluorescence intensity percentage of NBCDs-CUR was 2.1, 7.2, 17.1 and 25.1% after one week, one month, three and six months, respectively. Also, these values for NBCDs-PTX were 2, 3.8, 11 and 16.9%, respectively. According to previous study, the analyses of Electron-dispersive X-ray spectroscopy (EDS), EDS layered image, X-ray photoelectron spectroscopy (XPS) and TEM image were performed to evaluate the percentage of constituent elements and morphology of NBCDs [ 26 ]. The results confirms the successful formation of –COOH, –OH, –NH 2 , and –B(OH) 2 functional groups on the surface of semi-spherical NBCDs [ 27 , 37 ]. To study the stability (or photostability) properties of the produced dispersion, zeta potential is an important index. Therefore, it can be understood that the lower absolute value of zeta potential, more particles agglomerate [ 49 ]. In this work, zeta potential analyses of the NBCDs and conjugated with drugs (in water and PBS) were carried out according to Figure S4 (A-F) and Table S3. The analysis of zeta potential results and salt bridge effect in buffer are fully explained in the Supplementary Information. Dynamic light scattering (DLS) analysis was also carried out. As illustrated in Figure S5, the particle size distribution of 14.5, 65.4 and 37 nm were corresponded to NBCDs, NBCDs-CUR and NBCDs-PTX, respectively. These changes in the size of the carbon dots under the same conditions can prove the loading of the drug on the surface of the carbon dots. Other evidence of CUR and PTX presence in drug-loading NBCDs is proton nuclear magnetic resonance spectroscopy ( 1 H-NMR), along with other techniques. The 1 H-NMR of NBCDs (Figure S6A), CUR (Figure S6B), NBCDs-CUR (Figure S6C), NBCDs-PTX (Figure S6D), and PTX (Figure S6E), were recorded in dimethyl sulfoxide-d 6 (DMSO-d 6 ) as solvent and tetramethylsilane (TMS) as internal standard. The 1 H-NMR analysis results are fully explained in the Supplementary Information. The summary of the results of 1 H-NMR study is listed in Table S4. Drug Loading onto the NBCDs Nanocarrier. The adsorption of selected drugs onto NBCDs is through the interactions such as van der Waals force, electrostatic attraction, π-π stacking and hydrophobic interaction [ 50 ]. After deprotonation of carboxylate groups onto the NBCDs at pH ~ 7.4, hydrogen bond between CUR (as hydrogen bond donor) and carbon dots (as hydrogen bond acceptors) can be formed [ 28 ]. Conjugation of PTX with NBCDs is created through the formation a amide bonding by the reaction between amino groups of NBCDs and carboxyl groups of PTX [ 8 ], that is sensitive to acidic medium. To study of conjugation of NBCDs with CUR, maximum ratio between two parts was firstly estimated. Thus, the different concentrations of NBCDs (0.002–0.03 mg/mL) were gradually added to the constant concentration of dissolved CUR in methanol (0.02 mg/mL), and the process of complex formation between CUR and carbon dots was followed by recording the absorption spectra variations after each addition. In Figure S7A, the gradual addition of NBCDs, induced a progressive decrease the absorption intensity of NBCDs-CUR complex at ~ 400–440 nm and a progressive increase at ~ 210–350 nm. Based on results, the maximum ratio between CUR and NBCDs ([NBCDs]:[CUR]) is achieved at 1:1 (w/w) ratio. Also, for studying of conjugation between the NBCDs and the PTX (as a hydrophobic anticancer drug model) the different concentrations of NBCDs (0.001–0.018 mg/mL) were gradually added to the constant concentration of dissolved PTX in methanol (0.024 mg/mL), and the process of complex formation between PTX and NBCDs was followed by UV-Vis spectrophotometric method (see Figure S7B). The gradual addition of NBCDs, induced a progressive decrease the absorption of PTX-NBCDs complex at ~ 220–230 nm and a progressive increase at ~ 250–450 nm, respectively. Thus, the maximum ratio between PTX and NBCDs ([NBCDs]:[PTX]) achieved at 1:3 (w/w) ratio. These results is also exhibited that there are strong interactions between the graphitic carbon cores or functional groups in the NBCDs with the aromatic moiety of drugs (CUR or PTX) which leads to changes in their absorption spectra. Likewise, the residual pellet was dissolved in a known amount of methanol and thus, free CUR concentration was calculated by a standard curve (see Figure S8A). Therefore, the percentage of drug loading capacity (LC%) and adsorption efficiency (AE%) of CUR onto the NBCDs is calculable, so that, a value of 67% was obtained for each parameter. According to the definition, adsorption efficiency is defined as the amount of drug adsorbed/entrapped onto the NBCDs to the total amount of drug added (Eq. 1) whereas about the loading capacity (LC) of drug, it can be expressed as the amount of drug loaded per unit weight of the NBCDs (Eq. 2). For CUR drug, the drug loading capacity on the NBCDs was calculated by CUR standard curve (see Figure S8A). The same steps were performed for calculation of loading capacity of PTX drug on the NBCDs, by using calibration curve (according to Figure S9A) and absorption spectrophotometric method at 225 nm. Finally, the LC% and AE% were calculated for carbon dots and PTX, which were equal to 28.8% and 86.5%, respectively. pH-Dependent Release Kinetic Models. By using release kinetic models, some important physical parameters (such as drug diffusion coefficient) are measured. It is very important to know how to use these equations to understand the different factors that affect the dissolution behaviors. According to some literatures, the drug release from a released system can be controlled by various methods, such as diffusion, dissolution, osmosis, partitioning, swelling and erosion. For example, the diffusion method of the active agent is a strong function of the structure such as the polymer morphology [ 51 ]. As depicted in Fig. 3 , the released patterns of CUR, PTX, NBCDs-CUR and NBCDs-PTX were investigated in the buffer at pH 5.0 and 7.4 as release medium in a controlled manner, as simulated cancer cell environment and normal cell environment by a dialysis bag method. On the basis of obtained results of CUR release (see Fig. 3 A), the enhanced drug release under acidic conditions (pH 5.0) is maybe due to protonation of boron atom in the formed six-membered ring. In fact, the six-membered ring between the keto-enol groups of CUR and the boron hydroxyl (–B(OH) 2 ) groups on the surface of carbon dots (according to Scheme S1) that is opened under acidic conditions. Therefore, the enhanced CUR release at acidic pH is a desirable property to elicit its therapeutic effect in the tumor environment. The lower release rate of CUR at pH 7.4 compared to the pH 5.0 can be attributed to the stronger association between CUR and NBCDs at the pH 7.4 condition. The initial CUR release of NBCDs-CUR (in the first 10 h) was found to be ~ 14 and 10% at pH 5.0 and pH 7.4, respectively. The above feature is one of the practical importance for clinical therapy, because both extracellular (tumor tissues) and intracellular (endosome/lysosome) medium have low pH (pH ≤ 5) [ 52 ]. After 72 h, the total cumulative CUR release (%) from the NBCDs-CUR was determined to be ~ 54% at pH 5.0 and ~ 40% at pH 7.4. Likewise, PTX was selected as a hydrophobic drug model for conjugation to NBCDs via π-π stacking (as hydrophobic interaction), dative bond between –NH- (amine group) of PTX (with electron lone-pair) and B of –B(OH) 2 group on the carbon dots surface (with empty orbital), hydrogen bonding between the –NH group of NBCDs and –COOH of PTX and vice versa, according to Scheme S1B. Also, Fig. 3 B shows the cumulative release of PTX (%) from NBCDs at different pH values. The PTX release (like to CUR release) possess pH-dependent kinetics. Also, a nonlinear release profile (as a similar feature) was observed for both drug-loaded NBCDs and both pH conditions. Initial burst release of drug from NBCDs-PTX occurred during the first 5 h, so that ~ 23% and ~ 25% of PTX was released from NBCDs-PTX at pH 5.0 and pH 7.4, respectively. After 72 h, the total cumulative PTX release (%) from the NBCDs-PTX was determined to be ~ 80% at pH 5.0 and ~ 55% at pH 7.4. The sampling of drug release medium was performed at different time intervals (up to 72 h), so that 2 mL from release medium was taken, and replaced with 2 mL from fresh medium. Then, the absorbance of the released medium was measured at 225 nm through the calibration curve of PTX in PBS + 0.5% (v/v) tween 80, according to Figure S9B. The higher release rate of PTX at acidic pH, may be explained by protonation of both amine groups (in PTX and NBCDs surface) and boron hydroxyl/ carboxylate groups (in the NBCDs) which leads to a decrease in the electrostatic interaction between PTX and carbon dots [ 53 ]. In general, the experimental models of release were compared with default well-known models in the software. According to Table 1 , the correlation coefficient (R 2 ) of each model was evaluated to fit the accuracy of the proposed statistical models by the utilized software. In the present study, for any drug and under any pH condition, the higher R 2 (> 0.96) values of the Hill, Weibull, Higuchi and Korsmeyer-Peppas models suggest that the drug release kinetics from the nanocarrier, follows the corresponding kinetic model [ 54 ]. As an example, Figure S10 indicate the proposal release models of CUR from the NBCDs at pH = 5.0 against time (h), by using software. The experimental data and fitting curve were displayed in these plots. Table 1 Kinetics models and R 2 -values for analysis of cumulative drug (CUR or PTX) release from NBCDs nanocarreir (as output data of KinetDS3.0 software). Release Model R 2 CUR (pH 5.0) CUR (pH 7.4) PTX (pH 5.0) PTX (pH 7.4) Hill 0.9895 0.9893 0.9340 0.9836 Weibull 0.9857 0.9864 0.9355 0.9805 Higuchi 0.9617 0.9523 0.9729 0.3502 Korsmeyer-Peppas 0.9794 0.9824 0.9708 0.9738 Hikson- Crowell 0.6990 0.7043 0.7244 0.6692 Besides output results of software listed in Table 1 , the Korsmeyer-Peppas model was plotted for any drug and for each condition (see Fig. 4 ). This model not only can be used to predict the drug release mechanism from a polymeric system, but also it superpose diffusion and swelling as independent mechanisms of releasing [ 55 ]. This model is obtained by plotting the log of cumulative drug release (%) against the log of time (h) and M t / M ∞ , K KP , and n represent the fractional drug release, the Korsmeyer-Peppas rate constant, and release exponent, respectively. Noticeably, to find out the size of n, M t / M ∞ < 0.6 should only be used. The size of n characterizes the mechanism of the drug release and the value of it demonstrates that drug release is controlled by diffusion (Fickian model, case I), if n = 0.5 or by swelling (non-Fickian model, case II), if n = 1. When n = 1, drug release rate corresponds to zero-order release kinetics, but when 0.5 < n 1, the Super Case II model is characterized, constituting an extreme form of drug transport, so that in this state tension and breaking of the polymer occur [ 52 ]. The preferred Korsmeyer-Peppas model is most complex among the selected empirical models because they integrate different release mechanisms [ 56 ]. To better understand the interaction of drugs with carbon nanocarriers, the structure of drugs (A: CUR and B: PTX) is shown in Figure S11. Based on the Figure S11 and Scheme S1, the existence of the different functional groups can be formed different bonds between the drug and carbon dots (such as hydrogen bonding, π-π stacking, dative bonding, and imine bond between the C = O groups of CUR and NH 2 groups of NBCDs and etc.). CONCLUSIONS In summary, highly fluorescence boron and nitrogen co-doped carbon dots were synthesized by hydrothermal method and used as a suitable nanocarrier for curcumin and paclitaxel as hydrophobic drug models. Chemotherapeutic drugs, can be conjugated to the carbon dots through covalent bonding by functional groups or other non-covalent interactions like π-π stacking, electrostatic and also hydrogen bond and so on. After attaching the drug to the carbon dots, the capacity of drug loading and adsorption efficiency (67.65% for CUR, 28.83 and 86.5% for PTX) and release (CUR (pH 5): 54%, CUR (pH 7.4): 40%, PTX (pH 5): 80% and PTX (pH 7.4): 55%) were determined. The higher release efficiency of drug at pH 5.0 implies that prepared NBCDs-drug nanoconjugates possess the selective capability of drug release under acidic conditions as a unique feature of NBCDs-drug, which can enhance their ability in anticancer therapy. Consequently, the prepared nanoconjugates can enter to cancer cells and drugs be released under acidic environment of the tumor and act as an effective therapeutic agent. Declarations Competing interests The authors declare that they have no conflict of interest. Funding declaration This work was supported by University of Kashan. Author Contribution Seyed Mostafa Jafari: Methodology, Investigation, Visualization, Writing original draft. 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05:08:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7731800/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7731800/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":93901138,"identity":"f38525a8-8ff1-4468-a85f-30f3dbf59f08","added_by":"auto","created_at":"2025-10-20 05:28:34","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1782182,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-7731800/v1/d55d464623e560218f99fa11.docx"},{"id":93900630,"identity":"63188176-db87-4408-8d28-7f60cd2f8de9","added_by":"auto","created_at":"2025-10-20 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05:20:34","extension":"html","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":143339,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7731800/v1/2b2b423fd9f08c55d3014a54.html"},{"id":93901135,"identity":"b3bb3a32-9c1f-48f5-ba98-8ee90210dd31","added_by":"auto","created_at":"2025-10-20 05:28:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":224837,"visible":true,"origin":"","legend":"\u003cp\u003e(A) UV-Vis absorption spectra of the NBCDs (Inset: NBCDs solution images under day-light (left) and ultraviolet-light (right) using a 365 nm UV lamp, (B) UV-Vis absorption spectra of the NBCDs, CUR and their conjugation (C) UV-Vis absorption spectra of the NBCDs, PTX and their conjugation, and (D) Fluorescence spectra of the NBCDs (slit ex/em: 15/3) at different excitation wavelengths.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7731800/v1/c00063f9c5816580a63bfd4b.png"},{"id":93900631,"identity":"219a3c6e-c9f1-42f4-9e8f-6bb871fa5221","added_by":"auto","created_at":"2025-10-20 05:20:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":336590,"visible":true,"origin":"","legend":"\u003cp\u003e(A) FT-IR spectrum of dried and powdered NBCDs, CUR and NBCDs-CUR (B) FT-IR spectrum of dried and powdered NBCDs, PTX and NBCDs-PTX (both A and B spectrums were prepared using KBr disc method), and (C) XRD pattern of NBCDs powder\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7731800/v1/f01c3492ba6a90cebace02f7.png"},{"id":93900628,"identity":"a603cd2e-ed80-4ff8-8b51-ee697a4457c1","added_by":"auto","created_at":"2025-10-20 05:20:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":86426,"visible":true,"origin":"","legend":"\u003cp\u003eCUR and PTX release profile from the NBCDs-CUR (A) and NBCDs-PTX (B) under pH 5.0 (citrate buffer) and pH 7.4 (PBS) with three replications (n = 3).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7731800/v1/102e0c70f9b72bb116a0b752.png"},{"id":93901136,"identity":"f209cc65-2b80-449d-b6d1-07d6ba8af3df","added_by":"auto","created_at":"2025-10-20 05:28:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":117137,"visible":true,"origin":"","legend":"\u003cp\u003eDrug releasing data at two different pHs based on the Korsmeyer-Peppas mathematical model\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7731800/v1/5845549e0f4559f3de4bf49e.png"},{"id":93901622,"identity":"95892fd3-e213-4310-a47a-e0e6341ae295","added_by":"auto","created_at":"2025-10-20 05:52:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1290006,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7731800/v1/ec121b11-1795-4d59-a6f3-750fb3eb20db.pdf"},{"id":93901186,"identity":"e7bad1c0-8ad1-459f-829c-82c3c9ab90b3","added_by":"auto","created_at":"2025-10-20 05:36:34","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":3639872,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-7731800/v1/64838418f9c80712ee2c0f4b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"pH-Responsive Delivery of Hydrophobic Anticancer Drugs Using Boron and Nitrogen Co-Doped Carbon Dots as Fluorescent Nanocarriers","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eCancer is one of the most devastating diseases and prevailing threat in human owing to its high incidence, severe mortality and low survival rate, while development of nanotechnology offers promising methods to improve cancer diagnosis and therapy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. However, chemotherapeutic agents have been used to treat of cancers, yet. Among them, curcumin (CUR) and paclitaxel (PTX) as the most effective anticancer drug models, were used for variety of cancers. CUR as a polyphenolic and bioactive natural compound has numerous properties such as antioxidant, anticancerous, anti-inflammatory, antiviral, antifungal immunomodulatory, antiangiogenic, neuroprotective, antimicrobial, proliferation of cancer cells [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and also, as a potential therapeutic agent for treating Alzheimer's [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] and Parkinson's [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] diseases. Also it was used to wound healing [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and drug delivery systems [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In addition, PTX has been used as a potent anticancer drug to treat a wide range of tumors, including colon [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], primary epithelial ovarian [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], non-small cell lung [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], breast cancer [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], prostate cancer [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The most anticancer drugs are hydrophobic properties with low water solubility and thus suffer from unfavorable pharmacokinetics, rapid metabolism and poorly bioavailability [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. By using alternative formulation systems, such as liposomes, micelles and nanoparticles, the numerous attempts are being made to increase water-solubility of these drugs. The conventional and commercial approaches for solubilizing hydrophobic anticancer drugs is recommended by using surfactants and organic solvents. For instance, in the paclitaxel injection formulation (Taxol\u0026reg;) uses considerable amount of cremophor EL and dehydrated ethanol to improve its solubility. But, cremophor EL is poisonous to the human body and use of Taxol\u0026reg; in cancer treatment associated with some side effects as peripheral neuropathy, hypersensitivity reactions, and hyperlipidemia [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn recent years to improve the water-solubility and bioavailability of CUR and PTX, as hydrophobic anticancer drug models, nanoparticles have been used as promising nanocarriers in nano-sized drug delivery systems. Among the nanoparticles that have been synthesized so far, the fluorescent carbon dots have attracted tremendous attention, owing to their attractive properties including excellent biocompatible, low toxicity, multiple functional groups, excitation-dependent emission, high resistance to photobleaching and excellent photostability [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. These fascinating materials are nanoparticles with particle size within several nanometers. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] According to previous literatures, carbon dots were used as a desirable platform for the design of novel drug delivery systems therapeutic agents [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. So far, many methods have been proposed to enhance the targeting and bioavailability of CUR and PTX such as the use of nanocarriers [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Thereby, nano-based drug delivery systems can be improved the overall anticancer activity of CUR [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Anticancer effect is ascribed to its free-radical scavenging and antioxidant properties [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In the selection of drug delivery vehicles for cancer therapy, nanoparticles size, shape, charge and surface chemistry play a key role [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn the present work, we synthesized N/B co-doped CDs (NBCDs) using citric acid (as carbon source) and ethylenediamine / boric acid (as Nitrogen and Boron source) with high quantum yield by hydrothermal method, according to previous literatures [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In the following, we developed a desirable nanocarrier system to improve the water solubility and bioavailability of PTX and CUR. In the final step, CUR and PTX release kinetics behavior from the NBCDs-CUR and NBCDs-PTX conjugations, were studied at two different pH (7.4 as physiological and 5.0 as tumor cells conditions) using the release kinetics models over the time course of 72 h by KinetDS3.0 software. Based on the obtained drug release pattern, the drug release behavior from the surface of NBCDs is a pH-dependent process.\u003c/p\u003e"},{"header":"EXPERIMENTAL SECTION","content":"\u003cp\u003e\u003cb\u003eSynthesis of NBCDs.\u003c/b\u003e In our study, NBCDs were synthesized using the citric acid, boric acid and ethylenediamine as precursors by hydrothermal method [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The brown solution as hydrothermal product was purified with a dialysis membrane against of DI water. The purified solution was dried at room temperature and then the collected powder was homogenized and stored in a closed container for future uses. To characterization of prepared NBCDs, the UV-Vis absorption spectrophotometry, fluorescence spectroscopy, FT-IR, TEM, EDS, XPS, DLS and zeta potential methods were applied.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDrug Loading Studies.\u003c/b\u003e Both the conjugation and maximum ratio between NBCDs and drug, was investigated by titration method. In this state, the different concentrations of NBCDs were separately added to fixed concentration of methanolic CUR or PTX (1:1 w/v) and the complex formation process between NBCDs to these drugs was followed by recording the absorption spectra. After obtaining the ratio between drug and nanocarrier, a dispersed mixture of them was subjected to ultrasound and stirred for 24 h at room temperature in the dark condition. Then, the solvent was evaporated and the residual dried at ~\u0026thinsp;50\u0026deg;C using an oven. Then, it again was dispersed in 10 mL of DI water and centrifuged (5000 rpm, 10 min) and the supernatant collected. The pellet was dissolved in a known amount of methanol and the free drug concentration was determined using UV-Vis spectrophotometer and calibration curve for each drug. Thus, the loading capacity or adsorption efficiency of drug onto the carrier is calculable. According to the definition, adsorption efficiency (AE) is defined as the amount of drug adsorbed/entrapped onto the NBCDs to the total amount of drug added (Eq.\u0026nbsp;1), whereas about the loading capacity (LC) of drug, it can be expressed as the amount of drug loaded per unit weight of the NBCDs as nanocarriers (Eq.\u0026nbsp;2), as shown below [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]:\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eAE (%) =\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\:\\:\\frac{TDA-FDS}{TDA}\\times\\:100\\)\u003c/span\u003e\u003c/span\u003e (1)\u003c/h2\u003e\u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\u003ch2\u003eLC (%) = \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\frac{\\text{w}\\text{e}\\text{i}\\text{g}\\text{h}\\text{t}\\:\\text{o}\\text{f}\\:\\text{d}\\text{r}\\text{u}\\text{g}\\:\\text{l}\\text{o}\\text{a}\\text{d}\\text{e}\\text{d}\\:\\text{o}\\text{n}\\text{t}\\text{o}\\:\\text{C}\\text{D}\\text{s}}{\\text{w}\\text{e}\\text{i}\\text{g}\\text{h}\\text{t}\\:\\text{o}\\text{f}\\:\\text{C}\\text{D}\\text{s}}\\:\\times\\:100\\)\u003c/span\u003e\u003c/span\u003e (2)\u003c/h2\u003e\u003cp\u003ewhere AE, LC, TDA, FDS are corresponded to adsorption efficiency, loading capacity, total drug added and free drug in solution, respectively.\u003c/p\u003e\u003cp\u003eBriefly, for preparation of NBCDs-CUR, 50 mL of methanolic CUR solution (1:1 w/v) was added dropwise to 25 mL of NBCDs solution (2 mg/mL in PBS, 0.1 M and pH 7.4), while the mixture was stirred (500 rpm) for 30 min at room temperature. After sonication of mixture in a water bath (for ~\u0026thinsp;30 min), the stirring of mixture was continued for another 24 h at room temperature in dark conditions. In the next step, the methanol solvent was evaporated in an electrical oven. Eventually, to purify the prepared nanoconjugate (as a drug delivery system), it was transferred to a dialysis bag before being immersed in 50 mL of deionized water in a flask and 5 mL of methanol as a co-solvent. Indeed, the purification step was performed using dialysis method (for 2 h) to remove untreated materials (such as the free CUR). The orange-color residue was dried using an oven at 50\u0026deg;C and it was dissolved again in 10 mL of deionized water with helping from a magnetic stirrer. In the final step, the aqueous mixture was centrifuged at 5000 rpm for 10 min and the supernatant (including NBCDs-CUR) was collected. Likewise, for loading of PTX onto the carbon dots surface, a saturated solution of PTX in methanol (~\u0026thinsp;20 mg/mL) was prepared. Then, the PTX solution was gradually added to the NBCDs solution (60 mg/mL in PBS 0.1 M and pH 7.4) and the resulted solution was sonicated for ~\u0026thinsp;5 min and stirred (500 rpm) for 24 h at room temperature and dark conditions. Similar to above-mention section, the desired volume from the PTX methanolic solution was added to NBCDs solution (2 mg/mL in PBS 0.1 M and pH 7.4). Indeed, PTX drug was added to NBCDs at 3:1 w/w ratio. After mixing NBCDs with PTX solution, the methanol was evaporated in an electrical oven and the dried mixture was again dissolved in the appropriate amount of deionized water after stirring of mixture for ~\u0026thinsp;30 min. Then, the centrifugation (5000 rpm) of mixture was carried out for 10 min. Eventually, to purify the prepared mixture (as a drug delivery system), it was transferred to a dialysis bag before being immersed in 50 mL of deionized water in a flask containing 5 mL of methanol as a co-solvent. In fact, purification of the prepared mixture was performed using the dialysis bag method (for 2 h) to remove the untreated materials (such as the free PTX). Finally, the purified product was dried at 50\u0026deg;C and the homogenized powder was stored.\u003c/p\u003e\u003cp\u003e\u003cb\u003eIn Vitro Drug Release Studies.\u003c/b\u003e The study of drug release pattern from drug delivery systems is one of the main analyses to investigate the efficiency of drug delivery systems. In this study, the in vitro drug release profile was investigated at the two different pHs (5.0 and 7.4) based on physiological environment in cancer and normal cells, respectively. Then, the amount of drug release (% cumulative drug) from NBCDs was estimated over the time by calibration curve of drug in buffer. The percentage of drug release was calculated by using of Eq.\u0026nbsp;(3), which is shown below [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]:\u003c/p\u003e\u003cp\u003eDrug release (%) = \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\frac{\\:\\text{D}\\text{r}\\text{u}\\text{g}\\:\\text{r}\\text{e}\\text{l}\\text{e}\\text{a}\\text{s}\\text{e}\\:\\text{c}\\text{o}\\text{n}\\text{c}\\text{e}\\text{n}\\text{t}\\text{r}\\text{a}\\text{t}\\text{i}\\text{o}\\text{n}\\:\\:}{\\text{D}\\text{r}\\text{u}\\text{g}\\:\\text{l}\\text{o}\\text{a}\\text{d}\\text{i}\\text{n}\\text{g}\\:\\text{c}\\text{o}\\text{n}\\text{c}\\text{e}\\text{n}\\text{t}\\text{r}\\text{a}\\text{t}\\text{i}\\text{o}\\text{n}\\:}\\times\\:100\\)\u003c/span\u003e\u003c/span\u003e(3)\u003c/p\u003e\u003cp\u003eOwing to the lactic acid metabolism pathway, cancer cells possess a weak acid environment. In this study, the drug release was carried out by dialysis method. Briefly, the desired amount from each dried drug-loaded NBCDs was weighted and dispersed in phosphate-buffered saline (PBS) solution with 2% (v/v) tween 80 and infused to the dialysis bag before immersing in proper volume of PBS containing 0.5% (v/v) tween 80, as release medium [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Then, 2 mL of release medium were taken and replaced with 2 mL of the same fresh buffer and the absorbance value of released drug was obtained at the maximum absorption wavelength (λ\u003csub\u003emax\u003c/sub\u003e) of each drug by UV-Vis spectrophotometer. Concentrations of released drug were calculated from the drug standard curve. In detail, 8.38 mg of dried NBCDs-CUR was dispersed in 1 mL PBS with 2% (v/v) tween 80 and infused into a dialysis bag (the weighted amount for NBCDs-PTX was 7.73 mg). Then, the dialysis bag was immersed into a flask containing PBS (30 mL)\u0026thinsp;+\u0026thinsp;0.5% (v/v) tween 80 as release medium and solution stirred at 37 \u0026ordm;C under a constant rotation speed (200 rpm) by a hot plate equipped with a magnetic stirrer. The sampling of drug release medium was performed as follow: at different time intervals (up to 72 h), 2 mL from release medium was taken, and the absorbance of the released drug measured by drawing the calibration curve of CUR or PTX in PBS\u0026thinsp;+\u0026thinsp;0.5% (v/v) tween 80 as release medium at 425 nm (λ\u003csub\u003emax\u003c/sub\u003e of CUR) and 225 nm (λ\u003csub\u003emax\u003c/sub\u003e of PTX). After sampling of release buffer, 2 mL of fresh medium was replaced into the flask. As such, the drug release mechanism from NBCDs-drug nanoconjugate was investigated by fitting the data to various release models [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eKinetic Release Study.\u003c/b\u003e In general, mathematical models are useful tools to optimize the design of novel pharmaceutical formulations and evaluate (in vitro/ in vivo) drug release processes [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. These models help to understand mechanisms of release. Some of the main-release kinetics models were used to predict the release process. Well-known mathematical models including: zero-order, first-order, Korsmeyer-Peppas, Hill, Weibull, Hixson-Crowell and Higuchi, which used in most of literatures [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"RESULTS AND DISCUSSION","content":"\u003cp\u003e\u003cb\u003eCharacterization of NBCDs and Drug-Loaded NBCDs.\u003c/b\u003e To study the absorption properties of NBCDs, CUR, NBCDs-CUR, PTX and NBCDs-PTX samples, the absorption spectra of them were recorded by UV-Vis spectrophotometer (see Fig.\u0026nbsp;1). According to Fig.\u0026nbsp;1A, the absorption spectra of NBCDs indicated two original peaks at 215 nm that is assigned to the C\u0026thinsp;\u003cb\u003e=\u003c/b\u003e\u0026thinsp;C bond or aromatic π orbitals from the carbon core (π-π\u003csup\u003e*\u003c/sup\u003e transitions), and another peak at 350 nm that is due to n-π\u003csup\u003e*\u003c/sup\u003e transitions of C\u0026thinsp;=\u0026thinsp;O or C\u0026thinsp;=\u0026thinsp;N bond involving functional groups with electron lone- pair [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. In addition to the absorption peak at 215 nm, another shoulder peak is appeared around 230 nm. Typically, these absorption peaks are due to aromatic π system with extended conjugation as in the carbon dots structure. Thus, the peak around 230 nm can be related to π-π* transitions [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. As a result of trapping excited state energy at the surface states, the latter peak can be commonly attributed to in the highly fluorescent carbon dots [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. With respect to the existence of different groups on carbon dots surfaces, it can be suggested that each of these functional groups creates an energy level gap between the LUMO and HOMO orbitals. The water-soluble synthesized NBCDs were brownish and bright blue in color (inset in Fig.\u0026nbsp;1A) under day-light (left side) and UV-light (right side), respectively. The UV-Vis spectrum of CUR (dissolved in methanol, Fig.\u0026nbsp;1B) shows a weak peak at ~\u0026thinsp;240 nm corresponding to π-π\u003csup\u003e*\u003c/sup\u003e and a strong peak (as original peak) at ~\u0026thinsp;425 nm corresponding to n-π* transitions [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. According to Fig.\u0026nbsp;1B, the UV-Vis spectrum of NBCDs-CUR depicts two peaks at 215 and 340 nm with increased intensity compared to its corresponding peaks in carbon dots. Meanwhile, a blue-shift\u0026thinsp;~\u0026thinsp;10 nm (350\u0026rarr;340 nm) can be seen in the UV-Vis spectrum of NBCDs-CUR with respect to bare NBCDs spectrum (at 350 nm). Based on these spectra, a new additional peak was created at ~\u0026thinsp;275 nm at absorption spectrum of NBCDs-CUR. Thus, the changes in absorption peaks of NBCDs nanocarrier before and after loading with CUR drug were observed. These changes in the absorption spectra of carbon dots should be observed due to their interactions with CUR. In Fig.\u0026nbsp;1C, the PTX in methanol exhibit a strong peak at 225 nm that is due to π-π\u003csup\u003e*\u003c/sup\u003e transitions. So, the NBCDs-PTX conjugation exhibit two peaks at 215 nm and 340 nm.. With respect to Fig.\u0026nbsp;1C, the absorption peak of the NBCDs-PTX conjugate exhibits a 10 nm blue shift (225\u0026rarr;215 nm) and a decrease in intensity compared to the PTX spectrum. This is likely due to π-π stacking interactions between the π-groups of PTX and NBCDs. Additionally, an intense peak is observed compared to the NBCDs spectrum, accompanied by a 10 nm blue shift (350 \u0026rarr; 340 nm). This shift may result from interactions between electron lone pairs in PTX (e.g., the N in the -NH group) and functional groups of NBCDs (e.g., the B in the \u0026ndash;B(OH)₂ group), as well as their involvement in bond formation. Following PTX loading onto NBCDs and the formation of NBCDs-PTX, the shoulder peak at 230 nm (present in the NBCDs spectrum) disappears. The absorption spectra confirm that NBCDs could be successfully conjugated to both drugs. Also, the photoluminescence emitted spectra (Fig.\u0026nbsp;1D) of NBCDs were recorded at different excitation wavelengths (with 10 nm increment). The photoluminescence of NBCDs showed a maximum fluorescence intensity of NBCDs at 440 nm under an excitation wavelength of 360 nm. According to the previous studies, the emissive behavior of the carbon dots is immensely dependent on their surface functionalities [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. The fluorescence quantum yield (QY) of NBCDs and NBCDs-drug were measured by gradient method, according to Figures \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eA and S1B. The QY of NBCDs, NBCDs-CUR and NBCDs-PTX were obtained\u0026thinsp;~\u0026thinsp;60%, ~\u0026thinsp;21% and ~\u0026thinsp;57%, respectively. The fluorescence quenching of NBCDs can be explained by the spectral overlap between the absorption spectrum of the drug (CUR or PTX) with the excitation or emission spectra of NBCDs (Figure S2).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe FT-IR spectra related to drugs and NBCDs and drug-loaded NBCDs were demonstrated in Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eB. The FT-IR results of NBCDs, CUR, PTX and their conjugated products were listed in Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e and Table S2. Some of the prominent bands for NBCDs were existed in both drug-loaded carbon dots. The peak located at 1747 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e can be corresponded to C\u0026thinsp;=\u0026thinsp;O stretching vibration. The IR bands at 1081 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and 1342 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e are assigned the C\u0026ndash;B and B\u0026ndash;O stretching vibration modes, respectively [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The bonding of B\u0026ndash;O\u0026ndash;C or B\u0026ndash;O\u0026ndash;H deformation vibration or C\u0026ndash;O stretching vibration are supported by the absorption peak at around 1020 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The IR band at around 1237 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e is related to C\u0026ndash;N stretching vibration, showing that N atoms were successfully doped into NBCDs [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. The band at around 1554 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e is corresponded to N\u0026ndash;H bending vibration of amide groups. The peaks at around 3000 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e are related to ArC-H/ N\u0026ndash;H stretching vibration [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. In detail, the presence of a broad peak at around 3185 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and a peak at 798 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e can be a confirmation of the existence of primary amide groups on the carbon dots surface. Also, two peaks at 3185 and 3386 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e are indicated B-OH / -NH\u003csub\u003e2\u003c/sub\u003e and O-H groups, respectively. The excellent aqueous stability and hydrophilicity of NBCDs in water is due to many polar functional groups [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. The FT-IR spectrum of CUR (in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eA) was indicated absorption bands at 963 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (benzoate trans-CH vibration / C\u0026thinsp;=\u0026thinsp;C stretching benzene ring / O-H enolic in-plane bending), 1028 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (C\u0026ndash;O), 1274 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (C\u0026ndash;O\u0026ndash;C), 1433 and 1585 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (C\u0026thinsp;=\u0026thinsp;C stretching vibration), 2932 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (C\u0026ndash;H stretching, methyl ring), 3506 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (\u0026ndash;OH (phenolic) stretching) [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. After adding CUR to NBCDs, the B atom in the -B-OH functional groups on the surface of carbon dots can be conjugated to the enol / keto of the CUR, due to empty orbital of B atom. So, the bending vibration peak at 1183 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (B\u0026ndash;O\u0026ndash;H in carbon dot) and 1274 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (enol stretching in CUR) were disappeared after forming the six-membered in ring (Scheme S1). Also, after NBCDs-CUR formation (according to Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eA), the peaks at 1554, 1081 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (aromatic moiety of CUR) and 931 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (of NBCDs), were shifted to 1589, 1087 and 937 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, respectively. The removal of peaks at 1507, 1433 and 1274 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e related to CUR, after conjugating to carbon dots and existence of peak at 1399 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (as a sign for C\u0026thinsp;=\u0026thinsp;C stretching) in CUR and NBCDs can be a reason for conjugation between two parts. Indeed, after loading of CUR onto the NBCDs, we can see that peak at 1183 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (related to carbon dots) is disappeared, due to formation of NBCDs-CUR, that is due to removing B\u0026ndash;O\u0026ndash;H absorbance peak of carbon dots. Obviously, the 3386 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e peak of NBCDs is shifted to 3419 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e in NBCDs-CUR system, that it is again proved hydrogen bonding between CUR and NBCDs. In Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eB, for PTX drug, several characteristic peaks is observed at 3390 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (stretching of O-H), 2486 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (stretching of \u0026ndash;N-H), 2927 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (stretching of C-H), 1736 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and 1703 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (stretching of C\u0026thinsp;=\u0026thinsp;O carbonyl ketone), 1639 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (C\u0026thinsp;=\u0026thinsp;O amide stretching), 1432 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (CH2 scissoring mode), 1081 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (aromatic moiety or C-O stretching) and 614 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (bending of aromatic C-H bond) [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. After PTX loading onto NBCDs, the following peaks are indicated in FT-IR spectra of NBCDs-PTX: O-H and N-H stretching vibrations at 3442 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, -NH group of PTX at 2537 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and several peaks at 1641, 1441, 1408, 1102 and 609 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e were due to C\u0026thinsp;=\u0026thinsp;O stretching of NBCDs and PTX, CH\u003csub\u003e2\u003c/sub\u003e scissoring mode of PTX, C\u0026thinsp;=\u0026thinsp;C stretching, overlapping C-N stretching vibration of NBCDs with aromatic moiety vibration of PTX, respectively. So, these peaks confirm the successful loading of PTX on the NBCDs.\u003c/p\u003e\u003cp\u003eXRD analysis of NBCDs powder was also carried out. As observed in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eC, a broad amorphous peak was observed at 2θ\u0026thinsp;=\u0026thinsp;15\u0026deg;-27\u0026deg; in the XRD pattern for the prepared NBCDs, which confirms its graphitic nature and was consistent with previous reports. The presence of a sharp and high-intensity reflection at 2θ\u0026thinsp;=\u0026thinsp;28\u0026deg; along with several weak-intensity reflection, can possibly be related to the presence of nitrogen and cubic B\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003e according to the JCPDS card number 00-006-0297, in the peak list of Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eC. The inset in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003eC, shows the reaction of B\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003e formation from the boric acid at high pressure and temperature inside the autoclave.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eBased on the previous reports, carbon dots due to possess distinct optical and chemical properties allow us to (1) have optical properties compatible with living cells, (2) modify with suitable exogenous chemicals, and (3) be biocompatible and nontoxic [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Likewise, the high and stable fluorescent carbon dots can be a significant benefit for development of drug delivery systems. To study of photostability of the NBCDs, the fluorescence intensity of carbon dots was recorded at λ\u003csub\u003emax\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;360 nm (as excitation wavelength) and different time intervals. When NBCDs are used as a fluorescent nanocarrier, the stability index is an important factor for these purposes. According to Figure S3, it can be clearly seen that the fluorescence intensity or optical stability of carbon dots and drug-loaded carbon dots remains almost constant in different time intervals, after several weeks or with a slight decrease after several months. The decreased fluorescence intensity percentage of NBCDs-CUR was 2.1, 7.2, 17.1 and 25.1% after one week, one month, three and six months, respectively. Also, these values for NBCDs-PTX were 2, 3.8, 11 and 16.9%, respectively.\u003c/p\u003e\u003cp\u003eAccording to previous study, the analyses of Electron-dispersive X-ray spectroscopy (EDS), EDS layered image, X-ray photoelectron spectroscopy (XPS) and TEM image were performed to evaluate the percentage of constituent elements and morphology of NBCDs [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The results confirms the successful formation of \u0026ndash;COOH, \u0026ndash;OH, \u0026ndash;NH\u003csub\u003e2\u003c/sub\u003e, and \u0026ndash;B(OH)\u003csub\u003e2\u003c/sub\u003e functional groups on the surface of semi-spherical NBCDs [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. To study the stability (or photostability) properties of the produced dispersion, zeta potential is an important index. Therefore, it can be understood that the lower absolute value of zeta potential, more particles agglomerate [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. In this work, zeta potential analyses of the NBCDs and conjugated with drugs (in water and PBS) were carried out according to Figure S4 (A-F) and Table S3. The analysis of zeta potential results and salt bridge effect in buffer are fully explained in the Supplementary Information. Dynamic light scattering (DLS) analysis was also carried out. As illustrated in Figure S5, the particle size distribution of 14.5, 65.4 and 37 nm were corresponded to NBCDs, NBCDs-CUR and NBCDs-PTX, respectively. These changes in the size of the carbon dots under the same conditions can prove the loading of the drug on the surface of the carbon dots. Other evidence of CUR and PTX presence in drug-loading NBCDs is proton nuclear magnetic resonance spectroscopy (\u003csup\u003e1\u003c/sup\u003eH-NMR), along with other techniques. The \u003csup\u003e1\u003c/sup\u003eH-NMR of NBCDs (Figure S6A), CUR (Figure S6B), NBCDs-CUR (Figure S6C), NBCDs-PTX (Figure S6D), and PTX (Figure S6E), were recorded in dimethyl sulfoxide-d\u003csub\u003e6\u003c/sub\u003e (DMSO-d\u003csub\u003e6\u003c/sub\u003e) as solvent and tetramethylsilane (TMS) as internal standard. The \u003csup\u003e1\u003c/sup\u003eH-NMR analysis results are fully explained in the Supplementary Information. The summary of the results of \u003csup\u003e1\u003c/sup\u003eH-NMR study is listed in Table S4.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDrug Loading onto the NBCDs Nanocarrier.\u003c/b\u003e The adsorption of selected drugs onto NBCDs is through the interactions such as van der Waals force, electrostatic attraction, π-π stacking and hydrophobic interaction [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. After deprotonation of carboxylate groups onto the NBCDs at pH\u0026thinsp;~\u0026thinsp;7.4, hydrogen bond between CUR (as hydrogen bond donor) and carbon dots (as hydrogen bond acceptors) can be formed [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Conjugation of PTX with NBCDs is created through the formation a amide bonding by the reaction between amino groups of NBCDs and carboxyl groups of PTX [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], that is sensitive to acidic medium. To study of conjugation of NBCDs with CUR, maximum ratio between two parts was firstly estimated. Thus, the different concentrations of NBCDs (0.002\u0026ndash;0.03 mg/mL) were gradually added to the constant concentration of dissolved CUR in methanol (0.02 mg/mL), and the process of complex formation between CUR and carbon dots was followed by recording the absorption spectra variations after each addition. In Figure S7A, the gradual addition of NBCDs, induced a progressive decrease the absorption intensity of NBCDs-CUR complex at ~\u0026thinsp;400\u0026ndash;440 nm and a progressive increase at ~\u0026thinsp;210\u0026ndash;350 nm. Based on results, the maximum ratio between CUR and NBCDs ([NBCDs]:[CUR]) is achieved at 1:1 (w/w) ratio.\u003c/p\u003e\u003cp\u003eAlso, for studying of conjugation between the NBCDs and the PTX (as a hydrophobic anticancer drug model) the different concentrations of NBCDs (0.001\u0026ndash;0.018 mg/mL) were gradually added to the constant concentration of dissolved PTX in methanol (0.024 mg/mL), and the process of complex formation between PTX and NBCDs was followed by UV-Vis spectrophotometric method (see Figure S7B). The gradual addition of NBCDs, induced a progressive decrease the absorption of PTX-NBCDs complex at ~\u0026thinsp;220\u0026ndash;230 nm and a progressive increase at ~\u0026thinsp;250\u0026ndash;450 nm, respectively. Thus, the maximum ratio between PTX and NBCDs ([NBCDs]:[PTX]) achieved at 1:3 (w/w) ratio. These results is also exhibited that there are strong interactions between the graphitic carbon cores or functional groups in the NBCDs with the aromatic moiety of drugs (CUR or PTX) which leads to changes in their absorption spectra.\u003c/p\u003e\u003cp\u003eLikewise, the residual pellet was dissolved in a known amount of methanol and thus, free CUR concentration was calculated by a standard curve (see Figure S8A). Therefore, the percentage of drug loading capacity (LC%) and adsorption efficiency (AE%) of CUR onto the NBCDs is calculable, so that, a value of 67% was obtained for each parameter. According to the definition, adsorption efficiency is defined as the amount of drug adsorbed/entrapped onto the NBCDs to the total amount of drug added (Eq.\u0026nbsp;1) whereas about the loading capacity (LC) of drug, it can be expressed as the amount of drug loaded per unit weight of the NBCDs (Eq.\u0026nbsp;2). For CUR drug, the drug loading capacity on the NBCDs was calculated by CUR standard curve (see Figure S8A). The same steps were performed for calculation of loading capacity of PTX drug on the NBCDs, by using calibration curve (according to Figure S9A) and absorption spectrophotometric method at 225 nm. Finally, the LC% and AE% were calculated for carbon dots and PTX, which were equal to 28.8% and 86.5%, respectively.\u003c/p\u003e\u003cp\u003e\u003cb\u003epH-Dependent Release Kinetic Models.\u003c/b\u003e By using release kinetic models, some important physical parameters (such as drug diffusion coefficient) are measured. It is very important to know how to use these equations to understand the different factors that affect the dissolution behaviors. According to some literatures, the drug release from a released system can be controlled by various methods, such as diffusion, dissolution, osmosis, partitioning, swelling and erosion. For example, the diffusion method of the active agent is a strong function of the structure such as the polymer morphology [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. As depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e, the released patterns of CUR, PTX, NBCDs-CUR and NBCDs-PTX were investigated in the buffer at pH 5.0 and 7.4 as release medium in a controlled manner, as simulated cancer cell environment and normal cell environment by a dialysis bag method. On the basis of obtained results of CUR release (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003eA), the enhanced drug release under acidic conditions (pH 5.0) is maybe due to protonation of boron atom in the formed six-membered ring. In fact, the six-membered ring between the keto-enol groups of CUR and the boron hydroxyl (\u0026ndash;B(OH)\u003csub\u003e2\u003c/sub\u003e) groups on the surface of carbon dots (according to Scheme S1) that is opened under acidic conditions. Therefore, the enhanced CUR release at acidic pH is a desirable property to elicit its therapeutic effect in the tumor environment. The lower release rate of CUR at pH 7.4 compared to the pH 5.0 can be attributed to the stronger association between CUR and NBCDs at the pH 7.4 condition. The initial CUR release of NBCDs-CUR (in the first 10 h) was found to be ~\u0026thinsp;14 and 10% at pH 5.0 and pH 7.4, respectively. The above feature is one of the practical importance for clinical therapy, because both extracellular (tumor tissues) and intracellular (endosome/lysosome) medium have low pH (pH\u0026thinsp;\u0026le;\u0026thinsp;5) [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. After 72 h, the total cumulative CUR release (%) from the NBCDs-CUR was determined to be ~\u0026thinsp;54% at pH 5.0 and ~\u0026thinsp;40% at pH 7.4. Likewise, PTX was selected as a hydrophobic drug model for conjugation to NBCDs via π-π stacking (as hydrophobic interaction), dative bond between \u0026ndash;NH- (amine group) of PTX (with electron lone-pair) and B of \u0026ndash;B(OH)\u003csub\u003e2\u003c/sub\u003e group on the carbon dots surface (with empty orbital), hydrogen bonding between the \u0026ndash;NH group of NBCDs and \u0026ndash;COOH of PTX and vice versa, according to Scheme S1B. Also, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003eB shows the cumulative release of PTX (%) from NBCDs at different pH values. The PTX release (like to CUR release) possess pH-dependent kinetics. Also, a nonlinear release profile (as a similar feature) was observed for both drug-loaded NBCDs and both pH conditions. Initial burst release of drug from NBCDs-PTX occurred during the first 5 h, so that ~\u0026thinsp;23% and ~\u0026thinsp;25% of PTX was released from NBCDs-PTX at pH 5.0 and pH 7.4, respectively. After 72 h, the total cumulative PTX release (%) from the NBCDs-PTX was determined to be ~\u0026thinsp;80% at pH 5.0 and ~\u0026thinsp;55% at pH 7.4. The sampling of drug release medium was performed at different time intervals (up to 72 h), so that 2 mL from release medium was taken, and replaced with 2 mL from fresh medium. Then, the absorbance of the released medium was measured at 225 nm through the calibration curve of PTX in PBS\u0026thinsp;+\u0026thinsp;0.5% (v/v) tween 80, according to Figure S9B. The higher release rate of PTX at acidic pH, may be explained by protonation of both amine groups (in PTX and NBCDs surface) and boron hydroxyl/ carboxylate groups (in the NBCDs) which leads to a decrease in the electrostatic interaction between PTX and carbon dots [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. In general, the experimental models of release were compared with default well-known models in the software.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAccording to Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the correlation coefficient (R\u003csup\u003e2\u003c/sup\u003e) of each model was evaluated to fit the accuracy of the proposed statistical models by the utilized software. In the present study, for any drug and under any pH condition, the higher R\u003csup\u003e2\u003c/sup\u003e (\u0026gt;\u0026thinsp;0.96) values of the Hill, Weibull, Higuchi and Korsmeyer-Peppas models suggest that the drug release kinetics from the nanocarrier, follows the corresponding kinetic model [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. As an example, Figure S10 indicate the proposal release models of CUR from the NBCDs at pH\u0026thinsp;=\u0026thinsp;5.0 against time (h), by using software. The experimental data and fitting curve were displayed in these plots.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eKinetics models and R\u003csup\u003e2\u003c/sup\u003e-values for analysis of cumulative drug (CUR or PTX) release from NBCDs nanocarreir (as output data of KinetDS3.0 software).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eRelease Model\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCUR (pH 5.0)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCUR (pH 7.4)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePTX (pH 5.0)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePTX (pH 7.4)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHill\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.9895\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9893\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.9340\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.9836\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWeibull\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.9857\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9864\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.9355\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.9805\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHiguchi\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.9617\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9523\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.9729\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.3502\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKorsmeyer-Peppas\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.9794\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9824\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.9708\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.9738\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHikson- Crowell\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.6990\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.7043\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.7244\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.6692\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eBesides output results of software listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the Korsmeyer-Peppas model was plotted for any drug and for each condition (see Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e). This model not only can be used to predict the drug release mechanism from a polymeric system, but also it superpose diffusion and swelling as independent mechanisms of releasing [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. This model is obtained by plotting the log of cumulative drug release (%) against the log of time (h) and M\u003csub\u003et\u003c/sub\u003e/ M\u003csub\u003e\u0026infin;\u003c/sub\u003e, K\u003csub\u003eKP\u003c/sub\u003e, and n represent the fractional drug release, the Korsmeyer-Peppas rate constant, and release exponent, respectively. Noticeably, to find out the size of n, M\u003csub\u003et\u003c/sub\u003e/ M\u003csub\u003e\u0026infin;\u003c/sub\u003e \u0026lt; 0.6 should only be used. The size of n characterizes the mechanism of the drug release and the value of it demonstrates that drug release is controlled by diffusion (Fickian model, case I), if n\u0026thinsp;=\u0026thinsp;0.5 or by swelling (non-Fickian model, case II), if n\u0026thinsp;=\u0026thinsp;1. When n\u0026thinsp;=\u0026thinsp;1, drug release rate corresponds to zero-order release kinetics, but when 0.5\u0026thinsp;\u0026lt;\u0026thinsp;n\u0026thinsp;\u0026lt;\u0026thinsp;1, the model is non-Fickian model or anomalous transport. Finally, if n\u0026thinsp;\u0026gt;\u0026thinsp;1, the Super Case II model is characterized, constituting an extreme form of drug transport, so that in this state tension and breaking of the polymer occur [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. The preferred Korsmeyer-Peppas model is most complex among the selected empirical models because they integrate different release mechanisms [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. To better understand the interaction of drugs with carbon nanocarriers, the structure of drugs (A: CUR and B: PTX) is shown in Figure S11. Based on the Figure S11 and Scheme S1, the existence of the different functional groups can be formed different bonds between the drug and carbon dots (such as hydrogen bonding, π-π stacking, dative bonding, and imine bond between the C\u0026thinsp;=\u0026thinsp;O groups of CUR and NH\u003csub\u003e2\u003c/sub\u003e groups of NBCDs and etc.).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eIn summary, highly fluorescence boron and nitrogen co-doped carbon dots were synthesized by hydrothermal method and used as a suitable nanocarrier for curcumin and paclitaxel as hydrophobic drug models. Chemotherapeutic drugs, can be conjugated to the carbon dots through covalent bonding by functional groups or other non-covalent interactions like π-π stacking, electrostatic and also hydrogen bond and so on. After attaching the drug to the carbon dots, the capacity of drug loading and adsorption efficiency (67.65% for CUR, 28.83 and 86.5% for PTX) and release (CUR (pH 5): 54%, CUR (pH 7.4): 40%, PTX (pH 5): 80% and PTX (pH 7.4): 55%) were determined. The higher release efficiency of drug at pH 5.0 implies that prepared NBCDs-drug nanoconjugates possess the selective capability of drug release under acidic conditions as a unique feature of NBCDs-drug, which can enhance their ability in anticancer therapy. Consequently, the prepared nanoconjugates can enter to cancer cells and drugs be released under acidic environment of the tumor and act as an effective therapeutic agent.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003edeclaration\u003c/p\u003e\u003cp\u003eThis work was supported by University of Kashan.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eSeyed Mostafa Jafari: Methodology, Investigation, Visualization, Writing original draft. Saeed Masoum: Conceptualization, Methodology, Validation, Resources, Review \u0026amp; editing, Supervision, Project administration. Elahe Seyed Hosseini: Methodology, Validation, Review \u0026amp; editing, Supervision.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eThe authors are grateful to the University of Kashan for supporting this work by Grant NO 1311478/3.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe authors confirm that the data supporting the findings of this study are available within the article. Data can be provided by the authors upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eX. Han, J. Chen, M. Jiang, N. Zhang, K. Na, C. Luo, R. Zhang, M. Sun, G. Lin, R. Zhang, Y. Ma, D. Liu, Y. Wang, Paclitaxel-Paclitaxel Prodrug Nanoassembly as a Versatile Nanoplatform for Combinational Cancer Therapy, ACS Appl. Mater. Interfaces 8 (2016) 33506\u0026ndash;33513. https://doi.org/10.1021/acsami.6b13057.\u003c/li\u003e\n\u003cli\u003eT. Pal, S. Mohiyuddin, G. 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Kamaly, Meta-analysis of in Vitro Drug-Release Parameters Reveals Predictable and Robust Kinetics for Redox-Responsive Drug-Conjugated Therapeutic Nanogels, ACS Appl. Nano Mater. 4 (2021) 4256\u0026ndash;4268. https://doi.org/10.1021/acsanm.1c00170.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Carbon dots, Nanocarrier, Anticancer drug, Curcumin, Paclitaxel, Drug release models","lastPublishedDoi":"10.21203/rs.3.rs-7731800/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7731800/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn recent years, carbon dots have attracted a lot of attention among the nanocarbon family, due to their remarkable benefits and interesting properties like solubility, biocompatibility, tunable photoluminescence, and so forth. We can also design and synthesize carbon dots according to the capabilities that we expect from them (such as sensors, biosensors or drug delivery systems). In the current study, nitrogen and boron co-doped carbon dots (which is abbreviated as \"NBCDs\") were successfully used as efficient highly fluorescent nanocarrier to load two types of hydrophobic anticancer drugs including curcumin (CUR) and paclitaxel (PTX). The NBCDs were studied before and after conjugation with CUR and PTX drugs by spectroscopic techniques. After calculating drug loading capacity (LC%) and adsorption efficiency (AE%) for NBCDs nanocarriers, the drug release behavior from NBCDs was studied against two buffers (pH 5.0 and pH 7.4) as release media by dialysis bag method for 72 h. Finally, the pH-dependent release behavior of drugs was studied using several kinetic models.\u003c/p\u003e","manuscriptTitle":"pH-Responsive Delivery of Hydrophobic Anticancer Drugs Using Boron and Nitrogen Co-Doped Carbon Dots as Fluorescent Nanocarriers","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-20 05:20:29","doi":"10.21203/rs.3.rs-7731800/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-27T07:39:50+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-26T07:05:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-22T12:29:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"94367713801495407344131936425336822921","date":"2025-10-16T01:44:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-13T08:05:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"179845416781524036494318853764175796805","date":"2025-10-13T06:37:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-13T05:43:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"116721448226733654075015460129776074279","date":"2025-10-13T05:08:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"87269833361180566312705558420644351257","date":"2025-10-07T08:06:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"203424734545722718106387285687870561700","date":"2025-10-07T08:03:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-07T07:26:30+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-06T16:52:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-03T08:51:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-03T01:56:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-09-28T05:06:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"62d56a45-fb2f-4c68-a446-253af793eb93","owner":[],"postedDate":"October 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":56455618,"name":"Biological sciences/Biochemistry"},{"id":56455619,"name":"Biological sciences/Biotechnology"},{"id":56455620,"name":"Biological sciences/Cancer"},{"id":56455621,"name":"Physical sciences/Chemistry"},{"id":56455622,"name":"Biological sciences/Drug discovery"},{"id":56455623,"name":"Physical sciences/Materials science"},{"id":56455624,"name":"Physical sciences/Nanoscience and technology"}],"tags":[],"updatedAt":"2026-05-20T06:08:07+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-20 05:20:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7731800","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7731800","identity":"rs-7731800","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}