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. 2024 Mar 6;9(11):12575–12584. doi: 10.1021/acsomega.3c06252

Synthesis and Characterization of Carbon-Based Quantum Dots and Doped Derivatives for Improved Andrographolide’s Hydrophilicity in Drug Delivery Platforms

Nataniel Medina-Berríos †,‡,*, Wenndy Pantoja-Romero †,‡, Alexis Lavín Flores †,‡, Sebastián C Díaz Vélez †,‡, Anna C Martínez Guadalupe ‡,§, Mariana T Torres Mulero ‡,§, Kim Kisslinger ⊥, Magaly Martínez-Ferrer #,∇, Gerardo Morell ‡,∥, Brad R Weiner †,‡
PMCID: PMC10955586  PMID: 38524434

Abstract

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Carbon-based quantum dots (CBQDs), sulfur-doped carbon-based quantum dots (S-CBQDs), and nitrogen-doped carbon-based quantum dots (N-CBQDs) have strong potential for drug delivery platforms. They were conjugated with andrographolide, a well-known hydrophobic drug, to study the concomitant changes in hydrophilicity. The interactions between these nanomaterials and the drug were studied by characterizing the optical and structural properties of the nanoparticles before and after coupling with the drug. It was found that the interaction of the drug with these nanomaterials produced noticeable changes in their optical and structural properties. Moreover, the partition coefficient for the nanocomposites was determined by NMR. The results indicate that conjugating the drug with the nanoparticles significantly enhanced its affinity for the aqueous phase, from 2.632 to 0.1117, thereby opening the possibility of using this approach for developing an effective drug delivery platform for this hydrophobic drug.

1. Introduction

Andrographolide (ADG), a bicyclic diterpene-g-lactone found in the plant Andrographis Paniculata, possesses multidimensional therapeutic potential, e.g. anti-inflammatory, anti-HIV, and anticancer properties.1 Among its anticancer properties, it has been shown that ADG sensitizes prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand2 (TRAIL)-induced apoptosis.3 However, ADG is known to have low solubility in water (74 μg/mL), which limits its therapeutic use because of low bioavailability when administered orally.4 Andrographolide’s bioavailability, the proportion of a drug that reaches the systemic circulation in its active form5, has been found to range from 1 to 2%.6,7 As a result, a variety of methods have been studied to increase this bioavailability, as well as improve the solubility of ADG in water.8−10

There are a variety of methods to improve the solubility, including nanoparticles (NPs), liposomes, nanoemulsions (NE) or microemulsions (ME), cyclodextrins, microspheres, solid dispersions, and manipulation of the particle size distribution. Cyclodextrins (CDs) are cyclic oligosaccharides with a hydrophilic outer shell and a lipophilic cavity in the center. The α, β, and γ are the three most used forms of CDs.11 Ren et al.12 prepared an AND/HP-β-CD complex by solvent evaporation and characterized it by the phase solubility method. It showed that the solubility of ADG increased linearly as a function of HP- β-CD concentration, resulting in an AL-type phase solubility diagram. However, the parenteral administration of cyclodextrins can cause nephrotoxicity and hemolysis.13 In another study, an oil-in-water (O/W) ME loaded with ADG was developed by using isopropyl myristate, Tween 80, ethanol, and water. The solubility of ADG in this (O/W) ME was 8.02 mg/mL, 2 orders of magnitude higher than the solubility of ADG in water (74 μg/mL).14 Nonetheless, a suitable ADG carrier/delivery system has not yet been developed.

Nanoparticle-based drug delivery systems have shown promise in cancer treatments because they increase drug performance via improved pharmacokinetics and biodistribution characteristics.15 Improvement of drug delivery is possible because nanoparticle-based carriers can be adjusted to meet specific needs, such as spatial and temporal control of drug delivery and release, which improves medication efficacy. Nanocarriers may be designed to actively bind to specific cells by attaching targeting agents, such as ligands, to the surface of the nanoparticle. Most nanoparticles are engulfed through endocytosis and travel to endo/lysosomal compartments, which contain an acidic environment (pH = 4.5–5.5) compared to the extracellular environment (pH = 7.4). Since some cancerous cells have acidic properties, pH can act as an internal parameter for the design of a drug delivery system that may release drugs inside tumor cells, resulting in a significant improvement in the drug’s bioavailability.16 Carbon Based Quantum Dots (CBQDs) are zero-dimensional nanoparticles defined as graphene sheets with lateral dimensions less than 100 nm and thickness of fewer than 10 layers.17 They have applications in optoelectronics, organic photovoltaics, electronic devices, catalysts, electrochemistry, ion sensing, and bioimaging.18 CBQDs exhibit size-dependent luminescence19, high photo/pH-stability, high quantum efficiency, and chemical inertness compared to semiconducting quantum dots.20−22 Due to these properties, CBQDs are excellent candidates as multifunctional drug delivery platforms.23−26 Nonmetal heteroatom doping with atoms of similar size to carbon to produce doped CBQDs (D-CBDQs) has been used as a strategy to tailor the properties of the particles by changing their electronic structure. This similarity in size to carbon atoms produces uniform doping and structural defects.27 Compared with undoped CBQDs, doped-CBQDs with highly electronegative atoms (e.g., N and S) usually cause blue-shifted emission; however, those doped with atoms of low electronegativity (like P, B, and Se) result in a red-shifted emission.27 These changes in λmax of the luminescence toward the blue or red of the visible spectra occur because nonmetal heteroatom doping at specific sites can introduce more defect states and energy levels. This, in turn, alters the band gap of the D-CBQDs and produces strong fluorescence due to quantum confinement and edge effects.28

CBQDs can act as carrier probes for the therapy of cancer cells. In past reports, Doxorubicin (DOX) has been successfully loaded onto CBQDs as a trackable pH-sensitive biocompatible nanoparticle drug delivery system16, and further insights into CBQDs for DOX delivery have been studied in loading capacity, cytotoxicity on MCF-7 breast cancer cells, and drug conjugation characterizations.29

A molecular dynamics simulation and free energy calculation study modeled the drug delivery process through the cell membrane using CBQDs of different sizes using doxorubicin and deoxyadenosine as model drugs.30 The results suggest that the drug delivery process to the cell assisted by CBQDs involves a reduction of translocation-free energy permeating into the cell membrane. Due to the strong interaction between lipids and the CBQDs, the drugs were likely stabilized in the lipid membrane. The decrease in the translocation-free energy in the permeation process is thought to be because the CBQDs may protect the polar area of the drug from interactions with the hydrophilic heads of the lipids.30 These properties of CBQDs are the basis of the work reported here, in which nanoparticles are investigated as potential drug delivery platforms to help solubilize ADG in water.

An important initial step in the assessment of a nanoparticle for drug delivery is understanding the hydrophilicity of the conjugated drug nanoparticle system. The partition coefficient between 1-octanol and water (log P) is the common way of measuring the lipophilicity of a compound of pharmaceutical interest. In addition to the log P, there is the distribution coefficient (log D), which describes the lipophilicity of ionizable compounds. If the compound is not ionizable, log P and log D should be around the same value.31 The higher the value, the more lipophilic the molecule is.32 Since ADG has a high reported log P (2.632 ± 0.135)33 and a log D at pH 7.4 of 1.4,34 it is an ionizable molecule that is considered lipophilic. The log P may also serve as a comparison of the hydrophilicity of ADG before and after it has been modified or loaded into a drug delivery system. Nuclear magnetic resonance spectroscopy (NMR) has been previously used to determine this log P value in many molecules.35−37 This method is particularly useful since it utilizes a sensitive technique and enables the processing of many samples in a short period of time with a small amount of sample. This procedure enabled us to assess the changes in ADG’s log P when coupled with the CBQDs and D-CBQDs. Literature results of ADG solubility improvement sometimes mention the log P of the drug and/or the nanosystem alone but not how it changes after drug loading is done.38−41 The General Solubility Equation (GSE) is a reliable method for predicting the molar aqueous solubility (Sw) for nonelectrolytes42 and helps to establish possible trends with its estimates. To the best of our knowledge, this article shows the first measurement and comparison of the log P of a nanoformulation for ADG after drug loading versus the value of the drug alone.

2. Results and Discussion

2.1. Transmission Electron Microscopy (TEM)

The morphologies of CBQDs, N-CBQDs, and S-CBQDs were characterized using HR-TEM (Figure 1) As illustrated in the TEM images, the CBQDs show a monodisperse and spherical distribution with an average diameter of 3.2 ± 0.1 nm (Figure 1a). The doped N-CBQD nanocomposites (Figure 1b) are dispersed and have a uniform morphology with an average edge length of 3.3 ± 0.1 nm. Nitrogen’s atomic radius is less than the size of the carbon atom, which is consistent with nitrogen doping not influencing the interplanar distance as shown in the XRD patterns (Figure 2). The TEM images of S-CBQDs nanocomposites show nonhomogeneous morphologies with an average diameter of 4.0 ± 0.1 nm. The sulfur atom is larger than N and C and may influence the size of the nanocomposite (Figure 1c). The small size of CBQDs may be attributed to the fact that when synthesizing the CBQDs at pHs lower than 10, the presence of hydroxyl groups hinders the aggregation of the carbon nanoparticles.43 The coupling of ADG in hybrid composites denotes an increased size associated with the presence of the drug. The average in CBQDs -ADG is 3.6 ± 0.1 nm due to the same planar coupling of the ADG (Figure 1d), and the average diameters of N-CBQDs-ADG and S-CBQDs-ADG were 17.5 ± 0.4 and 125 ± 0.8 nm, respectively (Figure 1e,f). The drug coupling caused a noticeable size distribution change.

Figure 1.

Figure 1

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HR-TEM image and histogram (inset) of (a) CBQDs, (b) N-CBQDs, (c) S-CBQDs, and (d) CBQDs-ADG.

Figure 2.

Figure 2

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XRD pattern comparison of (a) CBQDs-ADG, ADG, and CBQDs, (b) NCBQDs-ADG, ADG, and NCBQDs, and (c) SCBQDs-ADG, ADG, and SCBQDs.

The elemental studies with EDS mapping confirm the coupling with N, S, and ADG in the CBQDs sheets (Figures S1–S6). The selected area electron diffraction (SAED) patterns of CBQD represent the characteristic graphite planes (002), (100), and (101) (Figure S7). The shifted peaks and broadness as compared with graphite/CBQDs patterns are attributable to the quantum dots’ small size and high crystallinity (Figure S7).44−46 The high crystallization degree of GQDs suggests their high thermal stability.47

2.2. Powder X-ray Diffraction Studies

The crystal structure was studied by PXRD patterns of the synthesized CBQDs nanocomposites and the hybrid with ADG. Figure 2 shows a comparison of CBQD, ADG, and doped-CBQD-ADG. It is noted that the CBQD has the characteristic graphite planes (002), (100), and (101), whereas ADG presents its characteristic planes (002), (100), and (012) at 10°, 11.9°, and 15°, respectively. However, CBQD-ADG presents new peaks in the region from 0° to 10°, also with characteristic graphite planes. It is worth noting that this can be attributed to the form in which the drug is coupled to the CBQD, generating new planes in the XRD (Figure 2a). In addition, doping CBQD with a hydrophobic drug like ADG most likely creates polar functional groups that are able to interact with the functional groups of ADG through electrostatic, H-bonding, and/or π–π stacking interactions. Such interactions increase the adsorption energy of the drug on the carrier surface. It can be seen in N-CBQD-ADG and S-CBQD-ADG XRD profiles (Figure 2b, c) that the characteristic signals from ADG are suppressed. This can be explained by the ADG arranged in a parallel orientation with respect to the doped-CBQDs’ surface.

2.3. NMR Studies for Interaction of ADG with CBQDs and D-CBQDs

1H and 13C NMR methods were used to characterize and compare CBQDs, doped-CBQDs, and the starting reagents such as CA and 3-MPA (Figures S8–S15). New signals were observed in both 1H NMR and 13C NMR spectra when comparing the CBQDs and doped-CBQDs with CA, particularly around 1.5–3.5 and 5.5–6.0 ppm in the 1H NMR spectra and around 80 and 165–180 ppm in the 13C NMR spectra (Figure 3). The 1H NMR signals around 1.5–2.6 ppm in the products are consistent with Ph–CH2–CH3, a group that is not present in CA. The 13C NMR signals around 120–140 ppm indicate the formation and presence of aromatic compounds in all the products, and those around 180 ppm present in both the reactants and the products are consistent with carboxylic acids. When 3-MPA acid was compared to the S-CBQDs, none of the reactant signals were observed in both 1H NMR and 13C NMR, indicating its consumption during the reaction and its absence in the product. N-CBQDs were not compared with ammonium chloride since the protons in ammonium chloride do not appear for a 1H NMR spectrum in D2O, due to rapid H/D exchange, and it possesses no carbons for a 13C NMR spectrum. It was determined that there were no reactive residues present in the synthesized products after the purification process.

Figure 3.

Figure 3

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(a) Stacked 13C NMR of CBQDs and (b) citric acid in D2O.

New signals and splitting patterns were observed between the CBQDs and the doped-CBQDs. When comparing the CBQDs with the S-CBQDs (Figures S9, S10, S13, and S14), an upfield shift was observed in both the 13C NMR and 1H NMR spectra. This shift was likely due to the S atom being less electronegative than C, creating a shielding effect.48,49 In the 1H NMR spectra, a new signal was observed around 7.27 ppm, indicative of a benzothiophene group. In the 13C NMR spectra, new signals were observed at around 15–40 ppm, consistent with the formation of thioesters. There was a change in splitting patterns for the signals around 130 ppm, regions where benzothiophenes and phenanthrene-like groups signals are found. A different splitting pattern was observed around 6.52 ppm, most likely caused by the integration of a pyrrole group, known to happen in N-CBQDs.50−52 In the 13C NMR spectra, a different splitting pattern was observed around 40 ppm, the characteristic of amines.53

1H and 13C NMR analyses were done to assess the coupling between the CBQDs and D-CBQDs with ADG. Signals observed when comparing the CBQDs and D-CBQDs spectra with the CBQD-ADG and D-CBQD-ADG loaded spectra in both 1H and 13C NMR spectra confirmed the ADG loading (Figures S17–S19 and S21–S23). CBQD-ADG’s 1H NMR and 13C NMR spectra were compared with CBQD’s and ADG’s spectra (Figures S9, S10, S11, S13, S14, S15, and S16–S23). In the 1H NMR spectra, shifts and splitting pattern changes were observed around 0.65–0.99 ppm; these two signals were present in ADG and CBQD spectra, respectively. Other shifts were observed around 1.77 ppm, a signal present in ADG spectra, and 6.28 ppm, a signal present in CBQD spectra. New signals were observed on CBQD-ADG’s 1H NMR around 8.40–8.61 ppm, indicative of aromatic groups. In the 13C NMR spectra, new signals were observed at around 16.85 and 57.45 ppm. The rest of the signals observed correspond to the CBQDs. The changes in signals observed from both starting compounds in CBQD-ADG suggest the successful loading of ADG onto CBQDs.

The 1H NMR and 13C NMR spectra for N-CBQD-ADG were compared with the 1H NMR and 13C NMR spectra for N-CBQDs and ADG (Figures S19, S23, S11, S15, S16, and S20). New signals were observed around 0.98 3.27, 3.64, and 3.95 ppm. Changes in splitting patterns were observed around 1.10, 1.17, 3.43, 3.69, and 4.13 ppm, while shifts were observed around 1.17 and 5.64 ppm when compared with the 1H NMR spectra for N-CBQDs. Splitting pattern changes were observed around 3.33 and 3.58 ppm, while shifts were observed around 8.38 ppm when compared with the 1H NMR spectra of ADG. When comparing N-CBQD-ADG and ADG 13C NMR spectra a shift was observed around 16.80 ppm, and new signals were observed around 57.43 ppm.

The 1H NMR and 13C NMR spectra for SCBQD-ADG were compared with the 1H NMR and 13C NMR spectra for S-CBQDs and ADG (Figures S18, S22, S10, S14, S16, and S2). For the 1H NMR spectra of S-CBQDs, new signals were observed around 6.26, 6.73, 6.89, 7.07, 7.17, and 8.11 ppm. Shifts were observed around 0.04, 2.85, and 5.77 pm. When compared with the 1H NMR spectra of ADG, a shift was observed around 5.77 ppm. Upon comparison of S-CBQD-ADG, S-CBQD, and ADG 3C NMR spectra, new signals were observed around 13.14, 18.81, 139.07, 169.30, 176.67, and 198.44 ppm. Shifts were observed around 33.18, 43.21, 73.22, and 168.53 ppm when comparing with S-CBQD. 13C NMR spectra and shifts around 62.10, 63.09, and 130.48 ppm were observed when comparing with ADG 13C NMR spectra (Figure 4).

Figure 4.

Figure 4

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Stacked 13C NMR of (a) andrographolide in DMSO-d6, (b) SCBQD-ADG in D2O, and (c) S-CBQDs in D2O.

The presence of CBQD and DCBQD signals along with ADG signals in the CBQD-ADG and D-CBQD-ADG 1H NMR and 13C NMR spectra indicate the successful loading of ADG onto the quantum dots. The change in splitting pattern, the appearance of new signals, and the disappearance of certain signals evidence the coupling interaction between ADG and the CBQDs and D-CBQDs.

2.4. Partition Coefficient and GSE Results

The NMR log P measurements were done in triplicate and reported as an average with the standard deviation. Figure 5 shows an example of an NMR partition coefficient test using a selected signal normalized to the D2O peak. Results are summarized in Table 1. ADG’s results showed to be closer to the documented log D value (1.4 at pH 7.4). Coupling with CBQDs and D-CBQDs showed a significant decrease in lipophilicity. CBQDs showed the most improvement in solubilizing ADG, followed by S-CBQD and finally N-CBQD. The differences in performance in solubilizing ADG between the doped and undoped nanoparticles are deduced to be because of the differences in surface defects.

Figure 5.

Figure 5

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Example of an NMR partition coefficient test using a selected signal normalized to the D2O peak. Corresponds to Replica 3 in Table 1. (A) ADG in D2O and (B) ADG in D2O after 1-octanol addition and 1 h of equilibrium.

Table 1. Results for Log P Tests by the NMR Method.

material x̅ SD
ADG 1.1064 0.0189
CBQD 0.1927 0.0262
CBQD-ADG 0.1117 0.0513
S-CBQD –0.6138 0.1047
SCBQD-ADG 0.2142 0.4029
N-CBQD 0.7594 0.1584
NCBQD-ADG 0.7775 0.0495
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Table 2 summarizes the improvements in ADG’s hydrophilicity in terms of concentration, while Table 3 shows GSE results to estimate water solubility. It can be noted that CBQD-ADG and SCBQD-ADG nanocomposites have a higher average concentration of ADG related to that of NCBQD-ADG left in water. GSE results show that there was over 331.36 times increase in water solubility for ADG with CBQDs, 261.70 times with S-CBQDs, and 71.53 times with N-CBQDs when compared with ADG’s Sw using its log P from literature for the GSE.33 Yen et al. reported the solubility of ADG in α-tocopherol as 2.51 ± 0.25 mg/mL, using nanoemulsion as a strategy for improving the oral bioavailability and solubility for ADG.54 On the other hand, Du et al.14 used a microemulsion to improve the solubility of ADG, obtaining a solubility value of 8.02 mg/mL. Compared to the results mentioned above to improve the solubility of ADG, the results herein show a comparable increase in solubility in relation to previous ME results without altering ADG’s structure, nor isolating ADG from water. It can be hypothesized that the increase in ADG solubility in this work was caused by the coupling of the drug with CBQDs and D-CBQDs mainly through the π–π interactions forming soluble nanocomposites.

Table 2. Results for Solubility Improvement in Terms of μg/mL Based on a Starting Concentration of 8.76 μg/mL of ADG.

material x̅ (μg/mL) SD ADG left in D2O (%)
ADG 0.64 0.03 7.26
CBQD-ADG 3.82 0.25 43.62
SCBQD-ADG 3.45 1.80 39.38
NCBQD-ADG 1.26 0.12 14.34
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Table 3. Results for GSE Calculations.

material log P Sw (μg/mL) ratio
ADG 2.63233 22.52 N/A
CBQD-ADG 0.1117 7463.32 331.36
SCBQD-ADG 0.2142 5894.30 261.70
NCBQD-ADG 0.7775 1611.14 71.53
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2.5. Fluorescence, UV–vis, and FTIR

To study the spectroscopic properties of the CBQDs and D-CBQDs and their nanocomposites, UV–vis absorption and FLU spectra with different wavelengths were carried out in water and ethanol. UV–vis spectra show that CBQDs present a strong band at 254 nm (Figure S24 left), indicating a size uniformity of sp2 clusters. Therefore, mostly π–π bonds were formed during the pyrolysis or carbonization, demonstrating that there is a considerable π-network. However, N-CBQDs show two absorption bands at 254 and 330 nm (Figure S4 left). The absorption band at 330 nm is attributed to the n−π* transition of the C–N55 It further indicates that the nitrogen element is successfully doped into the structure of N-CBQDs. S-CBQDs show an absorption band at 254 nm just as N-CBQDs, and CBQDs also due to the π → π* transition of the surface states56. The use of ethanol for ADG was necessary due to its low solubility in water, but the CBQDs-ADG and D-CBQDs-ADG composites were completely soluble in water. It was observed that the association of ADG on the CBQDs and D-CBQDs produced a shift in the peaks and the appearance of a new shoulder peak distinct from the absorption of pure ADG as well as the D-CBQDs, as shown in Figure S24 (right).

The fluorescence (FLU) spectra were obtained, as shown in Figure S25. The CBQDs and D-CBQDs were exposed to their corresponding excitation and emission values of λmax (Table 4). The peaks marked with arrows in Figure S25 correspond to Rayleigh peaks. Doping CBQDs with S and N atoms could effectively modulate the band gap and electronic density of CBQDs, leading to a significant fluorescence blue shift. The FLU of CBQDs is subject to the influence of surface functional groups, which are observed in two bands at 370 and 462 nm (Figure S25a).57 However, CBQD-ADG has strong excitation spectra compared to bare CBQD and ADG, which are excited at 380 nm with an emission wavelength of 484 nm. On the other hand, N-CBQDs have maximum excitation intensity at 367 nm with an emission wavelength of 435 nm which has been attributed to uniformity in size and emission sites of sp2 clusters in the N-CBQDs.58 N-CBQD-ADG, showed strong excitation spectra at 381 nm, a 14 nm shift from lone N-CBQDs, and an emission shift of 15 nm at 450 nm. S-CBQDs showed a well-defined emission band at 438 nm59. In the case of S-CBQD-ADG, no significant shifts were observed in the excitation and emission wavelengths.

Table 4. Excitation and Emission Wavelengths of CBQDs, D-CBQDs, and Loaded Products.

material excitation λmax (nm) emission λ (nm)
ADG 302 337 371
CBQD 370 462 882
CBQD-ADG 380 484
N-CBQD 367 435 851
N-CBQD-ADG 381 450 853
S-CBQD 354 438 851
S-CBQD-ADG 351 439 852
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CBQDs, doped-CBQDs, and their loadings were characterized by FT-IR to investigate any spectral changes of the functional groups after the coupling, and to corroborate the presence of ADG in the samples without losing their chemical integrity. An FT-IR spectra comparison of CBQD, N-CBQD, and S-CBQD with their characteristic starting materials was carried out (Figure S26). It can be observed that the peaks at 1212, and 1390 cm–1 correspond to C–S and C–N stretching in S-CBQDs, and N-CBQDs, respectively, while the peak 3100–3500 cm–1 is due to the presence of O–H in CBQDs, and D-CBQDs. Figure 6 shows comparison spectra of ADG with those of all nanocomposites. CBQD-ADG shows peaks at 2361 and 2339 cm–1 which are attributed to the conjugated C=C (Figure 6a), while these peaks are not so evident for NCBQDs-ADG, and SCBQDs-ADG. The peaks at 870 and 1398 cm–1 correspond also to C–N and S–O stretching vibration for NCBQD-ADG, and SCBQD-ADG, respectively (Figure 6b,c). CBQD-ADG, NCBQD-ADG, and SCBQD-ADG show peaks at 2983, 2908, 1643, 1081, and 1042 cm–1 due to the presence of sp2 C–H (C–C–H), sp3 C–H (C–C–H), C=O, C–O, and C–O–C bending of the lactone ring respectively, in the molecular structure of ADG (Figure 6a–c). However, these samples show displacements in the C=O band of the coupling samples concerning pure ADG (1727 cm –1). These vibrations confirm the presence of ADG molecules and support the interactions between ADG molecules and CBQDs/D-CBQDs previously confirmed in the NMR.

Figure 6.

Figure 6

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FT-IR comparison of (a) CBQD, ADG, and CBQD-ADG, (b) N-CBQDs, ADG, and NCBQD-ADG, and (c) S-CBQDs, ADG, and SCBQD-ADG.

3. Conclusions

CBQDs, N-CBQDs, and S-CBQDs were successfully synthesized with unprecedented crystallinity. They are water-soluble, have a spherical shape, and show monodispersed distributions with diameters in the 3.1–3.4 nm range. These characteristics make them excellent candidates for use as drug delivery platforms. We synthesized and studied the nanosystems consisting of ADG conjugated to the CBQDs and D-CBQDs’ surface, finding that they have a strong affinity for the aqueous phase. The log P of ADG was lowered by around 2 logarithmic units. Thereby, the carbon nanosystem hereby studied may facilitate the transport and delivery of ADG in aqueous media. The conjugated nanosystem opens the possibility of developing more effective ways of using ADG in therapeutic applications. This work could be expanded to explore the hydrophilicity improvement of other hydrophobic drugs.

4. Experimental Section

4.1. Chemicals

Citric acid (CA), 3-mercaptopropionic acid (MPA), ammonium chloride (NH4Cl), sodium hydroxide (NaOH), andrographolide (ADG), deuterium oxide (D2O), and 1-octanol were purchased from Sigma-Aldrich and Fisher Scientific. All glassware was rinsed with double-distilled water at least three times. All the solutions were prepared using deionized water by Aries Filter Works Gemini model GMS-105 with GMA-UV, PBS (Sigma-Aldrich), and ethanol.

4.2. Instrumentation

UV–vis absorption spectra were recorded on a Thermo Scientific Genesys 10S UV–vis spectrophotometer. Fluorescence emission and Fourier transform infrared (FTIR) spectra were obtained with a Bruker Tensor 27 Spectrofluorometer and a Bruker Tensor 27 FTIR system, respectively. NMR characterizations were performed on a Bruker Ascend Aeon 500 using deuterium oxide (D2O) as solvent. The solvent signals at 4.80 and 4.81 ppm were used as internal standards for protons. In order to study the morphology and dimensions of nanocomposites, X-ray microanalysis was recorded with a JEOL JSM-6480LV scanning electron microscope with an Evenhart Thomley secondary electron imaging (SEI) detector, an energy dispersive X-ray analysis (EDS) Genesis 2000 detector, and an FEI TALOS 200x high-resolution scanning/transmission electron microscope (TEM).

Powder diffractograms (PXRD) were collected at 300 K using a Rigaku XtaLAB SuperNova X-ray diffractometer with a microfocus Cu–Kα radiation (λ = 1.5417 Å) source and equipped with a HyPix3000 X-ray detector (50 kV, 1 mA). Powder samples were mounted on MiTeGen microloops. Powder diffractograms were collected between 6 and 60° with a step of 0.01° using the Fast phi move experiment.

4.3. Synthesis of CBQDs and Doped-CBQDs60

CBQDs were synthesized as reported in the literature.61 In a typical synthesis, 2 g of citric acid was placed into a beaker and heated using a heating mantle. The solution changes from colorless to yellow and then orange. The orange color indicates the formation of CBQDs. NaOH solution is added drop by drop until the obtained orange liquid, under vigorous stirring, is neutralized at pH 7. The neutralized solution is then filtered using a syringe filter with a pore size of 0.1 μm to remove any turbostratic graphene that may have been formed as a side product. The synthesis for doped-carbon-based quantum dots (D-CBQDs) was followed as reported in the literature62,63, where 2 g CA and MPA are pyrolyzed in a beaker with to form sulfur–carbon based quantum dots (S-CBQDs). To prepare nitrogen-doped carbon-based quantum dots (N-CBQDs) 0.8 g of citric acid is mixed with NH4Cl in a beaker. The solution is heated using a hot plate, and then the mixture changes from colorless to yellow and then orange, which indicates the formation of the product. For neutralization to pH 7.00, NaOH is added drop by drop to the solution. The purification of the D-CBQDs is done through a 12 kDa dialysis bag to remove residual reagents. After the dialysis, the D-CBQDs were filtered using a syringe filter with a pore size of 0.1 μm to remove any turbostratic graphene that may have been formed as a side product.

4.4. Synthesis of CBQDs-ADG and D-CBQD-ADG Nanocomposites60

CBQDs-ADG and D-CBQDs (S-CBQDs and N-CBQDs)-ADG were prepared through a one-step process. CBQDs and D-CBQDs solutions between 0.3 and 0.8 absorbances (A) at 430 nm were mixed with an ethanolic solution of ADG in a volume ratio of 1:1. The nanocomposites were incubated in a sonicator at a warm temperature.

4.5. Partition Coefficient Studies

The partition coefficient measurements were done through NMR spectroscopy following the method proposed by Cumming and Rücker.36 The partition constant and its logarithmic value (log P) are calculated from the ratio of the respective equilibrium concentrations of molecules in the two phases:

4.5. 1

The method consists of dissolving an amount of the compounds in D2O in an NMR tube. Then a 1H NMR spectrum is taken. Afterward, an equal volume of 1-octanol is added to the NMR tube, and the phases are mixed. Then, the tube is left unperturbed to allow the phases to separate and reach equilibrium. After the equilibrium time passes, an NMR spectrum of the aqueous (lower) phase is taken. D2O was used instead of water to increase andrographolide’s signal due to its low solubility in H2O. Finally, a characteristic of the peak of each compound is integrated within the D2O peak in both spectra. The first spectrum provides RIwinit, the second provides RIwequil, and Kow is calculated according to eq 2:

4.5. 2

where RIwinit = relative NMR signal integration of the materials in D2O before equilibration with 1-octanol and RIwequil = relative NMR signal integration of the materials in the aqueous phase after equilibration. The obtained Kow is then utilized as the partition constant and its logarithmic value (log Kow) is considered as the obtained log P.

4.6. General Solubility Equation (GSE) Calculations

Water solubility estimations were done by using the revised General Solubility Equation proposed by Jain and Yalkowsky42.

4.6. 3

The equation solved for Sw gives the molar aqueous solubility, which we then changed to μg/mL units. The MP is the melting point of the purchased Andrographolide in degrees Celsius (231 °C) and the log Kow is the partition coefficient (log P). We utilized experimental log P obtained by the NMR method for the GSE calculations. log P values were obtained at a neutral pH, which increases ionization and thus reduces the log P of ADG to its log D value.64

Acknowledgments

This research was carried out under the auspices of the Research Initiative for Scientific Enhancement program (RISE [5R25GM061151-20]), PR NASA EPSCoR (NASA Cooperative Agreement [80NSSC22M0025]), and Brookhaven National Laboratory (proposals number 307656 and 308523). This project is based upon work supported by the National Science Foundation under Grant No. 1626103.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c06252.

  • In situ EDS mapping, XRD, SAED, 1H and 13C NMR, fluorescence, UV–vis, and FTIR spectroscopy that complements the contents of this manuscript (PDF)

Author Contributions

N.M.-B. & W.P.-R.: data curation, formal analysis, investigation, methodology, project administration, validation, visualization, writing original draft and writing-review and editing. A.L.F.: data curation, formal analysis, validation, visualization, writing original draft and writing-review and editing. S.C.D.V.: data curation, formal analysis, investigation, visualization and writing original draft. A.C.M.G.: data curation, formal analysis, investigation, visualization and writing original draft. M.T.T.M.: data curation, formal analysis, investigation, visualization and writing original draft. K.K.: data curation, investigation. G.M.: funding acquisition, resources, supervision, validation, visualization, and writing-review and editing. B.R.W.: funding acquisition, resources, supervision, validation, visualization, and writing-review and editing. N.M.-B. and W.P.-R. contributed equally to this work.

The authors declare no competing financial interest.

Notes

Provisional patent number 63/492,024.

Supplementary Material

ao3c06252_si_001.pdf (1.5MB, pdf)

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