Nontoxic and renewable metal–organic framework based on α-cyclodextrin with efficient drug delivery

Abstract

A novel α-cyclodextrin based metal–organic framework (CD-MOF) with chiral helices, K₃(C₃₆H₆₀O₃₀)₂·7H₂O (1), was synthesized by vapor diffusion method, which contains infinitely long left-handed helical chains, interdigitated with six circumambient helical chains. Compound 1 exhibits efficient drug loading capacity and excellent sustained release behavior. In addition, by changing the synthetic method, another compound based on α-cyclodextrin, (C₃₆H₆₀O₃₀)·H₂O (2), was isolated by solvothermal synthesis, which contains left-handed chiral helical double channels, linked with adjacent four same helical channels. Moreover, the lower cytotoxicity of the two compounds indicates that they are a type of renewable, environmentally friendly and biocompatible drug carrier material.

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1. Introduction

Cyclodextrins (CDs), one of the biocompatibility truncated cone-shaped cyclic oligosaccharides, consist of six, seven, or eight α-1,4-linked D-glucoses (α-, β- γ-CDs, respectively), which display fascinating properties such as higher loading capacity and lower toxicity to the kidney.^1–3 CDs are nontoxic and biocompatible and have been approved to be safe to the human body by the US Food and Drug Administration (FDA), and therefore CDs and derivatives would have potential uses as drug delivery agents.^4–7 More recently, international research teams from Germany, the United States, Sweden, Denmark, Australia and other countries reported that CD as a drug could promote atherosclerosis regression via macrophage reprogramming.⁸

Metal–organic frameworks (MOFs),^9–16 a new class of crystalline solid material comprising metal ions and organic ligands, are being evaluated for diverse potential applications such as gas adsorption, storage, separation and drug delivery. As a special class of organic ligands, CDs display the –OCCO– binding motif on both their primary and secondary faces, auguring well for forming extended structures with metal cations (named as CD-MOFs).^17–19 Equally impressive, CD-MOFs can combine the porous features of MOFs with the excellent encapsulation capacity of CDs for drug molecules, which may possess not only high drug loading capacities but also good biocompatibility. Therefore, increasing attention is being paid to the design and synthesis of nontoxic and biocompatible CD-MOFs. Recently, many CD-MOFs based on α-, β-, γ-CDs and metal ions were reported,^20–22 which are expected as potential materials for absorption of some small molecules. However, due to the large number of chemically equivalent hydroxyl groups and differences in electronegativity between metal ions and hydroxyl oxygen atoms, the construction of CD-MOFs is a challenging and difficult task.

On the other hand, study about chiral helices is of particular interest, because living organisms utilize helices to store and transmit genetic information, and this relationship between structure and chirality, namely, how chiral building blocks form helical systems in the solid state, is still not well understood. We believe that helical construction based on CDs as inherently chiral natural products will contribute to understanding the relationship between structures and chirality. Therefore, we studied and reported some CD-MOFs based on β-CDs and alkali metal cations, which exhibit fascinating structures and good drug delivery.^23,24 As a follow-up work, the six-membered cyclic variant of α-CD (Scheme 1) with KOH are selected to construct CD-MOF by different synthetic methods, and two new compounds (1, 2) were successfully isolated. In addition, in order to elucidate the relationship between the cavities of α-CD-MOFs and drug delivery, 5-fluorouracil (5-FU, 3 × 6 Å) as a drug model is chosen in this study due to its small size, which is widely used as an anti-cancer chemotherapy drug.²⁵

Scheme 1 Structure formula of the asymmetric (C₁) α-1,4-linked D-glucopyranosyl residues and α-cyclodextrin (α-CD) with C₆ symmetry. The six C₆ hydroxy (OH) groups and the six glycosidic ring oxygen atoms constitute the primary face of α-CD molecules, and the 12 C₂ and C₃ OH groups constitute the secondary face.

2. Experimental section

2.1 Materials and methods

α-Cyclodextrin (α-CD, 98%) was purchased from Shanghai Jinsui Bio-Technology Co., Ltd, and tetramethylammonium hydroxide solution (25%) and 5-FU from SCR (Shanghai) and Counting Kit-8 from Beyotime Institute of Biotechnology, and all the organic solvents from Aladdin-reagent (Shanghai). Double distilled water was used to prepare all solutions. HepG2 cells were provided by Basic Medical College, Jiamusi University. Elemental analyses (C, H) were performed on a Perkin-Elmer 2400 CHN Elemental Analyzer. The IR spectra were obtained on an Alpha Centaurt FT/IR spectrometer with KBr pellet in the 400–4000 cm⁻¹ region. XRPD patterns were obtained by a Rigaku D/max 2500 V PC diffractometer with Cu-Kα radiation: the scanning rate was 4° s⁻¹, 2θ ranging from 5° to 40°. UV-vis absorption spectra were obtained on a 756 CRT UV-vis spectrophotometer.

2.2 Synthesis of K₃(C₃₆H₆₀O₃₀)₂·7H₂O (1)

α-CD (650 mg, 0.5 mmol) and KOH (220 mg, 4 mmol) and tetramethylammonium hydroxide solution (25%, 0.2 mL) were dissolved in H₂O (10 mL). The aqueous solution was filtered and MeOH (ca. 30 mL) was allowed to vapor diffuse into the solution during the period of a month. White block crystal, suitable for X-ray crystallographic analysis, was isolated, filtered and washed with MeOH. Yield: 75% (based on α-CD). Anal. calcd for K₃C₇₂O₆₇H₁₃₄ (2187): C 39.51, H 6.13 (%); found: C 39.44, H 6.22 (%). IR (solid KBr pellet cm⁻¹): 3417 (s), 2921 (m), 1640 (m), 1418 (m), 1158 (m), 1482 (s), 1074 (w) and 1026 (s).

2.3 Synthesis of (C₃₆H₆₀O₃₀)·H₂O (2)

A mixture of α-CD (650 mg, 0.5 mmol) and KOH (0.22 g, 4 mmol), tetramethylammonium hydroxide solution (25%, 0.2 mL) was added to MeOH (10 mL), magnetically stirred for 1 h in air, then sealed in a 20 mL Teflon-lined reactor and kept at 160 °C for 4 days. The reactor was then slowly cooled down to room temperature. White needle crystals, suitable for X-ray crystallographic analysis, were isolated. Yield: 45% (based on α-CD). Anal. calcd for C₃₆O₃₁H₆₂ (990): C 43.64, H 6.26 (%); found: C 43.56, H 6.35 (%). IR (solid KBr pellet cm⁻¹): 3416 (s), 2922 (m), 1638 (m), 1420 (m), 1146 (m), 1075 (w) and 1022 (s).

2.4 X-ray crystallography

Crystal data for compounds 1 and 2 were collected on an Agilent Technology Eos Dual system with focusing multilayer mirror optics and a Mo-Kα source (λ = 0.71073 Å). Empirical absorption corrections were applied to the intensities using the SADABS program.²⁶ The structure was solved by the directed methods and refined by full matrix least squares on F² using the SHELXTL crystallographic software package.^27,28 The positions of hydrogen atoms on carbon atoms were calculated theoretically. A summary of the crystal data, data collection, and refinement parameters for 1 and 2 are listed in Table 1. Selected bond lengths and angles for compounds 1 and 2 are listed in Tables S1 and 2.† Crystallographic data for the structures reported in this paper have been deposited in the Cambridge Crystallographic Data Center.

Table 1 Selected crystallographic data for 1 and 2^a,b

a R1 = Σ(||F0| − |Fc||)/Σ|F0|.b wR2 = Σw(|F0|^2 − |Fc|^2)^2/Σw(|F0|^2)^2]^1/2.
Chemical formula	K3C72O67H134	C36H62O31
Formula weight	2187	990
CCDC	1478771	1478996
Temperature (K)	293(2)	298(2)
Wavelength (Å)	0.71073	0.71073
Crystal system	Monoclinic	Orthorhombic
Space group	P21	P212121
a (Å)	13.813	9.3667(8)
b (Å)	33.186	20.0172(1)
c (Å)	13.971	25.3123(2)
α (°)	90.00	90.00
β (°)	118.69	90.00
γ (°)	90.00	90.00
V (Å^3)/Z	5618.0/2	4745.9/4
Density (g cm^−3)	1.238	1.325
Abs coeff. (mm^−1)	0.220	0.21
F(000)	2130.0	1928
Data collect θ range	3.363–24.999°	1.72–25.00°
Reflns collected	15214	14143
Independent reflns	19801	8054
Rint	0.0297	0.0423
Refinement method on F^2	Full-matrix least-squares	Full-matrix least-squares
Data/restraints/parameters	19801/7/1279	8054/6/604
Goodness-of-fit on F^2	1.056	1.136
Final R indices [I > 2δ (I)]	R1 = 0.0750, wR2 = 0.2096	R1 = 0.1113, wR2 = 0.2931
R indices (all data)	R1 = 0.0800, wR2 = 0.2170	R1 = 0.1423, wR2 = 0.3192
Largest diff. peak and hole (e Å^−3)	1.093 and −0.553	1.185 and −0.621

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2.5 The establishment of standard curve equation

The precision amount of 5-FU standard was dissolved in phosphate buffer solution (pH = 7.4), and then making into a certain mass concentration as the reference substance solution: 3.6 μg ml⁻¹, 5.4 μg ml⁻¹, 7.2 μg ml⁻¹, 9.0 μg ml⁻¹, 10.8 μg ml⁻¹, 12.6 μg ml⁻¹, 14.4 μg ml⁻¹, and 16.2 μg ml⁻¹. The measure wavelength is determined to be 266 nm according to the UV spectrophotometer of 5-FU. The process of standard curve equation is as follows:

A_{5-FU PBS} = 0.0496C + 0.0182 R² = 0.9997

According to the same method, the standard curve equation of 5-FU (λ = 264 nm) in ethanol as follows:

A_{5-FU ethanol} = 0.0533C + 0.004 R² = 0.9991

2.6 Drug loading and release assay

5-Fluorouracil (5-FU) (125 mg, 0.96 mmol) and α-CD (250 mg, 0.25 mmol) were dissolved in ethanol (50 mL), which was stirred for 12, 24, 36, 48 h forming a heterogeneous white solution. Then, the corresponding mixture was centrifuged and the solid (α-CD-5-FU) was filtered, washed with ethanol, and dried at room temperature. IR data (solid KBr pellet cm⁻¹): 3436 (s), 3069 (w),2921 (m), 1732 (w), 1642 (s), 1449 (s), 1269 (s), 1157 (s), 1077 (w) and 1032 (s). The 5-FU content was calculated through UV/Vis results (λ = 264 nm) (Fig. S1†). Employing the same procedure, 5-FU was also successfully loaded into compound 1 (named as compound 1-5-FU) and compound 2 (named as compound 2-5-FU). IR data (solid KBr pellet cm⁻¹): 3416 (s), 3101 (w), 2922 (m), 1672 (s), 1422 (w), 1263 (s), 1158 (s), 1080 (w) and 1033 (s) for compound 1-5-FU; 3421 (s), 3056 (w), 2921 (m), 1729 (w), 1659 (s), 1439 (s), 1247 (s), 1160 (s), 1078 (w) and 1033 (s) for compound 1-5-FU. And the loading rate (q) of compound towards 5-FU (the initial loading of the molar ratio of 5-FU to compound is 1 : 2.5) was calculated as follows:
where q_t is the loading rate at contact time t, V is the volume of drug solution (mL), C₀ is the initial concentration of drug (mg mL⁻¹), C_t is the concentration of drug at contact time t (mg mL⁻¹), and W is the weight of compounds (mg).

α-CD-5-FU (20 mg) was transferred into a dialysis bag, which was put in PBS buffer solution (500 mL pH = 7.4), and dialyzed (stirring speed of 100 rpm) at (37 ± 0.5 °C). During each time interval, 1 mL of the solution was sucked out to test and decanted back when the test was over. The releasing content of 5-FU in α-CD-5-FU was monitored by UV/Vis (λ = 266 nm). Employing the same method, the release of compound 1-5-FU and compound 2-5-FU is analyzed (Fig. S2†).

2.7 In vitro cytotoxic assay

Human hepatoma carcinoma cell line HepG2 was cultured in a 37 °C humidified incubator at 5% CO₂ with DMEM (Gibco, USA) containing 10% FBS (Gibco, USA), 100 units ml⁻¹ penicillin and 100 units ml⁻¹ streptomycin. The cytotoxicity study of compounds on HepG2 cells was tested by the Cell Counting Kit-8 (CCK-8) experiment. The experiments were divided into five groups: blank group (without cells), negative control group (cells with no drug), 5-FU drug group, α-CD group (α-CD, compound 1, compound 2), 5-FU loading group (α-CD-5-FU, compound 1-5-FU, compound 2-5-FU). Then, HepG2 cells were seeded in a 96-well plate (1.5 × 103 cells per well), and respective liquid (DMEM containing compounds, 1 mg mL⁻¹) was added to each well to make the final concentration of 100, 50, 25, 12.5, 6.25 μg mL⁻¹, and then cultured for 48 h. Finally, CCK-8 (each hole 10 μL) was added, and the cellular survival rate is monitored at BIV-TEK INSTRUMENTS INC (λ = 540 nm).

3. Results and discussion

3.1 Crystal structure of compound 1

Single crystal X-ray diffraction analysis reveals that compound 1 consists of two α-CD, six K⁺ ion and fourteen lattice waters. There are three crystallographically independent K⁺ ions, out of which four are coordinated by four oxygen atoms from four secondary hydroxyls (3-OH) of four contiguous α-CD molecules, and K–O bond distances are in range of 2.6715–2.7421 Å for K1, 2.6591–2.6964 Å for K2 and 2.6451–2.7310 Å for K3 (Fig. 1a). Moreover, there are two crystallographically independent α-CD (A-α-CD and B-α-CD), which link with three K⁺ ions via a-, b- and c-glucopyranosyl (Fig. 1b). It can be note that A-α-CD and B-α-CD are fused together forming [K₆(CD)₂] dimer torus in the secondary face to secondary face pattern (Fig. 1c). Furthermore, each [K₆(CD)₂] dimer torus link with adjacent six [K₆(CD)₂] dimer forming 2D layer on the [010] plane with both big pores (size ca.11.52 × 11.53 Å) and small pores (size ca.7.34 × 7.29 Å) (Fig. 2a) sharing with K1, K2 and K3 ions (Fig. 2).

Fig. 1 Stick representation of the coordination modes of K1, K2, K3 ion (a) and α-CD (b) and the [K₆(CD)₂] dimer torus (c).

Fig. 2 Stick/space-filling/topology representation of 2D structure of α-CD-MOF (a), and the left-handed helical chain via the route of K2–O21 (6-OH of b-glucopyranosyl of A-α-CD) O38 (6-OH of e-glucopyranosyl A-α-CD) K2–O51 (6-OH of b-glucopyranosyl B-α-CD) O65 (6-OH of e-glucopyranosyl of B-α-CD from adjacent [K₆(CD)₂] dimer)–K2 (b) and 2D chiral helical layer constructed by 1D left-handed helical chain via sharing K2 ions (c).

One fascinating feature is that α-CD-MOF exhibits a left-handed helical chiral layer by the ligation of K2 ions to the oxygen atoms on glucopyranosyl. More specifically, adjacent [K₆(CD)₂] dimer using its 6-OH from b-, e-glucopyranosyl link with K2 ions forming 1D left-handed helical chains along the a axis with a pitch of 13.8130 Å, which is consistent with the unit length of the a axis (a = 13.8130 Å). Then, each 1D left-handed helical chain with six circumambient helical chains fabricate 2D chiral helical layer via sharing K2 ions. Finally, 2D chiral helical layers are stacked together in parallel staggering fashion obtaining 3D structure via short interaction. Another interesting structural feature is that there exits another type of helical structure in the 3D framework. As shown in Fig. 3, along the b axis, α-CD from [K₆(CD)₂] dimer of different layer connects with K2 and K3 ions forming another left-handed helical via the route of -K3-O50–O5W–O63–K2–O37–O52– K3- with a pitch of 33.1860 Å, which is consistent with the unit length of b axis (b = 33.1860 Å). Then, each 1D left-handed helical chain is surrounded by adjacent helical chain forming 3D chiral helical framework via K2–O50 (ring O of d-glucopyranosyl of B-α-CD, 7.381 Å) and K3–O63 (ether oxygen between d-glucopyranosy and c-glucopyranosy of A-α-CD, 6.204 Å) and K2–O52 (ring O of b-glucopyranosy of A-α-CD, 5.693 Å).

Fig. 3 Ball/stick/schematic representation of 3D structure of α-CD-MOF (a); another 1D left-handed helical chain via the route of -K3 (B-α-CD)-O50 (ring oxygen of d-glucopyranosyl of B-α-CD) –O5W–O63 (ether oxygen between d- and e-glucopyranosyl of A-α-CD)-K2 (B-α-CD)-O37 (ether oxygen between d- and e-glucopyranosyl of B-α-CD of next layer)-O52 (ether oxygen of e-glucopyranosyl of A-α-CD of next layer)- K3 (B-α-CD of the third layer)-along b axis (b); topology (c) and schematic illustration (d) 3D chiral helical framework constructed by 1D left-handed helical chain via sharing K–O bond.

3.2 Crystal structure of compound 2

A single-crystal X-ray diffraction study performed on compound 2 reveals the formation of a left-handed helical double channel that crystallizes in the space group P2₁2₁2₁. Different form α-CD-MOF, there is a crystallographically independent α-CD molecule, and each α-CD molecule links with adjacent α-CD in the primary face to secondary face pattern forming 1D [α-CD]_n supramolecular chains via short interaction (2.713–3.015 Å, 3-OH of primary face and 6-OH of secondary face) (Fig. 4a). Then, two adjacent 1D [α-CD]_n chains connect each other via 2-OH⋯6OH short interaction (2.749–3.009 Å) forming double channels subunits along the a axis (Fig. 4b). Note that there is also the left-hand helical chain through the route of O2W–C8 (a-glucopyranosyl of A-α-CD)–O2W–C8 (a-glucopyranosyl of B-α-CD)–O2W with a pitch of 9.3667 Å, which is consistent with the unit length of the a axis (b = 9.3667 Å) (Fig. 4c). Finally, each left-hand helical chain with adjacent four same helical chains via short interaction fabricate 3D supramolecular framework with double channels along the a axis shown in Fig. 5.

Fig. 4 Stick representation of 1D single chain in primary face to secondary face stacking mode (a) and 1D double chains constructed by 1D single chain (b) and the left-handed helical chain via the route of O2W–C8 (a-glucopyranosyl of A-α-CD)–O2W–C8 (a-glucopyranosyl of B-α-CD)–O2W (c).

Fig. 5 Combined ball/stick/topology representation of the 3D chiral helical framework form the different orientations.

3.3 XRPD pattern of compounds

The XRPD pattern for 1 and 2 is presented in Fig. S3.† The diffraction peaks of both simulated and experimental patterns match well, thus indicating that the phase purity of the compounds is good. The difference in reflection intensities between the simulated and the experimental patterns is due to the different orientation of the crystals in the powder samples.

3.4 IR spectra of compounds

The IR spectra of compounds 1 and 2 (Fig. S4†) show prominent characteristic absorption bands at 3416 cm⁻¹ (for –OH stretching vibrations of multi-association body), 2922 cm⁻¹ (for C–H stretching vibrations of –CH₃ and –CH₂), 1640 cm⁻¹, 1418 cm⁻¹ and 1158 cm⁻¹ (for –OH bending vibration), 1074 cm⁻¹ and 1026 cm⁻¹ (for C–O and C–C stretching vibrations), which indicates that compounds 1 and 2 maintain the skeleton structure of α-CD. The IR spectra of 5-FU, α-CD-5-FU, compound 1-5-FU and compound 2-5-FU (Fig. S5†) show prominent characteristic absorption bands of 5-FU at 3010 cm⁻¹ (for N–H), 2800–3000 cm⁻¹ (for C–H), 1742 cm⁻¹ (for C=O), 1699 cm⁻¹ (for C–F). Compared with 5-FU parent, the broadening, weakening and shift of some features absorption peak intensity indicate that 5-FU have successfully loaded into the new carriers, α-CD, compound 1 and compound 2.

3.5 Loading and in vitro release of 5-FU

Fig. 6a shows the effect of loading time on the 5-FU drug loading rate, and the result shows that the loading rate is significantly enlarged with increasing time, then the drug loading capacity reaches saturation at 36 h, namely, the adsorption and desorption of 5-FU reaches equilibrium. It is clear that compound 1 shows remarkable 5-FU adsorption than that of compound 2 and α-CD matrix, and the loading rates are measured to be 0.257 g g⁻¹, 0.107 g g⁻¹ and 0.109 g g⁻¹, respectively, which attribute to the larger cavities or cages (25.26% for 1 and 15.11% for 2 of the cell volume calculated by PLATON). The kinetic process of 5-FU delivery in simulated body fluid at 37 °C is shown in Fig. 6b. 5-FU exhibits fast release and the cumulative release degree reaches 93.9% within 50 min. Moreover, loading 5-FU in the α-CD and derivatives show obvious sustained release behavior but low cumulative release degree (33% for α-CD-5-FU, 77% for compound 1-5-FU, 79% for compound 2-5-FU) within 350 min. The reasons are as follow: loading 5-FU in α-CD and derivatives need to transit the cavities into a solution, which extends the drug dissolution time. On the other hand, 5-Uu fails partly to transit the cavities and are detained in cavities, resulting in the poor cumulative dissolution percentage.

Fig. 6 5-FU drug loading rate (m(drug)/m(CD-MOF)) in α-CD, compound 1 and compound 2 (left) (in) and in vitro release profile of α-CD-5-FU, compound 1-5-FU and compound 2-5-FU (right).

3.6 Cytotoxic research of α-CD and derivatives

A comparison of cytotoxicity on HepG2 cells for 5-FU, α-CD, compound 1 or compound 2 (the equivalent drug concentration) is presented in Table S3.† The inhibitory effects against HepG2 show that 5-FU exhibits higher cytotoxicity, whereas α-CD, compound 1 and compound 2 show no cytotoxicity under the same drug concentration. The inhibitory effective cell 50% lethal concentration (IC₅₀) against HepG2 cells is 0.025, 0.1923, 10.0586 and 12.7548 nmol mL⁻¹ to 5-FU, α-CD, compound 1, compound 2, respectively, which indicates that compound 1 and compound 2 are a type of renewable, environmental friendly and biocompatibility drug carrier material.

4. Conclusions

In summary, two new α-CD based compounds were synthesized by different method, and they exhibit different left-handed helical structure. We believe that the two new α-CD based compounds are noteworthy because of their chirality and structures generated from readily available renewable natural products, which attributes to understanding the relationship between structures and chirality. Compounds 1 and 2 are nontoxic and can be synthesized under benign conditions, in which compound 1 shows efficient drug loading capacity and excellent sustained release behaviors. The successful isolation of compounds represents the perspective of a new generation of green, renewable and biocompatibility crystal materials.

Acknowledgements

This study was financially supported by the NNSF (no. 21271089), the New Century Excellent Talents Program in Heilongjiang Province (1253-NCET-022) and the Talent Team Culturing Plan for Leading Disciplines of University in Shandong Province.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1478771 and 1478996 contains the supplementary crystallographic data for compounds 1 and 2, respectively. Tables of selected bond lengths (Å), bond angles (deg) and IR and XRPD and others for compounds 1 and 2 are provided. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra16549d

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