Constructing Anti-Glioma Drug Combination with Optimized

(2) Temozolomide (TMZ, Scheme 1) is an oral alkylating agent prodrug and is the most effective chemotherapy drug in the treatment of malignant glioma...
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Constructing Anti-Glioma Drug Combination with Optimized Properties through Cocrystallization Jin-Mei Li,§ Xia-Lin Dai,§ Gao-Jie Li,§ Tong-Bu Lu,‡ and Jia-Mei Chen*,†,§ †

School of Chemistry and Chemical Engineering and ‡Institute for New Energy Materials and Low Carbon Technologies, Tianjin University of Technology, Tianjin 300384, China § School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China

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S Supporting Information *

ABSTRACT: Cocrystallization of two anti-glioma agents, Temozolomide (TMZ) and baicalein (BAI), resulted in a cocrystal presenting superior stability for unstable TMZ as well as optimized dissolution and pharmacokinetics for TMZ and BAI. Cocrystallization can be an efficient approach to construct anti-glioma drug combination systems at the molecular level.

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alignant gliomas, such as glioblastoma multiforme and anaplastic astrocytoma, are the most common and lethal malignant primary brain tumor in adults.1 As malignant gliomas are highly mobile and invasive, the current standard treatment includes removing the local lesion by surgery followed by adjuvant radiation and chemotherapy.2 Temozolomide (TMZ, Scheme 1) is an oral alkylating agent prodrug and is the most effective chemotherapy drug in the treatment of malignant glioma.3,4 It is rapidly and completely absorbed Scheme 1. Chemical Structures of TMZ, MTIC, AIC, and BAI

Figure 1. Crystal structure of (a) asymmetric unit and (b) 2D layer of TMZ-BAI cocrystal.

and spontaneously converts into the active metabolite 3methyl-(triazenyl-1-yl) imidazole-4-carboxamide (MTIC, Received: May 27, 2018 Revised: July 9, 2018 Published: July 17, 2018 © XXXX American Chemical Society

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DOI: 10.1021/acs.cgd.8b00807 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Figure 2. PXRD patterns of TMZ, BAI, and experimental and calculated TMZ-BAI cocrystal.

Figure 5. Mean plasma drug concentration vs time profile after oral administration of TMZ, BAI, and TMZ-BAI cocrystal to rats (n = 5).

Scheme 1) under physiological conditions.5 Then MTIC further breaks down to 5-aminoimidazole-4-carboxamide (AIC, Scheme 1) and the highly reactive methyldiazonium cation [CH3N2]+, the latter of which is the nascent alkylating agent and works by delivering a methyl group to purine bases of DNA inside tumor cells.6,7 TMZ was approved by the United States Food and Drug Administration (US FDA) for refractory anaplastic astrocytoma in 1999, followed by a firstline indication for glioblastoma multiforme in 2005.8 Although TMZ is active against malignant gliomas, it extends survival only by a few short months.9 One of important factors attributed to its limited therapeutic efficacy is the rapid elimination of TMZ after oral administration in patients, with a half-life averaging 1.8 h.10 It may limit the residence time and consequently therapeutic efficacy of TMZ at the site of action. In addition, there is still a stability issue associated with marketed TMZ tablets. Their color turn from white to light tan/pink upon storage, which is indicative of degradation of TMZ to AIC, thus making the prodrug less effective.11 Therefore, to ensure the safety and efficacy of TMZ, there exists an urgent need for products and methods, which could improve its stability and prolong its oral half-life. Baicalein (BAI) (5,6,7-trihydroxyflavone, Scheme 1) is one of the most important bioactive flavonoids found in the roots of traditional Chinese herb Sccutellaria baicalensis.12 BAI has been intensively investigated for its diverse pharmacological activities, such as antitumor, anti-inflammatory, anti-HIV, antibacterial, and anti-adipogenic activities.13−17 Previous studies have shown that BAI suppresses cancer cell proliferation and induces apoptosis and cell cycle arrest in human breast, prostate, hepatocellular, myeloma, and T24 bladder cancer cells, etc.18,19 Recent studies indicated that a synergistic therapeutic effect was observed when BAI was used in combination with certain cancer therapy drugs.20−22 Apart from this, BAI has obvious antitumor activity in orthotopic glioma models and markedly suppressed tumor growth and prolonged the survival of rats with gliomas.23 However, the application of BAI in the pharmaceutical field is greatly limited by the low oral bioavailability due to its poor aqueous solubility (∼16 μg/mL).24 Therefore, when combining TMZ and BAI to obtain a synergetic anti-glioma effect, it is necessary to address

Figure 3. Changes in TMZ assay values during storage under 40 °C/ 75% RH for TMZ and TMZ-BAI cocrystal (n = 3).

Figure 4. Powder dissolution profile of TMZ, BAI, and TMZ-BAI cocrystal in pH 1.2 (n = 3).

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DOI: 10.1021/acs.cgd.8b00807 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Table 1. Mean Pharmacokinetic Parameters (±S.D., n = 5) after Oral Administration of TMZ, BAI, and TMZ-BAI Cocrystal to Ratsa parameter

TMZ

TMZ (cocrystal)

BG (BAI)

BG (cocrystal)

Cmax (μg/mL) tmax (h) t1/2 (h) AUC0‑t (μg·h/mL) AUC0‑∞ (μg·h/mL)

21.13 ± 3.05** 0.80 ± 0.21 9.57 ± 1.08* 136.55 ± 15.60** 216.33 ± 33.04

6.42 ± 1.90 2.35 ± 1.54 24.64 ± 8.33 89.63 ± 9.14 208.15 ± 35.01

− − − − −

13.90 ± 21.90 0.55 ± 0.11 2.56 ± 0.37 21.97 ± 3.98 24.18 ± 3.77

−: not measurable. *p < 0.05 TMZ-BAI cocrystal with respect to TMZ. **p < 0.001.

a

BAI molecules and O7−H10···O2 (2.5850(17) Å, 172.7°) between TMZ and BAI molecules, to form a one-dimensional ribbon (Figure 1b). The adjacent ribbons are connected with each other through weak C19−H14···O1 interactions (3.344 Å, 153.8°) and van der Waals forces to produce twodimensional layers, which are further packed by interlayer π···π interactions to generate the three-dimensional structure of the cocrystal (Figure 1b and Figure S1). The experimental PXRD pattern of TMZ-BAI cocrystal showed a clear difference with those of pure TMZ and BAI (Figure 2), indicating the formation of a new crystalline phase. In addition, all the peaks displayed in the measured pattern closely match those in the calculated pattern generated from SCXRD data, confirming bulk purity and phase homogeneity of the cocrystal (Figure 2). The displacement of the peaks at the high angle regions between experimental and calculated patterns is mainly caused by the different measuring temperature between the powder patterns (room temperature) and the single crystal data (100 K). The same trend was also observed in the IR spectra, where the cocrystal exhibited a clearly differentiated pattern versus those of the individual components (Figure S2), indicating the hydrogen bonding changes involved in the bulk cocrystal production. From TG and DSC thermograms it can be found that TMZ-BAI cocrystal is free of solvents and starts to decompose before melting. The onset and peak of decomposition temperature are 183 and 192 °C, respectively (Figure S3). NMR and HPLC analysis of the cocrystal revealed a composition of 1:1 stoichiometry of TMZ and BAI (Figure S4 and Table S3), in accordance with the observed SCXRD results. The cocrystal formation may modulate the stability of TMZ since it leads to changes in molecular arrangements and interactions of the relevant chemical entity. Stability tests under accelerated ICH conditions (40 °C/75% RH) were performed for TMZ-BAI cocrystal and the results were compared with TMZ itself. The samples were collected and submitted to PXRD, HPLC, and physical examination at the intervals of 1, 2, and 3 months. Pure TMZ turned from a white powder to pink under 40 °C/75% RH in one month, and further turned into dark brown after 3 months, indicating the degradation of TMZ as reported (Figure S5). The results of PXRD measurements indicated that TMZ started to transform into TMZ hydrate (2θ of 11.7°) after 2 months, and a strong peak indicative of transformation to AIC hydrate appeared at 2θ of 12.9° and 27.2° after 3 months (Figure S6a). Furthermore, the assay values of TMZ were found to drastically decrease to 84.54 ± 3.33% after 2 months and abruptly to 15.95 ± 0.84% after 3 months (Figure 3). In contrast, not only did the cocrystal not show any discoloration or phase transformation under the same accelerated stress storage conditions up to 3 months (see Figure S5 and S6b), but it also had significantly higher assay values of TMZ at all

the issues with solubility differences and incompatibility between two parent drugs. Pharmaceutical cocrystals are defined as “stoichiometric multi-component crystalline single phase materials composed of an active pharmaceutical ingredient (API) and other pharmaceutically acceptable compounds those are solids under ambient conditions, and interact by noncovalent interactions such as hydrogen bonds”.25,26 Cocrystallization has recently established itself as an effective approach to modify the properties of an API without covalent modification of its molecular structure.27−32 Cocrystallization of two APIs, namely, drug−drug cocrystallization, could realize combination drugs at a molecular level, which provide an alternative approach that is expected to overcome the problems associated with traditional combination drugs, because it offers a way to optimize the properties of both APIs at the same time.33,34 Thus, cocrystallization of TMZ and BAI may be a feasible approach to enhance the stability, diminish the solubility difference, and subsequently improve the pharmacokinetic property and ensure synergetic anti-glioma efficacy. For both TMZ and BAI, more than one cocrystal were reported.27−29 Cocrystals of TMZ with a library of carboxylic acids and amides exhibited improved stability compared to the pure drug27,28 while cocrystals of BAI presented superior dissolution behavior and even bioavailability compared with plain BAI.29 On the basis of crystal structures of these cocrystals, we can see that the multiple phenolic hydroxyl groups of BAI and the carboxamide group and aromatic N atoms of TMZ are commonly used hydrogen bonding sites. Thus, it is likely to form O−H···Namide and/or O−H···Narom heterosynthons when cocrystallizing TMZ and BAI. These previous studies inspired us to prepare a cocrystal of TMZ and BAI, aiming to improve the stability, slow the release and prolong the oral half-life of TMZ, and enhance the solubility and oral bioavailability of BAI at the same time. The cocrystal reported here was obtained by slurrying of an equimolar mixture of TMZ and BAI in methanol. Crystal structural analysis revealed that the cocrystal belongs to the P21/c space group with the asymmetric unit containing one TMZ molecule and one BAI molecule (Table S1 and Figure 1a). TMZ adopts stable conformation A35 with one intramolecular hydrogen bond (N6−H6···N5, 2.803(2) Å, 105.9°) between the anti-NH and the imidazole nitrogen. There are also two intramolecular hydrogen bonds (O5−H8···O4, 2.6164(17) Å, 145.3°; O6−H9···O7, 2.7234(17) Å, 112.5°) in each BAI molecule. TMZ and BAI are linked through two intermolecular hydrogen bonds (N6−H5···O5, 3.057(2) Å, 161.8°; N6−H5···O6, 2.897(2) Å, 126.2°) between the carboxamide and phenolic hydroxyl groups to form a dimer (Figure 1a). The dimers are held together through three hydrogen bonds, including O6−H9···O4 (2.7305(18) Å, 159.3°) and O5−H8···O7 (2.7982(17) Å, 123.8°) between C

DOI: 10.1021/acs.cgd.8b00807 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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glioma drugs combination systems with optimized properties at a molecular level.

sampling points (Figure 3). These stability studies indicate that the cocrystal demonstrates a superior physical and chemical stability as compared to pure TMZ. The powder dissolution of TMZ-BAI cocrystal was studied by slurrying excess amounts of solids in pH 1.2 media with pure TMZ and BAI as controls. The drug concentration data at each time interval were obtained from HPLC. The powder dissolution plots of TMZ, BAI, and TMZ-BAI cocrystal up to 1 h are depicted in Figure 4. As we can see, there is a huge difference of the solubility between pure TMZ and BAI, suggesting potential compatibility issues between the two drugs. However, after the formation of the cocrystal, the release of BAI was faster and the maximum solubility was vastly higher (25-fold) from the cocrystal than from BAI alone, suggesting a potential for increasing the oral bioavailability of BAI. In contrast, the release of TMZ was slower and the maximum solubility was dramatically decreased (∼90%) from the cocrystal than from TMZ alone, which can be seen as a potential advantage, since it may lead to a more sustained liberation of TMZ, resulting in a longer half-life. Further, the diminishment of solubility difference via the cocrystal formation may also favor the integration and synergy of the two drugs. Thus, TMZ-BAI cocrystal showed a significant advantage in in vitro release performance of both TMZ and BAI. To confirm whether this in vitro advantage of the cocrystal was able to convert to in vivo pharmacokinetic advantage, TMZ-BAI cocrystal was assessed for the oral pharmacokinetics in Sprague−Dawley rats along with the individual compounds as controls. As baicalein-7-O-glucuronide (BG) is the active metabolite of BAI and the mainly existing form in rat plasma, the concentration of BG, instead of BAI, was determined for bioavailability calculation and statistical analysis.29 The plasma drug concentration vs time profile is given in Figure 5, and the pharmacokinetic parameters are summarized in Table 1. It can be found that no reliable pharmacokinetic parameters for pure BAI could be obtained owing to its low plasma BG concentrations. In contrast, the Cmax and the AUC0→t of BG from the cocrystal are 13.90 ± 2.90 ug/mL and 21.97 ± 3.98 μg·h/mL, demonstrating a significant enhancement in oral bioavailability of BAI. For the case of TMZ, the Cmax and the AUC0→t are decreased by 70% and 34% after the formation of cocrystal. However, the reduction of the bioavailability of TMZ after cocrystallization may be addressed by increasing dosage of the cocrystal drug. More importantly, the t1/2 of TMZ was delayed from 9.57 ± 1.08 h to 24.64 ± 8.33 h, which illustrated that cocrystallization slows the elimination of TMZ, suggesting a longer duration of TMZ at the site of action and consequently improved therapeutic efficacy. Therefore, the cocrystal displayed an optimized pharmacokinetic property compared with the individual drugs, implying a promising advantage of clinical effects. In conclusion, a cocrystal composed of two anti-glioma agents, TMZ and BAI, in a 1:1 molecular ratio was prepared with the intention to overcome the defects of both individual APIs and realize drugs combination at a molecular level. The cocrystal drug was subjected to stability and dissolution tests as well as in vivo pharmacokinetic evaluation. The results highlight that not only does TMZ-BAI cocrystal demonstrate improved physical and chemical stability for TMZ; it also diminishes the solubility difference and optimizes pharmacokinetics of TMZ and BAI. The present study demonstrates that cocrystallization can be an efficient approach to construct anti-

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.8b00807. Experimental, DSC and TG thermoanalytical, IR and 1 HNMR spectroscopic, and crystallographic details, and color comparison and PXRD analysis with regard to stability study (PDF) Accession Codes

CCDC 1842673 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

* E-mail: [email protected]. ORCID

Tong-Bu Lu: 0000-0002-6087-4880 Jia-Mei Chen: 0000-0002-3959-901X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21571194). REFERENCES

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