Water-soluble docetaxel anticancer drug compound and preparation method and use thereof

Abstract

The present invention discloses a water-soluble docetaxel anticancer drug compound having the structure of Formula I below: ##STR00001## in which R=CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, or CH.sub.2CH.sub.2CH.sub.2CH.sub.3; and n=5-500. The active moiety docetaxel in the anticancer drug compound is covalently conjugated to a polyethylene glycol monoalkyl ether through a linker diglycoloyl (carbonyl methoxyacetyl) to form the water-soluble docetaxel anticancer drug compound. The present invention also relates to a preparation method of the drug compound and use thereof.

Claims

1. A water-soluble docetaxel anticancer drug compound of Formula I below: ##STR00007## wherein R is C1-C5 alkyl, and n=5-500.

2. The water-soluble docetaxel anticancer drug compound according to claim 1, wherein in Formula I, R=CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, or CH.sub.2CH.sub.2CH.sub.2CH.sub.3.

3. A method for preparing the water-soluble docetaxel anticancer drug compound according to claim 1, comprising: 1) reacting a polyethylene glycol monoalkyl ether with diglycolic acid or diglycolic anhydride to produce a polyethylene glycol monoalkyl ether diglycolate; and 2) reacting the polyethylene glycol monoalkyl ether diglycolate obtained from Step (1), or an acyl chlorinated product of the polyethylene glycol monoalkyl ether diglycolate with docetaxel to produce the water-soluble docetaxel anticancer drug compound of Formula I.

4. The method according to claim 3, wherein, in Step (1), the reaction between the polyethylene glycol monoalkyl ether with diglycolic anhydride is carried out in the presence of tin (II) 2-ethylhexanoate, aluminum trichloride, or cesium carbonate as a catalyst.

5. An injection of the water-soluble docetaxel anticancer drug compound according to claim 1, comprising the water-soluble docetaxel anticancer drug compound of Formula I and one liquid that is water, saline, or a glucose solution.

6. The injection according to claim 5, wherein the drug compound of Formula I accounts for 0.005% to 5.0% by weight of a total weight of the injection.

7. The method according to claim 3, wherein, in Step (1), the reaction between the polyethylene glycol monoalkyl ether with diglycolic acid is carried out in the presence of 4-dimethylaminopyridine and 2-chloro-1-methylpyridinium iodide as a catalyst, or in the presence of N,N-dicyclohexylcarbodiimide and 4-dimethylaminopyridine as a catalyst.

8. The method according to claim 3, wherein, in Step (2), the acyl chlorinated product of the polyethylene glycol monoalkyl ether diglycolate is obtained by reacting the polyethylene glycol monoalkyl ether diglycolate with an acyl chlorinating agent.

9. The method according to claim 8, wherein the reaction between the acyl chlorinated product of the polyethylene glycol monoalkyl ether diglycolate with docetaxel is in the presence of a base as a catalyst to produce the water-soluble docetaxel anticancer drug compound of Formula I.

10. The method according to claim 3, wherein the reaction between the polyethylene glycol monoalkyl ether diglycolate with docetaxel is carried out in the presence of 4-dimethylaminopyridine and 2-chloro-1-methylpyridinium iodide as a catalyst or in the presence of N,N-dicyclohexylcarbodiimide and 4-dimethylaminopyridine as a catalyst.

11. The method according to claim 8, wherein the acyl chlorinating agent is thionyl chloride.

12. The method according to claim 9, wherein the base is selected from the group consisting of triethyl amine, pyridine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, and cesium carbonate.

13. A method of treating cancer, comprising: administering the water-soluble docetaxel anticancer drug compound of Formula I according to claim 1 to a patient in need thereof, wherein the cancer is human lung cancer.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a 1H NMR spectrum of a water-soluble docetaxel anticancer drug compound (polyethylene glycol monomethyl ether docetaxel-2-diglycolate, in which the polyethylene glycol monomethyl ether has an average molecular weight Mn of 1000).

(2) FIG. 2 is a mass spectrum of a water-soluble docetaxel anticancer drug compound (polyethylene glycol monomethyl ether docetaxel-2-diglycolate, in which the polyethylene glycol monomethyl ether has an average molecular weight Mn of 1000).

(3) FIG. 3 shows the average micelle size distribution when a solution of the drug compound XBB-023 in water is 2.5 mg/mL.

(4) FIG. 4 shows the average micelle size distribution when a solution of the drug compound XBB-023 in water is 5 mg/mL.

(5) FIG. 5 shows the variation in the content of docetaxel in percent by weight at various times after the hydrolysis of the drug compound XBB-023.

(6) FIG. 6 shows the variation in the content of the drug compound XBB-023 in percent by weight at various times after the hydrolysis.

(7) FIG. 7 shows three dimensional overlay chromatograms of the drug compound XBB-023 after hydrolysis.

(8) FIG. 8 shows the growth inhibition of the drug compound XBB-023 on A549 human lung cancer xenografts in nude mice.

(9) FIG. 9 shows the effect of the drug compound XBB-023 on the tumor weight of A549 human lung cancer xenografts in nude mice.

(10) FIG. 10 shows the effect of the drug compound XBB-023 on the body weight of the test animals, that is, nude mice with A549 human lung cancer xenografts.

(11) FIG. 11 shows photographs showing the growth inhibition of the drug compound XBB-023 on nude mice with A549 human lung cancer xenografts.

DETAILED DESCRIPTION OF THE INVENTION

(12) The following examples are provided for illustrating the synthesis, preparation, in vitro cell experiments and in vivo pharmacodynamics of the water-soluble docetaxel anticancer drug compound of the present invention. In these examples, detailed descriptions are given with polyethylene glycol monomethyl ether docetaxel-2-diglycolate as an example. The water-soluble docetaxel anticancer drug compounds within the scope of the present invention are synthesized by using the same or similar synthesis method, which are verified to have the same or similar results. The examples described facilitate the understanding and implementation of the present invention and do not constitute limitations on the present invention.

Example 1. Synthesis of Polyethylene Glycol Monomethyl Ether (Mn=1000) Docetaxel-2-Diglycolate

(13) The water-soluble docetaxel anticancer drug compound was synthesized through a process comprising of the following steps.

(14) 1) Synthesis of Polyethylene Glycol Monomethyl Ether (Mn=1000) Diglycolate

(15) Method 1:

(16) The reaction scheme was as shown below:

(17) ##STR00005##

(18) Experimental Steps:

(19) To a 100 mL round-bottom flask, 2.400 g (2.4 mmol) of dried polyethylene glycol monomethyl ether (Mn=1000), 0.557 g (4 mmol) of diglycolic anhydride, and 200 mg of tin (II) 2-ethylhexanoate were added, followed by 30 mL of xylene. The mixture was stirred and heated to reflux under nitrogen atmosphere until the reaction was complete. The xylene was removed from the reaction solution by rotary evaporation. 20 mL of ethyl acetate was added and stirred. 10 mL of diethyl ether was then added, and a white solid was precipitated out. The solid was filtered off, and the filtrate was concentrated to 10 mL by rotary evaporation. After separation by column chromatography (on 100-200 mesh silica gel as a stationary phase, eluting with a mixture of acetonitrile and 1,4-dioxane), 1.865 g of polyethylene glycol monomethyl ether (Mn=1000) diglycolate was obtained (yield 69.3%).

(20) Method 2: To a 100 mL round-bottom flask, 0.644 g (4.8 mmol) of diglycolic acid, 1.450 g (12 mmol) of 4-dimethylaminopyridine, 1.530 g (6 mmol) of 2-chloro-1-methylpyridinium iodide, and 30 mL of N,N-dimethyl acetamide were added and electromagnetically stirred. A solution of 2.400 g (2.4 mmol) of dried polyethylene glycol monomethyl ether (Mn=1000) and 30 mL of N,N-dimethyl acetamide was slowly added dropwise to the reaction solution. The reaction was continued for 12 hrs at room temperature under nitrogen atmosphere. The filtrate was concentrated to 10 mL by rotary evaporation. After separation by column chromatography (on 100-200 mesh silica gel as a stationary phase, eluting with a mixture of acetonitrile and 1,4-dioxane), 1.631 g of polyethylene glycol monomethyl ether (Mn=1000) diglycolate was obtained (yield 60.6%).

(21) 2) Synthesis of Polyethylene Glycol Monomethyl Ether (Mn=1000) Docetaxel-2-Diglycolate (XBB-023)

(22) The reaction scheme was as shown below:

(23) ##STR00006##

(24) 1.667 g (1.49 mmol) of polyethylene glycol monomethyl ether (Mn=1000) diglycolate was dissolved in 30 mL of anhydrous toluene in a 100 mL round-bottom flask. 550 L (7.45 mmol) of thionyl chloride and 2 drops of DMF were added, electromagnetically stirred, and reacted for 4 h at room temperature under nitrogen atmosphere. Toluene and excess thionyl chloride were removed by distillation under reduced pressure and a vicous liquid was obtained. 10 mL of anhydrous chloroform was added to obtain a solution A.

(25) 0.958 g (1.18 mmol) of docetaxel was dissolved in 20 mL of chloroform in a 50 mL reaction flask, and 495.9 L (3.558 mmol) of triethyl amine was added, cooled in an ice-salt bath, and stirred. 10 mL of the solution A was slowly added, and reacted for 4 hrs at room temperature under nitrogen atmosphere. After reaction, chloroform was removed from the reaction solution by distillation under reduced pressure. 20 mL of ethyl acetate was then added to the reaction flask, and stirred. The resulting white solid was filtered off, and then the filtrate was concentrated to 10 mL. After separation by column chromatography with gradient elution (on 100-200 mesh silica gel as a stationary phase, eluting with a mixture of acetonitrile and 1,4-dioxane), 1.205 g of polyethylene glycol monomethyl ether (Mn=1000) docetaxel-2-diglycolate as a viscous white liquid was obtained (yield 53.6%).

(26) The mass spectra and 1H NMR spectrum of the synthesized compound are shown in FIGS. 1 and 2.

(27) MS (Positive ESI): m/z=1885.0, 1840.9, 1796.9, 1752.9, 1708.9, 1664.9, 1620.8, 1576.8.

(28) MS(Negative ESI): m/z=1906, 1861.9, 1816.9, 1773.9, 1728.8, 1685.8, 1640.8, 1596.7, 1553.7, 1508.7.

(29) .sup.1H NMR (300 MHz, CDCl3): ppm: 8.12948.1051 (d, 2H, J=7.29 Hz), 7.63387.5848 (t, 1H, J=7.35 Hz), 7.52717.4775 (t, 2H, J=7.44 Hz), 7.42587.3779 (m, 2H), 7.34657.2837 (m, 3H), 6.26706.2131 (t, 1H), 5.70255.6791 (d, 1H, J=7.02 Hz), 5.4493 (m, 2H), 5.2145 (s, 1H), 4.97754.9508 (d, 1H, J=8.01 Hz), 4.37054.1828 (m, 9H), 3.94493.9220 (d, 1H), 3.6429 (m, 84H), 3.57663.5320 (m, 2H), 3.3784 (s, 3H), 2.61562.5076 (m, 1H), 2.4342 (s, 3H), 2.43402.3501 (m, 2H), 1.9523 (s, 3H), 1.9401.9109 (m, 1H), 1.9043 (s, 3H), 1.3345 (s, 9H), 1.2327 (s, 3H), 1.1301 (s, 3H).

Example 2. Formulations of Water-Soluble Docetaxel Anticancer Drug Compound (XBB-023)

(30) In this example, injections of XBB-023 with water, saline (0.9% sodium chloride) or a glucose solution (5%) are provided. The injections contain the water-soluble docetaxel anticancer drug compound of the present invention, where the content of each component in the formulation is in percentages by weight.

(31) 1). Injection of Water-Soluble Docetaxel Anticancer Drug Compound in Water

(32) 100 mg of the water-soluble docetaxel anticancer drug compound (XBB-023) was added to a 10 mL volumetric flask, added with water q.s. to 10 mL, and shaken to provide an injection having a composition comprising:

(33) TABLE-US-00001 XBB-023 1.0% Water 99.0%.

(34) The injection produced was filtered through a 0.2 m filter, and filled in a sterilized glass vial.

(35) 2) Injection of Water-Soluble Docetaxel Anticancer Drug Compound in Saline (0.9% Sodium Chloride)

(36) 50 mg of the water-soluble docetaxel anticancer drug compound (XBB-023) was added to a 10 mL volumetric flask, added with saline (0.9% sodium chloride) q.s. to 10 mL, and shaken to provide an injection having a composition comprising:

(37) TABLE-US-00002 XBB-023 0.5% Saline 99.5%.

(38) The injection produced was filtered through a 0.2 m filter, and filled in a sterilized glass vial.

(39) 3) Injection of Water-Soluble Docetaxel Anticancer Drug Compound in 5% Glucose Solution

(40) 50 mg of the water-soluble docetaxel anticancer drug compound (XBB-023) was added to a 10 mL volumetric flask, added with 5% glucose solution for injection q.s. to 10 mL, and shaken to provide an injection having a composition comprising:

(41) TABLE-US-00003 XBB-023 0.5% 5% glucose for injection 99.5%.

(42) The injection produced was filtered through a 0.2 m filter, and filled in a sterilized glass vial.

Example 3. Determination of Micelle Size of Water-Soluble Docetaxel Anticancer Drug Compound (XBB-023)

(43) Micelles were formed after the water-soluble docetaxel anticancer drug compound XBB-023 was dissolved in water. The micelle size was determined by using the ZetaPlus laser scattering particle size analyzer from BROOKHAVEN, USA. 5 mg and 10 mg of the drug (XBB-023) were put into 2 mL of distilled water respectively, stirred to be fully dissolved, and allowed to stand for 10 minutes. After the bubbles disappeared, the liquid was added to a sample cell (cuvette). During the process, caution should be taken to avoid the generation of bubbles. Then, the cuvette was placed in a groove corresponding to the base of the sample cell for measurement. Each sample was triplicated and the three measurements were averaged.

(44) The experimental results are shown in FIGS. 3 and 4. The results show that when the concentration of the aqueous XBB-023 solution is 2.5 mg/mL and 5 mg/mL, the average particle size is 101.2 nm and 345.0 nm respectively.

Example 4. In Vitro Test for the Action of Sustained Release of the Water-Soluble Docetaxel Anticancer Drug Compound (XBB-023)

1. Instruments and Reagents

(45) Shimadzu LC-20AT high performance liquid chromatograph, SPD-20A detector, Lab Solutions chromatography workstation (Shimadzu Corporation, Japan); DF-1 heat-collection thermostatic magnetic stirrer (Shanghai Jiangxing Instrument Co., Ltd.); and FA2004B electronic balance (Shanghai Yueping Scientific Instrument Co., Ltd.).

(46) Methanol: chromatographic grade, purchased from Tedia (USA); KH.sub.2PO.sub.4 and NaOH: analytically pure, purchased from Sinopharm Chemical Reagent Co., Ltd.; and water for test: distilled water.

(47) A phosphate buffer (0.05M KH.sub.2PO.sub.4, 0.04M NaOH) at pH 7.40 was formulated.

2. Test Method

(48) 10 mg of XBB-023 was accurately weighed into a screw cultivation flask, and then 3 ml of the phosphate buffer was added, and magnetically stirred until clear.

(49) The oil bath temperature of the heat-collection thermostatic magnetic stirrer was set to 37 C., and the XBB-023 formulation was placed therein for hydrolysis.

(50) At 0, 1, 2, 5, 6, 7, 25, 31, 48, 55, 72, 79, 103, and 168 h after hydrolysis, 60 L of the XBB-023 reaction solution was pipetted into a chromatographic bottle and 540 L of acetonitrile was added to obtain a 0.33 mg/ml sample, which was then subjected to HPLC analysis.

3. HPLC Analysis

(51) Chromatographic column: C18 column (5 m, 150 mm5 mm); mobile phase: acetonitrile:water (50:50); detection wavelength: 227 nm; flow rate:1.0 ml/min; volume of injection: 5 L; and column temperature: 40 C.

(52) XBB-023 and docetaxel can be detected simultaneously using the above HPLC analysis conditions. Target retention time t.sub.xBB-023=9.6 min, and t.sub.docetaxel=8.0 min.

4. Experimental Results

(53) The percentage contents of docetaxel and XBB-023 at various times after the hydrolysis of XBB-023 can be obtained by area normalization method. The experimental results are shown in Tables 1 and 2, and FIGS. 5, 6 and 7. It can be known from the comparison of the chromatograms of XBB-023 at various hydrolysis times that with the elapse of time, the XBB-023 peak area gradually declines and the peak height gradually decreases. In the meanwhile, a peak appears at the retention time of docetaxel, the peak area gradually increases, and the peak height rises gradually. This suggests that XBB-023 is continuously hydrolyzed to release docetaxel over the time.

(54) TABLE-US-00004 TABLE 1 Percentage content of docetaxel at various times after the hydrolysis of XBB-023 Hydrolysis time (hr) Area % 0 0.151 1 8.764 2 15.654 5 34.732 6 41.899 7 46.871 25 70.097 31 70.969 48 73.189 55 74.509 72 74.38 79 75.506 103 75.61 168 74.708

(55) TABLE-US-00005 TABLE 2 Percentage content of XBB-023 at various times after the hydrolysis of XBB-023 Hydrolysis time (hr) Area % 0 98.489 1 89.088 2 81.724 5 58.427 6 50.359 7 44.823 25 13.289 31 10.279 48 6.213 55 5.384 72 4.156 79 3.861 103 3.299 168 1.721

5. Conclusions

(56) The results show that the drug compound XBB-023 can be gradually hydrolyzed to release docetaxel in vitro in a buffer solution (pH 7.40) at 37 C. Therefore, as a prodrug, the drug compound XBB-023 can be directly dissolved in water, saline, or a glucose solution to prepare an injection or other preparations, which can release docetaxel in vivo to inhibit the tumor growth.

Example 5. Pharmacodynamic Test of Growth Inhibition of Water-Soluble Docetaxel (XBB-023) on A549 Human Lung Cancer Xenografts in Nude Mice

(57) 1) Formulation Method

(58) 48 mg of the drug XBB-023 was accurately weighed at each administration, to which 10 ml of 0.9% sodium chloride solution (manufactured by Chenxin Pharmaceutical Co., Ltd.; lot number: 1403222705; specification: 250 ml: 12.5 g) was added to give a concentration of 4.8 mg/ml. The dose volume was 0.4 ml per 20 g, that is, the dose was 96 mg/kg. Then, the solution was diluted to other desired concentrations with 0.9% sodium chloride solution.

(59) 2) Control Agent

(60) Docetaxel injection, manufactured by Jiangsu Hengrui Pharmaceutical Co., Ltd., lot number: 15011215, specification: 0.5 ml: 20 mg. Formulation method: during use, 20 mg of docetaxel injection of the above specification was added to 1.5 ml of a solvent for the docetaxel injection to give a concentration of 10 mg/ml, and then fully diluted with saline to 1 mg/ml. The dose volume was 0.2 ml per 20 g, that is, the dose was 10 mg/kg.

(61) 3) Source, Germline, and Strain of Test Animals

(62) BALB/c nude mice, provided by Changzhou Kavens Laboratory Animal Co., Ltd. (Experimental Animal Production License: SOCK (Su) 2011-0003), age: 35-40 days, weight: 18-24 g, female.

(63) 4) Grouping of Test Animals

(64) TABLE-US-00006 Negative control group (Blank control) 12 animals Positive control group (Docetaxel, 10 mg/kg) 6 animals Treatment group (XBB-023, 96 mg/kg) 6 animals Treatment group (XBB-023, 48 mg/kg) 6 animals Treatment group (XBB-023, 24 mg/kg) 6 animals

(65) 5) Xenografts

(66) A549 human lung cancer xenografts in nude mice was established by inoculating human lung cancer A549 cell line subcutaneously to the axillary fossa of nude mice in an amount of 2*10.sup.6 cells/animal.

(67) 6) Test Method

(68) Human lung cancer A549 cell line in logarithmic growth phase was prepared into a cell suspension of 110.sup.8 cells/ml under aseptic conditions and subcutaneously inoculated to the right axillary fossa of nude mice in a volume of 0.1 ml. The size of the xenograft in the nude mice was measured with a vernier caliper. After the xenografts grew to 100-300 mm.sup.3, the animals were randomly grouped. The anti-tumor effect of the test agents was dynamically observed by measuring the size of the xenografts. The size of the xenografts was measured once every 3 days. The dose volume was 0.4 ml/20 g. Twenty-one days later, the mice were sacrificed and the tumors were surgically excised and weighed. The tumor volume (TV) is calculated by a formula below:
TV=ab.sup.2

(69) in which a and b denote the length and width respectively.

(70) The relative tumor volume (RTV) is calculated based on the measurements by a formula: RTV=V.sub.t/V.sub.0, where V.sub.0 is the measured tumor volume upon being caged (i.e., d.sub.0) and V.sub.t is the tumor volume at each measurement. The evaluation index of the anti-tumor activity is relative tumor growth rate T/C (%), which is calculated by a formula below:

(71) $T\text{/}C\left(\%\right)=\frac{T_{\mathrm{RTV}}}{C_{\mathrm{RTV}}}100$

(72) in which T.sub.RTV is the RTV of the treatment group; and C.sub.RTV is the RTV of the negative control group.

(73) The tumor inhibition rate is calculated by a formula below:

(74) $\mathrm{Tumor}\mathrm{inhibition}\mathrm{rate}\left(\%\right)=\left(1-\frac{T_{\mathrm{weight}}}{C_{\mathrm{weight}}}\right)100$

(75) T.sub.weight is the average tumor weight of the treatment group; and C.sub.weight is the average tumor weight of the negative control group.

(76) 7) Results and Discussion

(77) The experimental results are shown in Tables 3 and 4, and FIGS. 8 to 11. The drug XBB-023 is administered via the tail vein at the doses of 96 mg/kg, 48 mg/kg, and 24 mg/kg, respectively, once every 3 days for a total of 7 doses. The T/C ratio of the A549 human lung cancer xenografts in nude mice in the experimental groups is 12.83%, 25.56%, and 56.30%, respectively; and the tumor inhibition rate is 88.45%, 68.55%, and 34.73%. After docetaxel (10 mg/kg) is administered once every 3 days via tail vein injection for a total of 7 doses, the T/C ratio of the A549 human lung cancer xenografts in nude mice is 21.15% and the tumor inhibition rate is 72.16%.

(78) Extremely significant effect on the body weight of the experimental mice (P<0.01) is exhibited in the positive control group administered with 10 mg/kg docetaxel and in the group administered with 96 mg/kg XBB-023, and significant effect on the body weight of the experimental mice (P<0.05) is exhibited in the group administered with 48 mg/kg XBB-023. The test results show that the inhibition rate of the drug XBB-023 at 96 mg/kg is 16.29% higher than that in the positive control group with 10 mg/kg docetaxel, but the effect on the body weight of the experimental mice is less, indicating that the efficacy of XBB-023 at a high dose is better than that of docetaxel, and the toxicity is lower.

(79) TABLE-US-00007 TABLE 3 Effect of the drug XBB-023 on the tumor volume of A549 human lung cancer xenografts in nude mice (X SD, Tumor volume: in mm.sup.3) Dosage 0 d 3 d 6 d Group (mg/kg) Tumor volume Tumor volume RTV T/C Tumor volume RTV T/C Blank 100.53 20.71 275.54 90.21 2.88 1.17 348.56 80.33 3.60 1.04 control group Docetaxel 10 100.58 20.87 157.30 26.48** 1.62 0.37** 56.09% 147.47 41.99** 1.49 0.39** 41.39% XBB-023 96 102.83 14.74 154.44 15.73** 1.54 0.31** 53.47% 129.15 19.29** 1.26 0.15** 35.11% XBB-023 48 101.49 18.47 159.57 38.77** 1.59 0.35** 55.23% 180.89 31.39** 1.80 0.18** 49.90% XBB-023 24 101.08 20.73 232.16 79.30* 2.27 0.52** 78.90% 244.45 80.88** 2.38 0.37** 66.13% 9 d 12 d Tumor volume RTV T/C Tumor volume RTV T/C Blank 100.53 20.71 449.69 83.72 4.65 1.17 617.35 78.42 6.37 133 control group Docetaxel 10 100.58 20.87 155.55 44.12** 1.59 0.47** 34.23% 208.93 68.26** 2.15 0.81** 33.77% XBB-023 96 102.83 14.74 15628 17.71** 1.54 0.22** 33.18% 156.91 35.05** 1.54 0.33** 24.19% XBB-023 48 1.01.49 18.47 245.14 40.82** 2.46d 0.37** 52.80% 302.66 60.48 3.02 0.53 47.50% XBB-023 24 101.08 20.73 289.34 82.35** 2.85 0.39** 61.19% 371.41 95.01** 3.68 0.51** 57.80% 15 d 18 d Tumor volume RTV T/C Tumor volume RTV T/C Blank 100.53 20.71 802.08 171.71 8.36 2.57 932.09 302.48 9.69 3.70 control group Docetaxel 10 100.58 20.87 224.22 57.63** 2.24 0.43** 26.80% 186.80 42.03** 1.87 0.28** 19.30% XBB-023 96 102.83 14.74 107.31 27.45** 1.06 0.28** 12.63% 114.16 17.61** 1.13 0.21** 11.66% XBB-023 48 101.49 18.47 264.78 68.29** 2.61 0.47** 31.23% 257.22 76.37** 2.50 0.37** 25.76% XBB-023 24 101.08 20.73 522.84 249.70* 4.91 1.58** 58.72% 602.28 288.50** 5.68 1.66** 58.60% 21 d Tumor volume RTV T/C Blank 100.53 20.71 1103.90 314.12 11.34 3.41 control group Docetaxel 10 100.58 20.87 226.65 56.45* 2.40 0.99* 21.15% XBB-023 96 102.83 14.74 146.15 20.51** 1.46 0.32** 12.83% XBB-023 48 101.49 18.47 299.13 86.76** 2.90 0.37** 25.56% XBB-023 24 101.08 20.73 660.00 210.71* 6.39 0.81* 56.30% Note: compared with the blank control group, *P < 0.05, **P < 0.01

(80) TABLE-US-00008 TABLE 4 Inhibition of the drug XBB-023 on the tumor growth of A549 human lung cancer xenografts in nude mice (X SD) Initial Final number number Tumor Dosage Administration Initial body of Final body of Tumor weight inhibition Group (mg/kg) frequency weight (g) animals weight (g) animals (g) rate (%) Blank 22.75 1.92 12 24.08 2.06 12 1.20 0.53 control group Docetaxel 10 Once every 3 days 22.50 1.26 6 15.17 0.90** 6 0.33 0.15** 72.16% XBB-023 96 Once every 3 days 22.00 0.82 6 16.00 2.31** 6 0.14 0.03** 88.45% XBB-023 48 Once every 3 days 21.33 1.37 6 20.00 0.82** 6 0.38 0.14** 68.55% XBB-023 24 Once every 3 days 22.17 1.57 6 23.17 0.90* 6 0.78 0.22 34.73% Compared with the blank control group, *P < 0.05, **P < 0.01