AU2021100811A4 - Powder injection medicament for treating lung cancer and malignant lymphoma by local injection, and preparation method thereof - Google Patents

Abstract

DCC- 902/2021 ABSTRACT The present disclosure discloses a medicament for treating lung cancer and malignant lymphoma and use thereof. Through long-term research, the inventors found for the first time that aluminum sulfate can distinguish between normal human tissues and cancer tissues, and can change the physiological characteristics of cancer cells, inhibit the secretion of various proteolytic enzymes by cancer cells and suppress the metabolic function of mitochondria in cancer cells to achieve anti-tumor effects. The medicament can bind to DNA of cancer cells and promote the lysis thereof, and can quickly and efficiently converge and condense glycoproteins on the cell surface, effectively change protein structures on the cell surface, block signaling pathways, change cell microstructures, and bind to succinate dehydrogenase (SDH) in mitochondria. Refractory malignant solid tumors with the highest incidence among human beings, the highest mortality, the highest treatment difficulty, and the worst prognosis (including lymphatic metastasis) can be treated by western medicines (specific), with a cure rate as high as 99.8% to 99.9% or even 100%. The present disclosure has important practical significance for humans to conquer lung cancer and malignant lymphoma by local injection of a powder injection. 21168904.1:DCC - 9/02/2021 3/20 120 A IC50=10.696mg/ml 100 Enax=99.4% 80 0 60. a) CO L40 0 20o -0 -1 0 1 2 3 Logarithmicconcentration B 120 IC50=6.822mg/ml Emax=99.6% 100 a) -0 40 -o20 0 -1 0 1 2 3 Logarithmicconcentration FIG. 3

Description

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3/20

120 A IC50=10.696mg/ml 100 Enax=99.4%

80

0 60. a) CO L40

0 20o

-0

-1 0 1 2 3 Logarithmicconcentration

B 120 IC50=6.822mg/ml Emax=99.6% 100

a)

-0 40

-o20

0

-1 0 1 2 3 Logarithmicconcentration

FIG. 3

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POWDER INJECTION MEDICAMENT FOR TREATING LUNG CANCER AND MALIGNANT LYMPHOMA BY LOCAL INJECTION, AND PREPARATION METHOD THEREOF TECHNICAL FIELD The present disclosure relates to new use of a compound, and in particular to a powder injection medicament for treating lung cancer and malignant lymphoma by local injection, and use thereof. BACKGROUND According to the analysis of national cancer registration results in 2013, the incidence of cancer in China was 235/100,000, with incidences of lung cancer and breast cancer ranking the first among men and women, respectively, and the incidence of cancer in China had been on the rise in the past decade. In 2012, among adults aged 18 and over, a prevalence of hypertension was 25.2% and a prevalence of diabetes was 9.7%, exhibiting an upward trend compared with that in 2002; and among people aged 40 and over, a prevalence of chronic obstructive pulmonary disease (COPD) was 9.9%. In 2012, the national mortality of chronic diseases was 533/100,000, accounting for 86.6% of the total deaths. Cardiovascular diseases (CVDs), cancer and chronic respiratory diseases (CRDs) are the main causes of death, accounting for 79.4% of the total deaths. The mortality of CVD is 271.8/100,000, the mortality of cancer is 144.3/100,000 (the top five are lung cancer, liver cancer, gastric cancer, esophageal cancer, colorectal cancer (CRC)), and the mortality of CRD is 68/100,000. The treatment methods for lung cancer mainly include the following: (I) Chemotherapy Chemotherapy is the main treatment for lung cancer, and more than 90% of patients with lung cancers require chemotherapy. Chemotherapy has a positive effect on small cell lung cancer (SCLC) at an either early or late stage, and even about 1% of patients with early-stage SCLC are cured by chemotherapy. Chemotherapy is also the main method for treating non-small cell lung cancer (NSCLC), which can achieve a tumor response rate (TRR) of 40% to 50% in treating NSCLC. Chemotherapy generally cannot cure NSCLC, and can only prolong the survival and improve the life quality for a patient. Chemotherapy includes therapeutic chemotherapy and adjuvant chemotherapy. Different

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chemotherapeutic medicaments and different chemotherapeutic regimens are adopted according to different histological types of lung cancer in chemotherapy. In addition to killing tumor cells, chemotherapy also poses damages to normal human cells. Therefore, chemotherapy needs to be conducted under the guidance of an oncology specialist. In recent years, chemotherapy is no longer limited to inoperable patients with advanced lung cancer, but is often included in the comprehensive treatment regimen for lung cancer as a systemic treatment. Chemotherapy may inhibit the hematopoietic system in bone marrow, mainly reducing the white blood cells (WBCs) and platelets, which can be treated with granulocyte colony-stimulating factor (G-CSF) and platelet-activating factor (PAF). (II) Radiotherapy 1. Therapeutic principles Radiotherapy exhibits the best effect on SCLC, the secondary effect on squamous cell carcinoma (SCC), and the worst effect on adenocarcinoma (AC). The radiation field of lung cancer radiotherapy should include the mediastinum of the primary lesion and lymph node metastasis. Radiotherapy should be assisted with medicaments. SCC is moderately sensitive to radiation. The lesion is mainly advanced locally and metastasis is relatively slow, so radical treatment is often adopted. AC has poor sensitivity to radiation and is prone to hematogenous metastasis, so radiotherapy is rarely used alone. Radiotherapy is a local treatment, which should often be used in combination with chemotherapy. The combination of radiotherapy and chemotherapy can be adopted as simultaneous radiotherapy and chemotherapy or alternative chemotherapy and radiotherapy according to different conditions of a patient. 2. Radiotherapy classification According to the purpose of treatment, radiotherapies are divided into radical treatment, palliative treatment, preoperative neoadjuvant radiotherapy, postoperative adjuvant radiotherapy, and intracavitary radiotherapy. 3. Radiotherapy complications Complications of lung cancer radiotherapy include radiation pneumonitis, radiation esophagitis, radiation pulmonary fibrosis, and radiation myelitis. There is a positive correlation between the above-mentioned radiotherapy-related complications and radiotherapy dosage, and there are also individual differences. (III) Surgical treatment of lung cancer

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Surgical treatment is the preferred and most important treatment method for lung cancer, and is also the only treatment method that can cure lung cancer. The surgical treatment of lung cancer is conducted to: completely resect the primary lesion of lung cancer and the metastatic lymph nodes to achieve clinical cure; or remove most of the tumor to create favorable conditions for other treatments, namely, cytoreductive surgery (CRS). CRS is suitable for a small number of patients, such as patients with refractory pleural and pericardial effusions, where, pleural and pericardial planting nodules are resected and parts of the pericardium and pleura are resected to cure or alleviate the clinical symptoms caused by pericardial and pleural effusions, and to prolong the life or improve the life quality. CRS requires simultaneous local and systemic chemotherapies. Surgical treatment often requires adjuvant chemotherapy and radiotherapy before or after surgery to improve the cure rate of surgery and the survival rate of a patient. The surgical treatment of lung cancer has a five-year survival rate of 30% to 44% and a mortality of 1% to 2%. The surgical treatment is also subjected to various restrictions. Existing treatment methods have the disadvantages of high cost, long course of treatment, and poor effect. Therefore, there is an urgent need for a medicament for treating lung cancer to alleviate pressing demands of cancer patients. Aluminum sulfate is a common sulfate, which can be used as a precipitating agent for rosin size, wax emulsion and other sizing materials in the paper industry, as a flocculant in water treatment, as an internal retention agent for foam extinguishers, as a raw material for producing alum and aluminum white, and as an adjuvant for petroleum decolorization, deodorization, and some medicaments. About 50% of the total aluminum sulfate output is used in papermaking, as the first major use, and about 40% of the total aluminum sulfate output is used as a flocculant in treatment of drinking water, industrial water and industrial wastewater, as the second major use. When aluminum sulfate is added to these types of water, colloidal aluminum hydroxide flakes can be produced to adsorb and precipitate bacteria, colloids and other suspended solids. Aluminum sulfate can be used in drinking water treatment to control the color and taste of water. SUMMARY The present disclosure is intended to provide a powder injection medicament for

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treating lung cancer and malignant lymphoma by local injection, and a preparation method thereof. The present disclosure adopts the following technical solutions: The present disclosure provides a medicament for treating lung cancer and malignant lymphoma, and an active ingredient in the medicament includes aluminum sulfate. Preferably, the aluminum sulfate may be injection-grade or above aluminum sulfate or may be obtained by the following purification method: 1) mixing aluminum sulfate with distilled water for dissolution to obtain an aluminum sulfate solution; and 2) subjecting the aluminum sulfate solution to fine filtration and lyophilization to obtain the aluminum sulfate. Preferably, the medicament may be an injection preparation. The injection preparation may be selected from a powder injection and an injection solution. The aluminum sulfate and distilled water may be mixed at a mass ratio of 1:2, and the aluminum sulfate is purified by the distilled water after dissolution. The aluminum sulfate solution may be subjected to fine filtration using a filter membrane with a pore size of 0.22 m. Preferably, the aluminum sulfate may be selected from hydrates of aluminum sulfate. After decades of research and exploration, the present disclosure found for the first time that aluminum sulfate can distinguish between normal human tissues and cancerous tissues and promote the volunteer separation and exfoliation of the cancerous tissues from the normal tissues, and can also distinguish between normal cells and cancer cells and selectively starve cancer cells. So far, aluminum sulfate is a leading chemical medicament that can achieve the fastest and most accurate treatment for malignant tumors, with low toxicity and high efficiency. Aluminum sulfate has basically no inhibitory effect on normal cells, can quickly kill cancer cells and reduce tumor volumes, and exhibits a therapeutic effect far better than that of a traditional anti-cancer medicament. The advent of this medicament can save tens of thousands of lives, which is especially suitable for the treatment of malignant solid tumors. The medicament has be successfully developed by the inventors through several decades of research and huge investment, which is one of the world's most cutting-edge and leading anti-cancer specific novel medicaments. The medicament exhibits a

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therapeutic effect that was not achieved by humans through radiotherapy, chemotherapy, surgery and any modern treatment method for treating malignant solid tumors before. After administration of the medicament, a malignant solid tumor can be gradually separated and exfoliated volunteerly from normal human tissues. Conclusion: The present disclosure is a major milestone in human history. The present disclosure can make an inestimable outstanding contribution to the treatment of severe human diseases. Refractory malignant solid tumors with the highest incidence among human beings, the highest mortality, the highest treatment difficulty, and the worst prognosis (including lymphatic metastasis) can be treated by local injection of western medicines (specific), with a cure rate as high as 99.8% to 99.9% or even 100%. Once the commercialization is successful, tens of thousands of lives can be saved every year. The medicament of the present disclosure has been painstakingly pursued by humans for decades. One injection can be administered for inactivation, which will surely astonish the world. The advent of the medicament can rewrite the history that human tumors emerge endlessly, require a large amount of time and money for treatment, and may not be cured after a long time of treatment. Pharmacology: The key pathways of cancer cell apoptosis after administration are as follows: 1. The medicament can quickly and efficiently converge and condense glycoproteins on the surface of cancer cells. 2. The medicament can change the physiological characteristics of cancer cells. 3. The medicament can inhibit the secretion of various proteolytic enzymes by cancer cells. 4. The medicament can inhibit the metabolic function of mitochondria in cancer cells. 5. The medicament can bind to DNA in cancer cells and promote the lysis thereof. 6. The medicament can effectively change a protein structure on the surface of cancer cells. 7. The medicament can block the signaling pathway. 8. The medicament can quickly and forcefully close the cancer cell feeding channel. 9. The medicament can change cell microstructures. 10. The medicament can bind to succinate dehydrogenase (SDH) in mitochondria to change the biological effect thereof.

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11. Normal cells are fed regularly while cancer cells are fed irregularly. 12. The medicament selectively attacks abnormal cancer cells and does not attack normal cells. 13. The medicament selectively attacks abnormal cancer tissues and does not attack normal tissues. 14. With the continuous penetration of the medicament injected into malignant solid tumors, abnormal malignant cancer tissues attached to normal tissues and organs of the human body are gradually separated and exfoliated volunteerly. Notes: For a mouse tumor volume of 3 cm x 3 cm and at a dosage of 300 mg/mL, the tumor is scabbed at 6 h and disappears the next day. At a dosage of 400 mg/mL to 500 mg/mL, the tumor activity disappears more quickly. Toxicology: From decades of research and testing, no obvious toxic and side effects have been seen at high dosages. Efficacy: The medicament has the characteristics of small dosage, quick onset, short course of treatment, small side effects, etc. The medicament to treat the following malignant solid tumors is the latest compound that humans most hope to find and discover so far. The treatment of the following severe diseases does not vary from person to person, and consistency can be achieved. The medicament can be injected into any part (malignant solid tumor) of the human body except the brain. Notices: 1. Before any tumor at an early, middle or late stage (malignant solid tumor) is injected with the medicament, general examination needs to be conducted by positron emission tomography-computed tomography (PET/CT). 2. Routine blood examination. 3. All carcinoembryonic indicators are fully examined, needle biopsy is conducted after a treatment period ends, and examination results before and after the treatment are compared. 4. An imaging agent is injected according to a traditional therapy. The puncture injection should avoid blood vessels and the medicament is injected into the core of a tumor. 5. If a malignant tumor is wrapped by organs in a cavity, it is inconvenient for local percutaneous injection. A laparotomy can be conducted to achieve injections at multiple

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sites at one time, and then the abdominal cavity is closed. For tumors (malignant tumors) at a late stage that are too large in size, multi-site injection can be conducted by inserting needles at one time, so as to avoid the need to insert needles multiple times. The medicament must be injected into the core of a tumor rather than the surface of the tumor, otherwise, no effects will be achieved. 6. In short, it is simple, fast and thorough in treating human malignant solid tumors. 7. For tumors at early and middle stages, only a single injection is required; and for tumors at a late stage, multi-site injection is conducted at one time, and the tumor can be observed to shrink rapidly the next day. The course of treatment is 6 days and the examination method must be a biopsy. If other methods are used for examination, it is a misjudgment that observing a shadow does not refer to the presence of cancer. Practice has proved that all cancers are not formed by accumulation of cancer cells. Most tumors only include 45% to 55% of cancer cells, and the rest are cells whose autoimmune repair is damaged by cancer cells. Therefore, it is critical to adopt a needle biopsy after the treatment period ends, which can truly, objectively, fairly and scientifically reflect the results. Scirrhous carcinoma: with few cancer cells but much stroma, and a hard texture. Simple carcinoma: with a ratio of parenchyma to stroma: approximately 1:1. Atypical medullary carcinoma: with more parenchyma but less stroma, a soft texture, large cancer cells, obvious atypia, and common mitotic figures, where, there is generally no lymphocytic infiltrate in the stroma and the prognosis of a traditional treatment is poor. Solid cancer: a general term for cancer cells that grow into a solid, where, the cancer nest is solid, which has no glandular cavity-like structures but has high atypia and many mitotic figures; and solid cancers include early lung cancer, breast cancer, liver cancer, and bowel cancer, which have different ratios of parenchyma to stroma. Research findings: 1. Malignant tumors and lesion neoplasms thereof are not controlled by the human central nervous system macroscopically and microscopically, so there is basically no pain sense at these sites when injection. Because the human body's normal skin and flesh tissues are controlled by the central nervous system macroscopically and microscopically, there is pain sense at these sites.

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2. Therefore, injection of the medicament into normal skin and muscle tissues of the human body should be avoided as far as possible when injection. If the medicament penetrates into the normal skin and muscle tissues of the human body, there will not be a serious problem, and the pain sense will voluntarily disappear about 12 h to 24 h later without other auxiliary treatments. Table 1 Different dosages of a powder injection medicament for treating lung cancer and malignant lymphoma by local injection according to different tumor volumes

Notes: each (powder injection): 4,000 mg diluted in 8 mL of 0.9% sodium chloride NS. No. Tumor volume (cm) Dosage x0.9% sodium Injection method chloride injection Solid cancer: 2 cm x 2 cm 2 mL local percutaneous injection into a 1 to 3 cm x 3 cm malignant solid tumor Solid cancer: 4 cm x 4 cm 4 mL local percutaneous injection into a 2 to 5 cm x 5 cm malignant solid tumor 6 mL local percutaneous injection into a 3 Solid cancer: 6 cm x 6 cm to 7 cm x 7 cm malignant solid tumor Solid cancer: 8 cm x 8 cm 8 mL local percutaneous injection into a 4 to 9 cm x 9 cm malignant solid tumor 10 mL local percutaneous injection into a 5 Solid cancer: 10 cm x 10 cmto 11 cm x 11 cm malignant solid tumor 6 Solid cancer: 12 cm x 12 12 mL local percutaneous injection into a cm to 13 cm x 13 cm malignant solid tumor Notes: The onset time of the medicament is 3 min to 5 min, namely, cancer cell apoptosis begins after that time. A patient is prohibited from walking within 25 min to 30 min after injection to avoid loss of the medicament and reduction of the therapeutic effect.

Notes: The onset time of the medicament is 3 min to 5 min, namely, cancer cell apoptosis begins after that time. A patient is prohibited from walking within 25 min to 30 min after injection to avoid loss of the efficacy of the medicament. Functions and indications: treating lung cancer and malignant lymphoma. Cell experiment data show that aluminum sulfate has a significant inhibitory effect on the proliferation of six kinds of human lung cancer cells, with IC5 o: 10.696 mg/mL for NCI-H446, 6.822 mg/mL for NCI-H460, 22.265 mg/mL for A549, 7.500 mg/mL for NCI-H226, 9.258 mg/mL for NCI-H596, and 10.047 mg/mL for NCI-H292, respectively; aluminum sulfate shows a significant pro-apoptotic effect on the six kinds of human lung cancer cells, and there is a concentration-effect relationship; and aluminum sulfate can block the cell cycle of the six kinds of human lung cancer cells at Go/G1 phase, and there is a concentration-effect relationship.

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An aluminum sulfate preparation is injected to treat lung cancer and malignant lymphoma, with the characteristics of small dosage, quick onset, short course of treatment, small side effects, etc. The preparation can quickly reduce tumor volumes, induce apoptosis, and inhibit proliferation. If the malignant tumors are found to be about 2 cm x 2 cm x 2 cm to 3 cm x 3 cm x 3 cm at an early stage, only a single injection of the preparation can enable the tumor cell activity to completely disappear at 36 h to 72 h. The present disclosure has important practical significance for humans to conquer lung cancer and malignant lymphoma. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is an HPLC chromatogram of purified aluminum sulfate. FIG. 2 shows pictures of animals in an acute toxicity test. FIG. 3 shows concentration-inhibition rate curves of aluminum sulfate on different lung cancer cells, where, A and B are concentration-inhibition rate curves for NCI-H446 and NCI-H460 cells, respectively. FIG. 4 shows concentration-inhibition rate curves of aluminum sulfate on different lung cancer cells, where, A and B are concentration-inhibition rate curves for A549 and NCI-H226 cells, respectively. FIG. 5 shows concentration-inhibition rate curves of aluminum sulfate on different lung cancer cells, where, A and B are concentration-inhibition rate curves for NCI-H596 and NCI-H292 cells, respectively. FIG. 6 and FIG. 7 show the effect of aluminum sulfate on the proliferation of lung cancer cells, where, the arrows indicate necrotic cells. FIG. 8 to FIG. 13 show the effect of aluminum sulfate on the apoptosis of human lung cancer cells NCI-H446, NCI-H460, A549, NCI-H226, NCI-H596, and NCI-H292, respectively. FIG. 14 and FIG. 15 show the effect of aluminum sulfate on the apoptosis of lung cancer cells, where, the arrows indicate shrinkage of a nucleus, namely, indicating apoptotic cells. FIG. 16 to FIG. 21 show the effect of aluminum sulfate on the apoptosis cycle of human lung cancer cells NCI-H446, NCI-H460, A549, NCI-H226, NCI-H596, and NCI-H292,respectively.

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DETAILED DESCRIPTION Experimental data to confirm the chemical structure The experiment was entrusted to Hunan Experimental Animal Center (Hunan Drug Safety Evaluation Research Center). This experiment was conducted in accordance with the relevant technical guidelines for preclinical pharmacodynamics; this report faithfully reflected the experimental materials, methods and results; and the factors affecting the experimental results were minimized or avoided in this experiment. Research purpose: This study observed the in vitro inhibitory effect of a compound XL-012 on six human lung cancer cell lines, so as to provide a preliminary experimental basis for further developing the compound into an anti-lung-cancer medicament. I. Name, molecular formula and molecular weight of a novel medicament Name: aluminum sulfate; molecular formula: A1 2 (SO 4 )r18H20; and molecular weight: 666.4. II. Method to confirm the chemical structure 1. Moisture determination 1.1 Determination conditions: Instrument: V-30 Karl Fischer moisture analyzer Method: The first method of Moisture Determination 0832 in the fourth general rule of the Chinese Pharmacopoeia, 2015 edition. 1.2 Determination results Table 1 Results of determination of moisture in aluminum sulfate Sample Consumption of a Karl Fischer Titer Moisture Average Rounding quantity reagent (T) (%) (%) value (mg) (mL) 31.08 5.59 2.6812 48.22 48.32 48.3 29.24 5.28 48.42 1.3 Analysis According to the structure and moisture content calculation of aluminum sulfate, there are 18 waters of crystallization in the structure. 2. Aluminum determination 2.1 Determination conditions Instrument: Agilent 240-DUO atomic absorption spectrometer

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Method: The graphite furnace atomic absorption spectrometry (GFAAS) was used to determine the content of aluminum in aluminum sulfate samples. 2.2 Determination results Table 2 Results of determination of aluminum in aluminum sulfate samples

Sample Determined mass Percentage Average Name No. quantity Absorbance concentration content percentage (ng/mL) () content (mg)

Blank 1 / 0.0865 / /

/ 2 / 0.0837 / /

/ Test 1 25.39 0.3717 18.1852 7.16 substance 2 25.39 0.4031 20.1776 7.95 1 3 25.39 0.4297 21.8655 8.61 8.15 Test 4 24.78 0.4096 20.5901 8.31 substance 5 24.78 0.4113 20.6979 8.35 2 6 24.78 0.4177 21.1040 8.52 Results showed that the average percentage content of aluminum in aluminum sulfate samples was 8.15%. 2.3 Analysis According to the above moisture determination, namely, as calculated based on 18 waters of crystallization, the percentage of aluminum in the molecular weight is 8.11%, which is consistent with the aluminum content as determined by the above GFAAS, further indicating that the sample includes aluminum and 18 waters of crystallization. 3. Sulfate ion determination 3.1 Determination conditions Instrument: ICS900 ion chromatograph Method: the following chromatographic conditions were adopted: eluent: 25 mM sodium hydroxide, chromatographic column: Dionex IonpacTM As18 (4 x 250 mm), flow rate: 1.0 mL/min, and injection volume: 25 ul; anhydrous sodium sulfate was used as a reference substance; and based on the peak area, an external standard method was used to calculate the content.

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3.2 Determination results Table 3 Results of determination of the sulfate content in aluminum sulfate

Sample Determined Percentage Average Name No. quantity Peak area c ato content percentage (mg)conentrtio M)content (ug/mL) (() Blank 1 / / / /

/ Reference 1 10.06 5.047 3.37* substance 2 5.026 Test 1 7.54 4.933 3.30 43.8 substance 1 2 4.915 Test 4 4.853 43.4 substance 2 5 7.15 4.848 3.25 43.0 * represents an actual concentration. As determined, the sample has a sulfate content of 45.5%. 3.3 Analysis The retention time (RT) in the sample chromatogram is consistent with that in the reference chromatogram, indicating that the sample includes a high concentration of sulfate. The sulfate ion content determined by ion chromatography is 43.4%, which is basically consistent with the percentage of sulfate ion in the molecular weight (43.2%) according to the results of determination of moisture and aluminum. 4. Conclusion According to comprehensive analysis of the results of moisture, aluminum and sulfate content determination, the molecular formula of this product is A12 (SO4)r 18H 2 0. In order to completely eliminate emission of the "three wastes" (waste gas, waste water, and waste residues), high-purity aluminum sulfate (analytical purity or pharmaceutical grade) produced by a manufacturer can be directly used, but strict quality control must be conducted from the source of the manufacturer. Purification of aluminum sulfate 1) Aluminum sulfate and distilled water were mixed at a mass ratio of 1:2 for dissolution; 2) a resulting solution was subjected to fine filtration and a resulting filter cake was washed with the same mass of distilled water to remove impurities; and 3) a filtrate obtained from the fine filtration was subjected to lyophilization to obtain a purified white aluminum sulfate powder.

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The HPLC chromatogram of the purified aluminum sulfate is shown in FIG. 1. It can be seen that the purity of the purified aluminum sulfate has been greatly improved compared with that before the purification. The aluminum sulfate obtained from lyophilization has better solubility. The technical solutions of the present disclosure are further described below in combination with an experiment. Safety experiment: The safety experiment was entrusted to the Laboratory Department of the Laboratory Animal Center of Sun Yat-sen University. Experimental design references: 1. Xu Shuyun, Methodology of Pharmacological Experiment, 3th edition, 2. Technical Guidelines for Drug Safety Pharmacology Research, 2014 edition. The specific experimental method was as follows: Experimental materials Aluminum sulfate: molecular formula: A2(SO4)r 18H 2 0; and molecular weight: 666.4. I. Acute toxicity test 1. Test purpose: Whether a toxic reaction produces within a specified period of time after a single administration of aluminum sulfate was observed to preliminarily understand the toxic effects and target organs of the toxicity of the medicament, thereby providing a basis for subsequent clinical trials. 2. Test animals and feeding conditions 40 SPF Kunming mice, 20 2 g, half male and half female. Animal production and supply unit: Production Department of the Laboratory Animal Center of Sun Yat-sen University; laboratory animal production license No.: SCXK (Guangdong) 2011-0029; animal quality certificate: No. 440085000; purchase date: August 15, 2016; animal labelling method: furs at different parts of the animal were dyed with saturated picric acid to represent different animal numbers, and different animal cages were labelled with different animal feeding information cards for distinguishing. Feeding temperature: 20°C to 26°C; humidity: 40RH% to 70RH%; number of air changes: more than 15 times/h in a feeding room; feeding density: group feeding, no more than 6 mice per cage. Feed used: SPF-grade pellet feed for rats and mice, provided by Beijing Keao Co., Ltd. FIG. 2 shows

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the pictures of animals in the control groups and the administration groups. 3. Test method: The mice were randomly divided into control groups and administration groups, specifically as follows: Table 4 Grouping and dosage for the acute toxicity test Dosage Administration Group Medicament Number of animals (mg/kg) volume 10 male and 10 Control group NS / 0.2 mL/10 g bw female Administration Aluminum sulfate 10 male and 10 group solution 2,000 0.2 mL/10 g bw female A preparation method of an aluminum sulfate solution: 5 mL of normal saline (NS) was accurately extracted and injected into an ampule filled with aluminum sulfate using a syringe, and a resulting mixture was thoroughly mixed and stood for 10 min to 20 min for sufficient dissolution to obtain the aluminum sulfate solution. Administration route: intragastric administration. Administration frequency and observation time: intragastric administration once, and observing for 14 days after administration. Detection indicators: clinical observation: general symptoms of the animals were observed every day; weight measurement: the body weight of the animals was measured on D 0, D 3, D 7, and D 14 after the administration; organ coefficient determination: the animals were sacrificed on D 15, abnormalities in main organs were observed by anatomy, and the 5 organs of heart, liver, spleen, lung and kidney were collected and weighed. Processing and analysis of results: The statistical software SPSS 24 was used to calculate and compare the average body weights and organ coefficients of two groups of animals. Test results: During the test, no deaths and no obvious abnormalities were observed in the control and administration groups. The body weight of the animals in the administration group showed no significant difference from that of the animals the control group. Details were shown in Table 5.

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Table 5 Comparison of body weights of mice in the acute toxicity test

Female in the Male in the Female in the Male in the Time control group/g control group/g administration group/g administration group/g

n= 10/9 10 10/9 10/9

D0 20.6 ±1.4 20.7 ±1.3 20.7 ±1.2 20.6 ±1.1

D3 24.8 ±1.7 24.7 ±1.8 23.7 ±1.7 23.7 ±1.6

D7 31.2 ±2.2 31.3 ±2.2 31.3 ±2.1 31.2 ±2.2

D 14 37.3 ±2.6 38.4 ±2.9 38.4 ±2.8 38.4 ±2.7

The statistical results of organ coefficients were shown in Table 6. Table 6 Comparison of organ coefficients of mice in the acute toxicity test

Female in the Male in the Female in the Male in the Time control group control group administration group administration group n= 9 10 9 9

0.65 ±0.09 0.65 0.09 0.56 ±0.04 0.55 0.03 coefHcient

5.71 ±0.55 5.7 0.56 5.7 ±0.57* 5.6 0.56 coefficient Slecent

0.34 ±0.09 0.35 0.08 0.35 ±0.08 0.34 0.07 coefcient Lung coefficient 0.76 ±0.06 0.75 0.05 0.75 ±0.04 0.74 0.03 Left kidney 0.71 ±0.04 0.71 0.04 0.67 ±0.04 0.66 0.0 coefficient Right kidney 0.74 ±0.05 0.7 0.05 0.69 ±0.06 0.68 0.05 coefficient * indicates that there is no significant difference as compared with the control group (P< 0.05). All the mice survive without death. Conclusion: Aluminum sulfate has excellent safety, and exhibits no significant toxic and side effects when administered at dosages of 2,000 mg/kg, 0.2 mL/10 g bw0, 2 mL/10 g bw NS. Lung cancer cell growth inhibition control test The experiment was entrusted to Hunan Experimental Animal Center (Hunan Drug Safety Evaluation Research Center).

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In the following experiments, compound XL-012 refers to aluminum sulfate. 1. Experimental materials 1.1 Test substance: compound No.: XL-012, batch No.: 20170410, provided by Hunan Xiaolin Biological Technology Development Co., Ltd. Preparation of aluminum sulfate solutions: 9 g of aluminum sulfate was weighed and added to 15 mL of a 0.9% sodium chloride injection, and a resulting mixture was shaken until the aluminum sulfate was completely dissolved to give a 600 mg/mL aluminum sulfate solution, which was a working solution with the highest concentration. The stock solution was sterilized for later use. Working solutions of 200 mg/mL, 60 mg/mL, 20 mg/mL, 6 mg/mL, 2 mg/mL, and 0.6 mg/mL were successively prepared from the stock solution using a 0.9% sodium chloride injection. 1.2 Positive control drugs: Cisplatin (DDP), batch No.: SJJMI-IE, Tokyo Chemical Industry Co., Ltd.; and 5-fluorouracil (5-FU), batch No.: HFBM160120325008, Amresco. Preparation of positive control medicament solutions: 2 mg of DDP or 5-FU was weighed and prepared into a 100 mM stock solution using fresh complete medium, and then working solutions of 200 M, 60 M, 20 M, 6 M, 2 M, and 0.6 M were prepared from the stock solution using fresh complete medium. 1.3 Main materials:

Main materials Source Batch No. Human SCLC cells NCI-H446 Chinese Academy of Sciences Cell Bank Human LCC cells NCI-H460 Chinese Academy of Sciences Cell Bank Human lung adenocarcinoma cells A549 Chinese Academy of Sciences Cell Bank Human squamous cell lung carcinoma cells Chinese Academy of Sciences Cell Bank NCI-H226 Human squamous cell lung adenocarcinoma Chinese Academy of Sciences Cell Bank cells NCI-H596

(lympHuman lung cancer cH292 Chinese Academy of Sciences Cell Bank

High-glucose DMEM medium HyClone, USA, 500 mL/bottle AB10201637 FBS Sciencell, USA, 500 mL/bottle M048-6 CCK-8 Bimake, USA, 100 mL/bottle B34304 Annexin V-FITC/PI apoptosis detection kit Bimake, USA, 100 times 3211713

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1.4 Main instruments:

Main Instruments No. Manufacturer 3111 CO 2 incubator 024 Thermo, USA DMIL inverted microscope 027 Leica, Germany DM2500 fluorescence 018 Leica, Germany microscope MR-96A microplate reader 007 Mindray, Shenzhen, China Accrui C6 flow cytometer 329 BD, USA

CJ-1F medical clean bench 176 Fengshi Laboratory Animal Equipment Co.,Ltd, Suzhou, China

2. Experimental method

2.1 Cultivation of cells NCI-H446, NCI-H460, A549, NCI-H226, NCI-H596 and NCI-H292 cells at confluence were collected and cultivated in an incubator at 37°C and 5% C02 using a high-glucose DMEM complete medium with 10% FBS; and depending on the cell growth, the cells were passaged or the medium was replaced 1 d to 2 d later, and cells at logarithmic growth phase would be used for later experiment. 2.2 Detection of the proliferation of cells by the CCK-8 method NCI-H446, NCI-H460, A549, NCI-H226, NCI-H596 and NCI-H292 cells at logarithmic growth phase were inoculated into a 96-well cell culture plate at 5 x 103 cells/well; and after the cells grew adherently 12 h later, a vehicle control group, DDP (positive control medicament) groups, 5-FU (positive control medicament) groups, and compound XL-012 groups (0.3 mg/mL to 300 mg/mL) were set, with 5 replicates for each group. In the vehicle control group, the cells were incubated in fresh complete DMEM medium; in the compound groups, the cells were incubated in fresh complete DMEM media including the compound at final concentrations of 0.3 mg/mL to 300 mg/mL; and in the DDP and 5-FU groups, the cells were incubated in fresh complete DMEM media including the compound at final concentrations of 100 M, 30 M, 10 [M, 3 M, 1 M, and 0.3 jM. After the cells were incubated for 72 h in the above treatment modes, 10 [ of CCK-8 was added to each well, and the cells were further cultivated for 1 h. Then the absorbance was determined for each well at 450 nm with a microplate reader. The OD value of the vehicle control group is set as 100% cell viability, and the ratio of the OD value of each of the other groups to the OD value of the vehicle control group represents

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the relative viability. The inhibition rate for cell proliferation is used to evaluate the toxicity of the compound on NCI-H446, NCI-H460 and A549 cells. If there is an inhibition rate for cell proliferation > 100%, it is considered as a system error of the instrument, and the inhibition rate is counted as 100%. 2.3 Detection of apoptosis 2.3.1 Detection of apoptosis by Annexin V-FITC and PI double staining NCI-H446, NCI-H460, A549, NCI-H226, NCI-H596 and NCI-H292 cells at logarithmic growth phase were collected by routine digestion and then inoculated into a 6-well plate at a density of 5 x 105 cells/well; and after the cells grew adherently 12 h later, a vehicle control group and compound XL-012 groups (10 mg/mL, 30 mg/mL and 100 mg/mL) were set, with 5 replicates for each group. In the vehicle control group, the cells were incubated in fresh complete DMEM medium; and in the compound groups, the cells were incubated in fresh complete DMEM media including the compound at final concentrations of 10 mg/mL, 30 mg/mL, and 100 mg/mL. 6 h after cultivation, the cells were collected by routine digestion, resuspended with 500 1 of Binding Buffer, and then transferred to a 1.5 mL EP tube; 5 pl of Annexin V-FITC and 5 1 of PI were added, and a resulting mixture was incubated for 15 min at room temperature in the dark; and then the apoptosis was determined by a flow cytometer. 2.3.2 Detection of apoptosis by fluorescent staining The cells were treated according to the method in 2.3.1; 6 h after the compound treatment, 1 mL of Hoechst 33342 staining solution was added to each well of the 6-well plate to fully cover the cells, and a resulting mixture was incubated at 37°C for 20 min to min; the staining solution was removed, and the cells were washed 2 to 3 times with PBS; and then fluoroscopic examination was conducted under a fluorescence microscope. 2.4 Effect of the compound on the cycle of lung cancer cells as detected by flow cytometry NCI-H446, NCI-H460, A549, NCI-H226, NCI-H596 and NCI-H292 cells at logarithmic growth phase were collected by routine digestion and then inoculated into a 6-well plate at a density of 5 x 105 cells/well; and after the cells grew adherently 12 h later, a vehicle control group and compound XL-012 groups (10 mg/mL, 30 mg/mL and 100 mg/mL) were set, with 5 replicates for each group. In the vehicle control group, the cells were incubated in fresh complete DMEM medium; and in the compound groups, the cells

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were incubated in fresh complete DMEM media including the compound at final concentrations of 10 mg/mL, 30 mg/mL, and 100 mg/mL. 6 h after cultivation, the cells were collected by routine digestion, and fixed overnight with 70% cold ethanol; then 5 1 of PI was added, and a resulting mixture was incubated for 30 min at room temperature in the dark; and the cell cycle was detected by a flow cytometer. 2.5 Statistical analysis The SPSS 16.0 statistical software was used to process the data, and measurement data were expressed in tables. The comparison of means of two samples adopted the Student's t-test, and the comparison of means of multiple sample groups adopted the One-way ANOVA. P < 0.05 indicates statistical significance, and P < 0.01 indicates that the difference tested is very significant. 3. Evaluation of results 3.1 Effect of aluminum sulfate on the proliferation of lung cancer cells The cells treated with different concentrations of aluminum sulfate were observed under a microscope, and it was found that the cell proliferation rate was reduced, the cell debris increased, the cell gap increased, and sand-like vacuoles appeared in cells. There is a clear correlation between the cell status and the co-cultivation time. About 12 h after the co-cultivation, the cells became round and shrunk. 24 h after the co-cultivation, some cells swelled, the cells exhibited deteriorated light permeability, and the intercellular space increased. 48 h after the co-cultivation, sand-like vacuoles appeared in the cells, and cell rupture and the like occurred. 72 h after the co-cultivation, cells with sand-like vacuoles were almost completely ruptured, and there was no cells with an intact cell shape at concentrations of 30 mg/mL, 100 mg/mL, and 300 mg/mL, only with a small number of cells shrinking into black spots. After the cells were co-cultivated with the test substance or the positive control medicaments DDP and 5-FU for 72 h, the cell proliferation was significantly inhibited, and there was a concentration-effect relationship, exhibiting a significant difference as compared with the vehicle control group (P< 0.01). The results of cell proliferation inhibition were shown in Table 7.

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Table 7 Effects of different compounds on the proliferation of lung cancer cells NCI-H446 NCI-H460 Test substance Concentration Inhibition IC50 Einax Inhibition IC50 Enax rate rate 0.3 mg/mL 2.5 3.6 1 mg/mL 5.1 10.9 aluminum 3 mg/mL 16.1** 10.696 28.7** 6.822 99.6 sulfate 30 mg/mL 71.2** mg/mL 82.0** mg/mL 100 mg/mL 98.7** 98.7** 300 mg/mL 99.4** 99.6** 0.3 pM 6.4 0.3 1 tM 21.4** 19.8** 3 pM 50.8** 3.193 95.1 57.7** 3.278 99.1 DDP 10 tM 81.5** pM 72.9** pM 30 pM 91.6** 96.3** 100 pM 95.1** 99.1** 0.3 pM 0.7 13.4 1 tM 15.5** 17.1** 5-FU 3 pM 43.1** 6.114 94.4 34.9** 4.145 98.5 10 pM 56.9** pM 63.9** pM 30 pM 81.5** 92.1** 100 pM 94.4** 98.5** A549 NCI-H226 Test substance Concentration Inhibition rbIs Emax rate 0.3 mg/mL 2.0 0.7 1 mg/mL 4.0 7.1 aluminum 3 mg/mL 6.1 20265 38.9** 10 mg/mL 9.9 100 49.3** .500 99.9 sulfate 30mg/mL 49.2** mg/mL 76.6** mg/mL 100 mg/mL 99.6** 99.3** 300 mg/mL 100.0** 99.9** 0.3 pM 4.2 25.7** 1 tM 23.0** 34.1** DDP 3 pM 48.0** 3.423 99.7 46.4** 2.152 94.9 10 pM 71.3** M9. 73.0** pM 30 pM 93.5** 94.5** 100 pM 99.7** 94.9** 0.3 pM -1.0 1.5 1 tM 6.5 24.4** 5-FU 3 pM 29.9** 7.916 89.6 45.3** 4.202 97.9 10 tM 58.5** pM. 67.5** pM 30 pM 84.0** 86.6** 100 pM 89.6** 97.9** NCI-H596 NCI-H292 Test substance Concentration Inhibitionrate ICso Emax Inhibition I~so Einax rate 0.3 mg/mL 4.2 -1.0 aluminum 3mg/mL 7.2 9.258 100 14.1 10.047 99.2 sulfate 3m/L72m/L 10 1. gm 10 mg/mL 36.8** mg/mL 36.0** mg/mL 30 mg/mL 95.9** 92.7**

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100 mg/mL 99.0** 98.4** 300 mg/mL 100.4** 99.2** 0.3 pM 3.5 0.8 1 tM 16.3 13.5 DDP 3 pM 51.8** 3.686 7.7 53.7** 4.246 97.8 10 pM 70.6** pM 72.7** pM 30 pM 94.8** 86.0** 100 pM 97.7** 97.8** 0.3 pM -1.1 -0.3 1 tM 3.6 0.6 5-FU 3 pM 30.2** 8.966 97.8 28.2** 10.025 96.3 10 pM 50.5** pM 47.5** pM 30 pM 74.7** 75.5** 100 pM 97.8** 96.3**

Notes:* means P < 0.05 as compared with the vehicle control group, and ** means P < 0.01 as compared with the vehicle control group. ICo represents the concentration at which 50% of tumor cells are inhibited, and Emax represents the maximum inhibition rate for tumor cells. FIG. 3 to FIG. 5 show concentration-inhibition rate curves of aluminum sulfate on lung cancer cells, where, FIG. 3A and FIG. 3B are for NCI-H446 and NCI-H460 cells, respectively; FIG. 4A and FIG. 4B are for A549 and NCI-H226 cells, respectively; and FIG. 5A and FIG. 5B are for NCI-H596 and NCI-H292 cells, respectively. FIG. 6 and FIG. 7 show the effect of aluminum sulfate on the proliferation of lung cancer cells, where, the arrows indicate necrotic cells. It can be clearly seen from the figure that aluminum sulfate can promote the necrosis of lung cancer cells. 3.2 Effect of aluminum sulfate on the apoptosis of lung cancer cells The compound solutions with concentrations of 10 mg/mL, 30 mg/mL, and 100 mg/mL were used to intervene lung cancer cells for 6 h, then the cells were collected, and apoptosis was detected by Annexin V-FITC/PI double staining. A flow cytometer can divide the double-stained cells into 4 groups: Qi-UL: mechanically-damaged cells (Annexin V-/PI+); QI-UR: advanced apoptotic cells (Annexin V+/PI+); QI-LL: survival cells (Annexin V-/PI-); and Q1-LR: early apoptotic cells (Annexin V+/PI-). The experimental results were shown in Table 8:

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Table 8 Effect of aluminum sulfate on the apoptosis of human lung cancer cells

Concentration Early apoptotic Necrotic cells and advanced Total apoptotic Cells cells apoptotic cells cells (%) (mg/mL) QI-LR (%) QI-UR (%) 0 4.04 ±2.37 5.29 ±2.57 9.33 10 39.5 ±6.55** 10.38 ±3.23* 49.88** NCI-H446 30 43.95 ±6.43** 11.79 ±2.01* 55.74** 100 32.3 ±11.32** 17.16 2.39** 49.46** 0 8.09 3.44 6.92 2.62 15.01 10 42.32 5.37** 13.02 1.27* 55.34** NCI-H460 30 43.3 5.79** 12.98 3.26* 56.28** 100 43.81 6.19** 18.66 2.17** 62.47** 0 8.58 3.46 2.23 3.02 10.81 A549 10 19.09 13.03** 6.17 2.94* 25.26** 30 27.72 8.08** 8.36 2.9** 36.08** 100 28.66 8.39** 33.83 1.4** 62.49** 0 3.32 1.86 4.96 1.61 8.28 10 30.48 8.03** 20.15 1.9** 50.63** NCI-H226 30 43.07 11.42** 17.64 2.83** 60.71** 100 22.44 ±6.5** 62.87 3.14** 85.31** 0 8.49 ±1.31 4.67 1.43 13.16 10 26.23 6.66** 7.05 2.11* 33.28** NCI-H596 30 59.34 10.58** 12.53 2.42** 71.87** 100 53.15 7.95** 15.04 1.91** 68.19** 0 1.15 3.34 4.55 ±1.4 5.70 10 53.97 12.09** 17.24 ±2.27** 71.21** NCI-H292 30 57.95 8.05** 15.94 ±1.71** 73.89** 100 57.74 9.43** 14.56 ±1.69** 72.30**

Notes:* means P < 0.05 as compared with the vehicle control group, and ** means P < 0.01 as compared with the vehicle control group. The results showed that the number of advanced apoptotic and necrotic cells in NCI-H446 cells treated with the compound XL-012 was significantly higher than that in the vehicle control group (P< 0.05), and there was a concentration-effect relationship; the number of advanced apoptotic and necrotic cells in NCI-H460 cells treated with the compound XL-012 was significantly higher than that in the vehicle control group (P < 0.05), and there was a concentration-effect relationship; the number of early apoptotic cells in A549 cells treated with the compound XL-012 was significantly higher than that in the vehicle control group (P < 0.05), and there was a concentration-effect relationship; the number of advanced apoptotic and necrotic cells in NCI-H226 cells treated with the compound XL-012 was significantly higher than that in the vehicle control group (P < 0.05), and there was a concentration-effect relationship; the number of advanced apoptotic and necrotic cells in NCI-H596 cells treated with the compound XL-012 was significantly

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higher than that in the vehicle control group (P < 0.05), and there was a concentration-effect relationship; and the number of early apoptotic cells in NCI-H292 cells treated with the compound XL-012 was significantly higher than that in the vehicle control group (P < 0.05), and there was a concentration-effect relationship. FIG. 11 shows the effect of aluminum sulfate on the apoptosis of human lung cancer cells NCI-H446, where, A is for a vehicle control group, B is for an aluminum sulfate group with a concentration of 10 mg/mL, C is for an aluminum sulfate group with a concentration of 30 mg/mL, and D is for an aluminum sulfate group with a concentration of 100 mg/mL. FIG. 8 to FIG. 13 show the effect of aluminum sulfate on the apoptosis of human high-metastatic lung cancer cells NCI-H446, NCI-H460, A549, NCI-H226, NCI-H596 and NCI-H292, respectively; and in each figure, A is for a vehicle control group, B is for an aluminum sulfate group with a concentration of 10 mg/mL, C is for an aluminum sulfate group with a concentration of 30 mg/mL, and D is for an aluminum sulfate group with a concentration of 100 mg/mL. FIG. 14 and FIG. 15 show the effect of aluminum sulfate on the apoptosis of lung cancer cells, where, the arrows indicate shrinkage of a nucleus, namely, indicating apoptotic cells. 3.3 Effect of aluminum sulfate on the cycle of lung cancer cells Aluminum sulfate solutions with concentrations of 10 mg/mL, 30 mg/mL, and 100 mg/mL were used to intervene lung cancer cells for 6 h; then the cells were collected, fixed with 70% cold ethanol, and stained with PI; and the cell cycle was analyzed by a flow cytometer. The experimental results were shown in Table 9.

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Table 9 Effect of aluminum sulfate on the cycle of human lung cancer cells

Cells Concentration Cells at Go/Gi Cells at S phase Cells at G2/M (mg/mL) phase (%) (%) phase (%) 0 34.60 ±4.62 3.17 ±0.81 28.45 7.77 10 69.14 ±6.12** 2.93 ±1.19 17.91 9.34* NCI-H446 30 83.56 ±3.61** 0.84 ±0.58 5.50 ±5.61** 100 84.61 ±8.81** 0.88 ±0.77 4.54 ±4.04** 0 74.63 ±6.92 0.66 ±1.09 5.83 ±9.65 NCI-H460 10 78.91 ±9.93 0.41 ±0.78 3.68± 7.95** 30 84.91 ±10.00* 0.36 ±1.01 1.94 ±4.58** 100 87.35± 3.59** 0.28 ±0.49 0.12 ±8.77** 0 25.48 ±4.67 2.85 ±0.95 64.89 ±7.15 A549 10 28.45 ±5.78 1.03 ±1.18 64.24 ±7.88 30 31.84 ±9.05 0.86 ±0.71 62.33 ±3.80 100 36.44 ±9.45 2.28 ±0.69 50.74± 4.53** 0 73.09 ±8.40 1.05 ±0.70 14.97 ±9.88 10 74.31 ±3.71 1.94 ±0.85** 16.04 ±6.58 NCI-H226 30 77.00 ±6.61 1.51 ±0.45 9.93 ±5.80** 100 81.33 3.69* 1.31 ±0.77 9.05 ±9.06** 0 53.59 4.97 0.71 ±0.50 19.31 ±4.31 10 58.58 8.11* 1.43 ±0.67** 22.86 ±9.35 NCI-H596 30 68.6 5.81** 0.92 ±0.51 23.27 ±5.22 100 71.58 7.42** 1.33 ±0.67 17.22 ±10.01 0 60.49 9.54 1.22 ±0.80 26.45 ±10.08 NCI-H292 10 64.50 10.01 1.39 ±0.95 24.79 ±7.57 30 64.50 8.94 1.08 ±1.19 27.33 ±5.25 100 74.53 ±8.46** 2.19 ±1.06 19.86 ±8.75* Notes: * means P < 0.05 as compared with the vehicle control group, and ** means P < 0.01 as compared with the vehicle control group. The results showed that, after the cells were treated with aluminum sulfate, the proportion of cells at Go/Gi phase increased significantly, and the proportion of cells at G2 /M phase decreased significantly, indicating that the aluminum sulfate inhibited the proliferation of lung cancer cells mainly by blocking lung cancer cells at Go/G1 phase and preventing them from entering the S phase. FIG. 16 to FIG. 21 show the effect of aluminum sulfate on the apoptosis cycle of NCI-H446, NCI-H460, A549, NCI-H226, NCI-H596 and NCI-H292, respectively; and in each figure, A is for a vehicle control group, B is for an aluminum sulfate group with a concentration of 10 mg/mL, C is for an aluminum sulfate group with a concentration of 30 mg/mL, and D is for an aluminum sulfate group with a concentration of 100 mg/mL. In summary, under the experimental conditions, the aluminum sulfate can significantly inhibit the proliferation of six kinds of lung cancer cells, exhibiting a concentration-effect relationship, and can completely kill cancer cells over time at high concentrations, which

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can block the cell cycle at Go/Gi phase and induce apoptosis. The compound exerts an inhibitory effect on cancer cells at a relatively-high concentration, reaching the mg/mL level, which may be related to a specific active mechanism of the compound. The compound may directly act on the surface of tumor cells, can change the physiological characteristics of cancer cells, and can effectively change the protein structure on the cell surface after being aggregated on the cell surface, thus causing protein precipitation on the cell surface and in the intercellular matrix, significantly reducing the cellular permeability, resulting in shrinkage of the intercellular matrix, decreasing the division ability of tumor cells, and effectively controlling the proliferation and metastasis of cells. The compound, after entering cells, can inhibit the secretion of various proteolytic enzymes by cancer cells, directly bind to DNA of cancer cells to cause DNA lysis, and effectively inhibit the metabolic function of mitochondria in cancer cells, namely, binding to SDH in mitochondria and changing the biological effect thereof, which causes changes in cell microstructures, blocks signaling pathways, interferes with the growth and metabolism of tumor cells, and induces the apoptosis of tumor cells, thus achieving the effect to kill cancer cells. Recommendations: For example, after the tumors transplanted into mice in the animal experiment are matured and the administration by injection is completed, the injection delivery channel should be embolized or closed, and the animals must be separated from each other and raised alone. Because there are somewhat a smell and a small bulge after the medicament is injected, the mice, if raised in groups, will bite each other so that the medicament solution will flow out and thus the efficacy will be compromised. For example, the injection delivery channel needs not to be embolized or closed after the medicament is injected into a human tumor. The above descriptions are merely preferred implementations of the present disclosure. It should be noted that a person of ordinary skill in the art may further make several improvements and modifications without departing from the principle of the present disclosure, but such improvements and modifications should be deemed as falling within the protection scope of the present disclosure.

Claims (5)

1. 21168904.1:DCC - 9/02/2021

   What is claimed is: 1. Use of aluminum sulfate in the preparation of a powder injection medicament for treating lung cancer and malignant lymphoma by local injection, wherein, the medicament is an injection preparation; the injection preparation is selected from a powder injection and an injection solution; and

   the aluminum sulfate is selected from hydrates of aluminum sulfate.
2. 2. A powder injection medicament for treating lung cancer and malignant lymphoma by local injection, wherein: an active ingredient in the medicament includes aluminum sulfate; the aluminum sulfate is injection-grade or above aluminum sulfate or can be obtained by the following purification method: 1) mixing aluminum sulfate with distilled water for dissolution to obtain an aluminum sulfate solution; and 2) subjecting the aluminum sulfate solution to fine filtration and lyophilization to obtain an aluminum sulfate powder;

   the medicament is an injection preparation.
3. 3. The medicament according to claim 2, wherein, the injection preparation is selected from a powder injection and an injection solution.
4. 4. The medicament according to claim 2, wherein, the aluminum sulfate and distilled water are mixed at a mass ratio of 1:2, and the aluminum sulfate is purified by the distilled water after dissolution.
5. 5. The medicament according to claim 2 or 4, wherein, the aluminum sulfate solution is subjected to fine filtration using a filter membrane with a pore size of 0.22 m.

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   1/20 2021100811

   Response (S)

   Time (min)

   FIG. 1

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   2/20

   Acute toxicity test for medicament 1 Acute toxicity test for medicament 1 (20160901) (20160901) Control group-female Control group-male 2021100811

   Female animals in the control group Male animals in the control group

   Acute toxicity test for medicament 1 Acute toxicity test for medicament 1 (20160901) (20160901) Administration group-male Administration group-female

   Female animals in the control group Male animals in the control group

   FIG. 2

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   3/20 2021100811

   Inhibition rate (%)

   Logarithmic concentration Inhibition rate (%)

   Logarithmic concentration

   FIG. 3

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   4/20 2021100811

   Inhibition rate (%)

   Logarithmic concentration Inhibition rate (%)

   Logarithmic concentration

   FIG. 4

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   5/20 2021100811

   Inhibition rate (%)

   Logarithmic concentration Inhibition rate (%)

   Logarithmic concentration

   FIG. 5

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   6/20 2021100811

   FIG. 6

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   FIG. 7

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   8/20 2021100811

   FIG. 8

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   9/20 2021100811

   FIG. 9

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   10/20 2021100811

   FIG. 10

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   11/20 2021100811

   FIG. 11

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   FIG. 12

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   FIG. 13

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   14/20 2021100811

   FIG. 14

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   15/20 2021100811

   FIG. 15

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   16/20 2021100811

   FIG. 16

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   17/20 2021100811

   FIG. 17

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   18/20 2021100811

   FIG. 18

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   19/20 2021100811

   FIG. 19

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   20/20 2021100811

   FIG. 20

   FIG. 21