CN108445236B - Steroid derivative, preservation solution thereof and application thereof - Google Patents
Steroid derivative, preservation solution thereof and application thereof Download PDFInfo
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- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
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- C07J7/007—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified not substituted in position 17 alfa
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Abstract
The invention discloses a steroid derivative, a preservation solution and application thereof, and belongs to the technical field of in-vitro diagnostic reagents. The steroid derivative contains a cyclopentane multi-hydrogen phenanthrene mother nucleus, and at least one carbon position of the cyclopentane multi-hydrogen phenanthrene mother nucleus is substituted with a hydrophilic group. The preservation solution of the steroid hormone comprises a buffer solution and a surfactant dissolved in the buffer solution. The steroid derivative and the preservation solution are applied to preparation of a detection agent and a kit for detecting steroid hormones. The steroid derivative has good hydrophilicity and solubility, can be uniformly and stably dispersed in a solution, is used as a steroid hormone antigen, and can realize accurate detection of steroid hormone. The steroid hormone preserving fluid can effectively improve the solubility and the dispersion uniformity of the steroid derivatives and prevent the steroid derivatives from being adsorbed on the surface of a high molecular polymer.
Description
Technical Field
The invention belongs to the technical field of in-vitro diagnostic reagents, and particularly relates to a steroid derivative and application thereof, a preservation solution of the steroid derivative and application of the preservation solution.
Background
Steroid hormones are important endocrine hormones, and maintain homeostasis and normal physiological activities in the bodyPromoting the development of sexual organs, maintaining the functions of reproductive system, etc. Steroid hormone drugs are divided into corticoids and sex hormones by pharmacological action, the latter including androgens, estrogens and progestogens, and steroid contraceptives. Can be divided into androstane, estrane and pregnane according to chemical structure, wherein androgen belongs to androstane, estrogen belongs to estrane, adrenal cortex hormone, progestogen and steroid contraceptive belong to pregnane. The steroid hormone and compound have common basic skeleton, i.e. basic structure is cyclopentane-polyhydrophenanthrene mother nucleus (steroid), and its structural formula is shown in formula I0Shown as consisting of A, B, C, D four rings. A. Ring B, C is a six-membered ring and ring D is a five-membered ring. Based on the parent nucleus of cyclopentane multi-hydrogen phenanthrene, there are three general classes of steroid hormone molecules: androstanes, estranes, and pregnanes.
Modern clinical medical research shows that: the detection and monitoring of steroid hormones can assist in diagnosing endocrine and metabolic system diseases, particularly one of effective indexes of disease risk of gonad and adrenal gland diseases, and early warning can be effectively achieved on endocrine and metabolic system diseases by accurately and quantitatively measuring the steroid hormones in healthy human serum or plasma; the accurate quantitative determination of the substance for patients with endocrine and metabolic system diseases with certain clinical symptoms can help clinicians to carry out rapid and accurate disease diagnosis.
For example, Androstenedione (Androstenedione), which is a full name of 4-androstene-3, 17-dione, is a 19-carbon steroidal androgen (androgen, the mother nucleus being androstane) produced by the adrenal gland and gonad, and thus, the change in Androstenedione is directly related to the metabolism and endocrine balance of the female and male hormones in the body. The clinical significance of androstenedione is: in hyperandrogenism (e.g. polycystic ovary syndrome, hyperandrogenism), especially in abnormal hair growth (hirsutism) and virilization in women, androstenedione levels are often elevated.
The steroid hormone serum marker for detecting steroid hormone in serum or plasma has the physical property of insolubility or insolubility in water due to the fact that the molecular structure of the serum marker is cyclopentanoperhydrophenanthrene (namely, sterane). In the process of actually producing the calibrator and the quality control product of the in-vitro diagnostic reagent of the steroid hormone serum marker, most of the storage solution of the calibrator and the quality control product is hormone-removed serum products or buffer salt solution, because the steroid hormones in the calibrator and the quality control product are insoluble or insoluble in water and are subjected to molecular motion or diffusion, the steroid hormones are easy to mutually aggregate or agglomerate in a system, so that the thermodynamics of the whole solution system is unstable, and the actual concentration may be changed in the process of using the calibrator and the quality control product, thereby affecting the performance and the stability of the reagent.
Meanwhile, the packaging materials of the calibration product and the quality control product are mostly plastic vials (containing silica films) or glass bottles (containing rubber plugs). Because the materials of plastics, silica gel membrane and plug are mostly organic synthetic polymers, there are tiny gaps or holes that can not be observed by naked eyes in the plastic, silica gel membrane and plug which are made of high molecular polymers in the process of molding process, and meanwhile, because of the difference of the treatment process, the polymer surface has macromolecule polymer terminal groups, and is easy to naturally adsorb some small molecular substances (such as small molecular steroid hormones, the molecular weight is smaller, and the molecular weight is less than 1000). Once the small molecule substance (such as steroid hormone) is adsorbed by the surface of the packaging material, the content of the calibrator and the content of the quality control substance are reduced, so that the actual concentration of the calibrator and the quality control substance of the small molecule serum marker reagent product is changed, and the performance and the stability of the reagent are affected.
Due to the reasons, the existing standard product for detecting steroid hormones is unstable, and the correctness of a calibration curve is seriously influenced, so that the final detection is inaccurate.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, and provides a steroid derivative and application thereof, so as to solve the technical problem of inaccurate steroid hormone detection caused by strong hydrophobicity, insolubility or insolubility in water of the existing steroid hormone for detecting the steroid hormone.
The invention also aims to provide the steroid hormone preserving fluid to solve the technical problem that the actual concentration of the steroid hormone is unstable due to coagulation and adsorption of the steroid hormone in the conventional steroid hormone liquid preserving process.
The invention further aims to provide a detection agent and a kit for detecting steroid hormones, so as to solve the technical problems that the existing detection agent for detecting steroid hormones has unstable concentration and the detection result of the kit is inaccurate.
In order to achieve the above object, according to one aspect of the present invention, a steroid derivative is provided. The steroid derivative contains a cyclopentane multi-hydrogen phenanthrene mother nucleus, and at least one carbon position of the cyclopentane multi-hydrogen phenanthrene mother nucleus is substituted with a hydrophilic group.
Meanwhile, the invention provides application of the steroid derivative. The application of the steroid derivative is that the steroid derivative is used as a steroid hormone antigen for detecting steroid hormones.
In another aspect of the invention, a preservation solution of steroid hormone is provided. The steroid hormone preserving fluid is used for preserving the steroid derivative in a liquid state, and comprises a buffer solution and a surfactant dissolved in the buffer solution.
In still another aspect of the present invention, a detection agent for detecting steroid hormones is provided. The detection agent comprises a preservation solution and a steroid hormone antigen dissolved in the preservation solution, wherein the steroid hormone antigen is the steroid derivative, or the preservation solution is the preservation solution of the steroid hormone.
In still another aspect of the present invention, a kit for detecting steroid hormones is provided. The kit comprises at least one of the steroid derivative of the invention as a steroid hormone antigen and a preservation solution of the steroid hormone of the invention; or a detection agent for detecting steroid hormones of the present invention.
In still another aspect of the present invention, there is provided a method for using the detection reagent for detecting steroid hormone of the present invention or the kit for detecting steroid hormone of the present invention. The detection reagent or the kit provided by the invention is applied to clinical detection of steroid hormones.
Compared with the prior art, the steroid derivative has the advantages that at least one carbon position on the parent nucleus of the cyclopentane-polyhydrophenanthrene contained in the steroid derivative is substituted with a hydrophilic group, so that the steroid derivative is endowed with good hydrophilicity and solubility, the steroid derivative can be dissolved and uniformly and stably dispersed in a solution, and the coagulation phenomenon of the steroid derivative such as the existing steroid hormone is effectively avoided.
The steroid derivative of the invention keeps the conventional characteristics of steroid hormone, has good solubility, can be uniformly and stably dispersed in the solution, and effectively avoids the coagulation phenomenon of the steroid derivative such as the existing steroid hormone, so the steroid derivative is used as the steroid hormone antigen, and the accurate detection of the steroid hormone can be realized.
The steroid hormone preservation solution of the invention can effectively improve the solubility and the dispersion uniformity of the steroid derivatives dissolved in the preservation solution and avoid the coagulation phenomenon through the contained surfactant, and on the other hand, the surfactant can rapidly permeate into the inner surface of the surface gap or hole of the high molecular polymer for containing the preservation solution container to play a role of wetting, solubilization and suspension dispersion, so as to avoid the steroid derivatives dissolved in the preservation solution from being adsorbed by the surface of the high molecular polymer, thereby ensuring that the steroid derivatives can be effectively dissolved and uniformly and stably dispersed in the preservation solution.
The detection agent for detecting steroid hormone contains steroid derivatives, or further adopts the preservation solution of the steroid hormone to dissolve the steroid derivatives, so that the steroid derivatives contained in the detection agent for detecting steroid hormone are uniformly dispersed, and the concentration content is stable and accurate.
The kit for detecting steroid hormone of the invention contains steroid derivatives as steroid hormone antigens and/or the preservative solution for steroid hormone of the invention, or comprises the detection agent for detecting steroid hormone of the invention, therefore, the reagent containing the steroid hormone to be detected prepared by adopting the preservative solution or the steroid derivatives in the detection agent have good solubility, and the concentration content is stable and accurate, thereby ensuring that the kit can accurately detect the steroid hormone in samples, and is convenient and rapid.
Drawings
Figure 1 is a schematic representation of the linear correlation between androstenedione and the respective androstenedione derivatives provided in examples 11-13, detecting affinity/potency;
figure 2 is a graphical representation of the linear correlation between testosterone and the affinity/potency assay provided in example 14 between testosterone derivatives;
FIG. 3 is a graph showing the linear correlation between estradiol, the estradiol derivatives provided in example 14, and the measured affinity/potency;
FIG. 4 is a graphical representation of the linear correlation between progesterone, the progesterone derivatives provided in example 14, and the affinity/potency assays performed thereon;
figure 5 is a graphical representation of the linear correlation between cortisol, the cortisol derivative provided in example 14, and the measured affinity/potency.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the embodiments and the accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The embodiment of the invention is explained by the terms:
steroid hormones: also known as steroid hormones, are important bioactive substances for maintaining life, maintaining normal life, promoting the development of sexual organs, and maintaining fertility. In particular to an active substance secreted by a human body with cyclopentane-polyhydrophenanthrene structure, which comprises three active substances of androstane, estrane and pregnane.
Steroid derivatives: is a compound which is based on the steroid hormone and is substituted with a hydrophilic group on at least one carbon position of the parent nucleus of the cyclopentane-polyhydrophenanthrene of the steroid hormone.
In one aspect, embodiments of the present invention provide a steroid derivative with hydrophilicity. The steroid derivative is formed by substituting hydrophilic groups on at least one carbon position of a cyclopentane-polyhydrophenanthrene mother nucleus. Particularly, a hydrophilic group is substituted on any one or at least one carbon position of 1-17 of the nuclear carbon of the cyclopentane polyhydrophenanthrene mother. Therefore, as the carbon position of the parent nucleus of the cyclopentanoperhydrophenanthrene contained in the steroid derivative is substituted with the hydrophilic group, the steroid derivative is effectively endowed with good hydrophilic performance, has good water solubility, can be dissolved and uniformly dispersed in water, avoids the coagulation phenomenon of the existing steroid hormone, and is stable in aqueous solution and long in storage time.
In one embodiment, the hydrophilic group may be one or more of a hydroxyl group, an ester group, a carboxyl group, a sulfate group, a sulfonate group, a phosphate group, an amino group, an aldehyde group, and a quaternary ammonium group. Specifically, one hydrophilic group is substituted on one carbon position of the cyclopentane-polyhydrophenanthrene mother nucleus contained in the steroid derivative, the same hydrophilic group is substituted on more than two carbon positions of the cyclopentane-polyhydrophenanthrene mother nucleus contained in the steroid derivative, and the different hydrophilic groups are substituted on more than two carbon positions of the cyclopentane-polyhydrophenanthrene mother nucleus contained in the steroid derivative. The steroid derivative formed after the cyclopentane-hydrophenanthrene parent nucleus is substituted by the hydrophilic group does not affect the original characteristics of steroid hormone originally providing the cyclopentane-hydrophenanthrene parent nucleus, and endows the steroid derivative with good hydrophilic performance, so that the steroid derivative has good water solubility, the water solution of the steroid derivative does not generate coagulation phenomenon, and the steroid derivative can be kept stable for a long time.
In another embodiment, the cyclopentane-hydrophenanthrene parent nucleus is provided by at least one steroid hormone selected from the group consisting of androgen, estrogen, progestin and corticoid, that is, the steroid derivative is derived from at least one steroid compound selected from the group consisting of androgen, estrogen, progestin and corticoid, specifically, a hydrophilic group is substituted on the carbon position of the cyclopentane-hydrophenanthrene parent nucleus contained in at least one steroid compound selected from the group consisting of androgen, estrogen, progestin and corticoid, or a functional group of at least one steroid compound selected from the group consisting androgen, estrogen, progestin and corticoid, which is bonded on the contained cyclopentane-hydrophenanthrene parent nucleus, is modified into a hydrophilic group.
Wherein the androgen can be at least one of androstenedione, testosterone, dihydrotestosterone, dehydroepiandrosterone, androsterone, and androstenediol. The estrogen may comprise at least one of estrone, estriol, estradiol. The progestogen may be at least one of progesterone, 17 α -hydroxyprogesterone, pregnenolone, and 17-hydroxyprogesterone. The corticosteroid may include at least one of cortisol, aldosterone, deoxycorticosterone, 11-deoxycorticosterol, and corticosterone.
Based on the above embodiments, the steroid derivative may specifically be at least one of the following molecular structural formulas:
The steroid derivatives with the molecular structural formula are subjected to substitution modification based on the existing steroid hormones, so that the steroid derivatives have good hydrophilicity and water solubility.
In addition, the steroid derivatives described in the above examples can be prepared according to the existing methods.
Since the steroid derivatives described above are a class of compounds modified based on existing steroid hormones, they are obtained by modification based on steroid hormones such as androstane, estrane and pregnane. Therefore, the steroid derivative contains a cyclopentane-polyhydrophenanthrene mother nucleus and a substituent group substituted on the cyclopentane-polyhydrophenanthrene mother nucleus. Based on the molecular structure characteristics of the steroid derivatives, the application of the steroid derivatives is researched.
In one aspect, the embodiments of the present invention provide an application method of the steroid derivative. The application of the steroid derivative is that the steroid derivative is used as a steroid hormone antigen for detecting steroid hormones. The steroid derivative contains cyclopentane multi-hydrogen phenanthrene mother nucleus and has the characteristics of steroid hormone, so that when the steroid derivative is used as a steroid hormone antigen, the steroid hormone can be effectively detected, for example, the steroid hormone can be used as a calibrator or a quality control product for detecting the steroid hormone, and the quantitative detection of the steroid hormone can be realized.
On the other hand, the embodiment of the invention also provides the steroid hormone preserving fluid which can effectively improve the solubility of the steroid derivatives and improve the dispersion uniformity and stability of the steroid derivatives. The steroid hormone preserving fluid comprises a buffer solution and a surfactant and other components dissolved in the buffer solution. Because the preservation solution of the steroid hormone contains a surfactant, and because of the molecular structure characteristic of the surfactant, the preservation solution contains hydrophilic groups, the preservation solution of the steroid hormone endows the surfactant with hydrophilic polarity characteristic; the other part contains a hydrophobic group or an oleophilic group, which imparts the non-polar character or the hydrophobic character of the surfactant. Therefore, the surfactant can be effectively adsorbed on the interface of the solution, the interfacial tension is remarkably reduced, and the surfactant has excellent characteristics of wetting, emulsification, dispersion, penetration and the like, and on one hand, the surfactant plays a role in solubilization and improves the solubility of the steroid derivative in the preservation solution; on the other hand, the method can effectively reduce two kinds of interfacial tension of the steroid derivative dissolved in the preservation solution and a solvent of the preservation solution, reduce the mutual attraction force between the steroid derivative dissolved in the preservation solution, and prevent the aggregation and agglomeration of the steroid derivative during mutual collision, thereby improving the stability of the steroid derivative dissolved in the preservation solution; on the other hand, the steroid derivative can rapidly permeate into the inner surface of a gap or a hole on the surface of the high molecular polymer of the container for containing the preservation solution, and the steroid derivative dissolved in the preservation solution is prevented from being adsorbed on the surface of the high molecular polymer through the wetting effect and the suspension dispersion effect, so that the stability of the steroid derivative dissolved in the preservation solution is improved.
In one embodiment, the concentration of the surfactant in the preservation solution is 0.05% to 3% w/v, and may be 1% w/v. By adjusting the concentration of the surfactant, the effects of the three aforementioned aspects of the preservation solution are improved, and the stability of the steroid derivative dissolved in the preservation solution is further improved.
In various embodiments of the preservation solution, in one embodiment, the surfactant contained in the preservation solution may include at least one of an anionic surfactant and a nonionic surfactant. In particular embodiments, the anionic surfactant comprises at least one of a long chain alkyl carboxylate, a long chain alkyl sulfonate, a long chain alkyl sulfate, a long chain alkyl phosphate. In another embodiment, the nonionic surfactant includes at least one of a polyoxyethylene ether surfactant and a polyoxyethylene ester surfactant. The selected surfactants can effectively improve the solubility and stability of the steroid derivative dissolved in the preservation solution and avoid aggregation and agglomeration; on the other hand, the penetration and wetting effects are improved, the steroid derivative dissolved in the preservation solution is prevented from being adsorbed on the surface of the high molecular polymer, and the stability of the steroid derivative dissolved in the preservation solution is improved.
In another embodiment, the buffer solution contained in the preservation solution comprises at least one of phosphate buffer, acetate buffer, citrate buffer, borate buffer, Tris-hydrochloric acid buffer, and carbonate buffer. These buffer solutions are selected to assist the surfactant in effectively increasing the solubility and stability of the steroid derivative.
The term "actual composition" as used herein means that the composition does not contain any components other than those which can be optionally added (for example, preservatives, pH regulators and the like which are added to usual preparations) which will be described later.
In each embodiment of the preservation solution, the preservation solution of steroid hormone is used for liquid preservation of steroid derivatives, and specifically, the steroid derivatives described in each embodiment of the steroid derivative application are used as described above. Of course, if the solubility of the steroid hormone is not considered, the preservation solution of the steroid hormone can also be used for liquid preservation of the existing steroid hormone, so as to avoid the adsorption of the steroid hormone dispersed in the preservation solution of the steroid hormone on the surface of the high molecular polymer, such as the adsorption on the wall and the cover surface of a storage container, and further improve the stability of the steroid hormone.
The steroid hormone preserving solution further contains a buffer solution and a surfactant dissolved in the buffer solution, and further contains at least one of a preservative and other common auxiliary components which may be added as needed. When the preservation solution of the steroid hormone further comprises a preservative, the preservation solution of the steroid hormone can be prevented from being polluted by microorganisms, so that the stability of the preservation solution of the steroid hormone is protected. In one embodiment, the preservative may be at least one of sodium azide, proclin, thimerosal, and the like, but may be added depending on the storage time of the steroid hormone preservative solution.
In yet another aspect, embodiments of the present invention provide a detection agent for detecting steroid hormones. The detection agent for detecting the steroid hormone comprises preservation solution and steroid hormone antigen dissolved in the preservation solution.
Wherein, the steroid hormone antigen contained in the detection agent for detecting steroid hormone is the steroid derivative described in the above embodiments, and for the sake of brevity, the steroid derivative is not described herein again. Therefore, the steroid hormone detection agent contains stable antigen content of the steroid hormone, and is difficult to generate coagulation phenomenon, and the accuracy of steroid hormone detection is effectively ensured. In addition, the concentration of the steroid hormone antigen in the preservation solution can be flexibly adjusted according to the actual application requirement.
The preservation solution contained in the detection agent for detecting steroid hormones can be a diluent or a buffer solution which is conventionally used for preparing a calibrator and a quality control product of an in-vitro diagnostic reagent of a steroid hormone serum marker, and is preferably the preservation solution of the steroid hormones in the embodiment of the invention. Therefore, on the basis of the good water solubility and stability of the steroid derivative contained in the detection agent, the preservation solution of the steroid hormone contained in the detection agent can further improve the water solubility of the steroid derivative, and meanwhile, the adsorption of a container wall or a cover containing the detection agent on the steroid derivative is avoided, so that the dispersion stability of the steroid derivative is further improved, and the stability and the accuracy of the actual concentration of the detection agent are ensured.
And secondly, according to the characteristics of the effective components contained in the detection agent, the detection agent can be used as a calibrator and a quality control material for detecting steroid hormones. When the detection agent is used as a calibrator and a quality control product for detecting steroid hormones, the concentration of the steroid hormone antigen in the detection agent is indicated, namely is definite, and the concentration can be adjusted according to the detection requirement. Therefore, the steroid hormone antigen dissolved in the calibrator and the quality control product has high solubility and stable content, thereby ensuring the detection accuracy of the steroid hormone.
Therefore, the detection agent for detecting steroid hormone, such as calibrator and quality control, is obtained by using the steroid derivative as the steroid hormone antigen, or further using the preservation solution of steroid hormone as the diluent. Therefore, the detection agent, such as the calibrator and the quality control material, can be stored for a long time, and the dispersion stability of the steroid hormone antigen is effectively ensured, so that the concentration stability of the detection agent, such as the calibrator and the quality control material, is improved, and the detection accuracy of the steroid hormone is ensured.
The above "stable" means that the RLU relative deviation (deviation 1) is within ± 15% after 7 days of treatment in an environment of 4 ℃; RLU relative deviation (deviation 2) within + -15% after 7 days of treatment in 37 deg.C environment; after 7 days of treatment, the relative deviation of RLU (deviation 3) was within. + -. 15% in the environment of 2 ℃ to 8 ℃ and 37 ℃.
In another aspect, the embodiments of the present invention provide a kit for detecting steroid hormones. In one embodiment, the kit for detecting steroid hormones comprises the following reagents: at least one of the steroid derivatives of the present embodiment described above as the steroid hormone antigen, the preservative solution of the steroid hormone of the present embodiment described above, or the detection agent for detecting a steroid hormone of the present embodiment described above.
When the kit contains the steroid derivative in each of the above embodiments, the steroid derivative can be dissolved in a conventional solvent for preparing a detection reagent such as a calibrator and a quality control product as a freeze-dried powder, or can be directly dissolved in the preservation solution of the steroid hormone of the above embodiments of the present invention to prepare a detection reagent such as a calibrator and a quality control product for detecting the steroid hormone in a sample.
When the kit contains the preservation solution of steroid hormone according to the embodiment of the present invention described above, the steroid hormone antigen dissolved in the preservation solution is the steroid derivative described in each embodiment above, and is directly dissolved in the preservation solution described above contained in the kit to be prepared into a detection reagent for detecting steroid hormone in a sample, such as a calibrator and a quality control.
Of course, the kit may contain both the steroid derivative as the steroid hormone antigen and the preservative solution as described above. When the kit is used, the steroid derivative is dissolved in the preservation solution to be prepared into a detection reagent for detecting steroid hormone in a sample, such as a calibrator and a quality control product.
When the kit contains the detection agent for detecting steroid hormone described above, the detection agent can be used directly as a calibrator and quality control for detecting steroid hormone in a sample, and the concentration is known.
In addition, regardless of which reagent is contained in the kit for detecting steroid hormones, the specification such as volume of the corresponding reagent can be flexibly set according to the specification of the kit, wherein the concentration of the steroid derivative contained in the detection agent such as calibrator and quality control can also be flexibly adjusted according to the need of detection. In one embodiment, when the detection agent is prepared from at least one of the steroid derivative and the storage solution described above contained in the kit, or when the detection agent is contained in the kit as described above, the calibrator is a calibrator or a quality control, and the quality control may be conventionally set to control 1 and control 2. Wherein, the concentrations of the low-concentration calibrator, the high-concentration calibrator, the quality control product 1 and the quality control product 2 are prepared according to the concentrations of the conventional calibrator and the conventional quality control product.
Of course, the kit also comprises other necessary reagents for detecting the steroid hormone, such as chemiluminescence immunoassay related reagents, specifically, a steroid hormone antibody coated magnetic ball reagent, a labeled steroid hormone antibody reagent labeled by a labeling reagent for labeling the steroid hormone antibody, and the like. The steroid hormone antibody can be a conventional steroid hormone antibody. The labelling agent may be an ABEI labelling agent.
Therefore, the kit for detecting steroid hormones comprises the steroid derivatives or/and the preservation solution of the steroid hormones in the embodiments of the invention described above, or comprises the detection agent for detecting the steroid hormones in the embodiments of the invention described above, so that the content of the steroid hormones detected by the kit is accurate, convenient and quick.
In addition, the steroid hormone content in the sample detected by the kit for detecting steroid hormone can be operated according to a conventional chemiluminescence immunoassay method.
The steroid derivative, the preparation method and the application thereof, the preservation solution of steroid hormone and the application thereof according to the embodiment of the present invention will now be described in further detail with reference to specific examples.
1. Examples of steroid derivatives and methods for their preparation
Example 11 example 17
Each of examples 11-17 provides a steroid derivative. The structural formulas of the steroid derivatives in the respective examples 11 to 17 are shown in the following table 1:
TABLE 1
2. Examples of preservation solutions for steroid hormones
Example 21-example 24 and comparative example 1
Examples 21 to 24 and comparative example 1 each provide a preservation solution for steroid hormones. The components contained in the preservation solutions of examples 21 to 24 and comparative example 1 are respectively shown in the following table 2:
TABLE 2
3. Detection agent for detecting steroid hormones and kit embodiments
Example 31-example 310 and comparative example 31-comparative example 36
This example 31-310 respectively provide a kit for detecting steroid hormones, which comprises the following components:
(1) steroid hormone antibody coated magnetic microspheres, wherein the concentration of the magnetic microspheres is as follows: 1mg/mL, the concentration of the anti-steroid hormone antibody is 10 mug/mL;
(2) ABEI-labeled steroid hormone antibodies, wherein ABEI concentration: 250ng/mL, concentration of anti-steroid hormone antibody: 5000 ng/mL;
(3) the standards in examples 31 to 310 and comparative examples 31 to 36 shown in Table 3:
a low-concentration calibrator comprising the steroid derivative antigens shown in examples 11 to 17 in table 1, wherein the steroid derivative antigens shown in examples 11 to 17 are each dissolved in a preservative solution shown in table 2;
a high-concentration calibrator containing the steroid derivative antigens shown in examples 11 to 17 in table 1, wherein the steroid derivative antigens shown in examples 11 to 17 are each dissolved in a storage solution shown in table 2;
(4) examples 31 to 310 and comparative examples 31 to 36 shown in Table 3 had quality controls:
a quality control material 1 comprising the steroid derivative antigens shown in examples 11 to 17 in Table 1, wherein the steroid derivative antigens shown in examples 11 to 17 are dissolved in the storage solutions shown in Table 2;
the quality control product 2 contains the steroid derivative antigens shown in examples 11 to 17 in Table 1, and the steroid derivative antigens shown in examples 11 to 17 are dissolved in the storage solutions shown in Table 2 at concentrations
(5) The storage diluent of the low concentration calibrator, the high concentration calibrator, the quality control 1 and the quality control 2 was 50mM PBS buffer (containing 0.5% BSA, 0.2% NaN)3) And the concentration of each calibrator and quality control product is adjusted according to different and required steroid derivative antigens. The calibration products and the quality control products are stored in any one of plastic bottles, glass bottles with rubber stoppers, and the like.
TABLE 3
Experimental methods, data and results analysis
1. Affinity/potency validation of steroid derivatives:
1.1 methods for affinity/potency validation of steroid derivatives are as follows:
weighing 1mg of pure or standard (analytically pure) steroid serum marker molecules, dissolving the pure or standard (analytically pure) with DMF (dimethyl formamide) to obtain 1mg/mL, diluting the pure or standard with DMF in a certain proportion in a gradient manner to obtain 5 samples with concentration, detecting the samples with corresponding steroid serum marker determination kits (chemiluminescence methods) respectively, and measuring and recording RLU (radio determination unit) of the samples;
weighing 1mg of the pure steroid derivative provided by the embodiments 11 to 17, dissolving the pure steroid derivative with DMF (dimethyl formamide) to obtain a nominal concentration of 1mg/mL, diluting the pure steroid derivative with a gradient according to a specific proportion in the step I to obtain samples with 5 concentrations, detecting the samples with corresponding steroid serum marker determination kits (chemiluminescence methods) respectively, and measuring and recording RLU (radio remote Unit) of the samples;
thirdly, performing linear fitting on the RLU of the 5 existing steroid serum marker samples with different concentrations obtained by the step one and the RLU of the 5 steroid derivative samples with corresponding concentrations obtained by the step two by using a least square method, and calculating a linear correlation coefficient (R) when R is measured2And (3) being more than or equal to 0.95, namely the linear correlation coefficient (r) being more than or equal to 0.9900, the affinity/titer of the steroid serum marker molecule modifier is in accordance with the requirement, otherwise, the affinity/titer is not in accordance with the requirement.
1.2 Experimental data and results analysis for affinity/potency validation of steroid derivatives
(1) Affinity verification experimental data for androstenedione derivatives are shown in table 4:
TABLE 4
The measurement RLU for the 5 androstenedione samples at different dilution ratio concentrations in table 4 and the measurement RLU for the 5 androstenedione derivative samples at corresponding dilution ratio concentrations in table 1 were linearly fitted by the least square method, and the curve of the linear fitting was as shown in fig. 1. Wherein the linear correlation coefficient of androstenedione with androstenedione derivative of example 11 is R2When the linear correlation coefficient of androstenedione with androstenedione derivative of example 12 is R, 0.99942When the linear correlation coefficient of androstenedione with androstenedione derivative of example 13 is R, 0.998520.9966. Thus, R2≥0.95，(r) ≥ 0.9900, indicating that the affinity/potency of androstenedione provided in examples 11-13 meet the requirements for use in kit calibrators and quality controls.
(2) Affinity verification experimental data for testosterone derivatives are shown in table 5:
TABLE 5
The RLU measurements for the 5 testosterone samples at different dilution ratios in table 5 were fitted to the RLU measurements for the 5 testosterone derivative samples at corresponding dilution ratios using a least squares fit, the curve of which is shown in figure 2. Wherein the linear correlation coefficient of testosterone to the testosterone derivative of example 14 is R20.9969. Thus, R20.95 ≧ 0.9900 (r), indicating that the affinity/potency of the testosterone derivative provided in example 14 meets the requirements for use in kit calibrators and quality controls.
(3) The data of the affinity verification experiment of the estradiol derivatives are shown in table 6:
TABLE 6
The RLU for measurement of 5 estradiol samples at different dilution ratios in table 6 and the RLU for measurement of 5 estradiol derivative samples at corresponding dilution ratios in table 3 were linearly fitted by the least square method, and the curve of the linear fit is shown in fig. 3. Wherein the linear correlation coefficient of estradiol with the estradiol derivative of example 15 is R20.9969. Thus, R2And (r) is not less than 0.95 and not less than 0.9900, which indicates that the affinity/potency of the estradiol derivative provided in example 15 meets the requirements for a kit calibrator and a quality control material.
(4) Affinity verification experimental data for progesterone derivatives are shown in table 7:
TABLE 7
The measurement RLU for the 5 progesterone samples with different dilution ratio concentrations in table 7 and the measurement RLU for the 5 progesterone derivative samples with corresponding dilution ratio concentrations were fitted linearly by the least square method, and the curve of the linear fit is shown in fig. 4. Wherein the linear correlation coefficient of progesterone to the progesterone derivative of example 16 is R20.9964. Thus, R2Not less than 0.95, (r) not less than 0.9900, indicating that the affinity/potency of the progesterone derivatives provided in example 16 meets the requirements for use in kit calibrators and quality controls.
(5) The data of the affinity verification experiments for cortisol derivatives are shown in table 8:
TABLE 8
The RLU for measurement of 5 cortisol samples at different dilution ratios in table 8 and RLU for measurement of 5 cortisol derivative samples at corresponding dilution ratios in table 5 were fitted to each other by a straight line using the least square method, and the curve of the straight line fitting is shown in fig. 5. Wherein the linear correlation coefficient of cortisol with the cortisol derivative of example 16 is R20.9967. Thus, R2Not less than 0.95, (r) not less than 0.9900, indicating that the affinity/potency of the cortisol derivative provided in example 17 meets the requirements for use in a kit calibrator and quality control.
2. Effect verification of the calibrator and quality control stable preservation method for steroid serum markers (i.e., calibrator and quality control for detection of steroid hormones) (i.e., verification of simulated transport stability at 4 ℃ and 37 ℃) of calibrator and quality control):
2.1 the effect verification method for the stable preservation method of the calibrator and the quality control material for detecting steroid hormones:
the test kit comprises: the kits for detecting steroid hormones (chemiluminescence methods) provided in examples 31 to 310 (test group) and comparative examples 31 to 36 (control group);
and (3) testing conditions are as follows: oscillating the low-concentration calibrator, the high-concentration calibrator, the quality control product 1 and the quality control product 2 provided by the test group at a constant temperature of 180r/min at 37 ℃, and storing the low-concentration calibrator, the high-concentration calibrator, the quality control product 1 and the quality control product 2 in any one of a rubber bottle or a glass bottle with a rubber plug; the low-concentration calibrator, the high-concentration calibrator, the quality control product 1 and the quality control product 2 provided by the control group are subjected to constant-temperature oscillation at 4 ℃ and 180r/min and are stored in a glass bottle without adsorption and a rubber plug under an ideal state;
testing a sample: low-concentration calibrator, high-concentration calibrator, quality control 1 and quality control 2 contained in the test group and the control group;
wherein the concentrations of the androstenedione and the androstenedione derivative are respectively as follows: 0.3ng/ml, 6ng/ml,1.5ng/ml and 6 ng/ml;
the concentrations of a low-concentration calibrator, a high-concentration calibrator, a quality control product 1 and a quality control product 2 of testosterone and testosterone derivatives are respectively as follows: 0.5ng/ml, 11ng/ml,1ng/ml and 10 ng/ml;
the concentrations of a low-concentration calibrator and a high-concentration calibrator of estradiol and estradiol derivatives, namely a quality control product 1 and a quality control product 2 are respectively as follows: 90pg/ml, 2000pg/ml,200pg/ml, 3000 pg/ml;
the concentrations of the low-concentration calibrator and the high-concentration calibrator of the progesterone and the progesterone derivative, the quality control product 1 and the quality control product 2 are respectively as follows: 0.5ng/ml, 60ng/ml, 2ng/ml and 40 ng/ml;
the concentrations of a low-concentration calibrator and a high-concentration calibrator of cortisol and a cortisol derivative, a quality control product 1 and a quality control product 2 are respectively as follows: 16ng/ml, 500ng/ml, 20ng/ml and 360 ng/ml.
And (3) testing time: continuously tracking for 7 days;
other descriptions: continuously tracking the test samples under two groups of test conditions for 7 days, simulating the stability of steroid serum marker molecules in a calibrator and a quality control product in the transportation process of the product, and respectively calculating a relative deviation 1, a deviation 2 and a deviation 3 according to the following formulas to obtain the stability effect;
the acceptance standard of the quality control product/calibrator is that the relative deviation (deviation 1) of RLU is within the range of +/-15% after the RLU is treated in an environment at 4 ℃ for 7 days; RLU relative deviation (deviation 2) within + -15% after 7 days of treatment in 37 deg.C environment; after 7 days of treatment, the relative deviation of RLU (deviation 3) was within. + -. 15% in the environment of 2 ℃ to 8 ℃ and 37 ℃.
Wherein i in the deviations 1 to 3 is 1, 2, 3, …, 6, 7
2.2 Effect verification data and results of the stable preservation method of the calibrator and the quality control material for detecting steroid hormones:
the results of the method for stably storing the calibrator and the quality control material for measuring steroid hormones are shown in table 9. As can be seen by comparing the experimental data in table 9,
(1) comparative example 31, example 31 and comparative example 36 prove that the androstenedione molecule can cause certain influence on the stability of the product when the surfactant is not modified or added into the diluent, and because the detection principle of the androstenedione is a competition method, the increase of RLU indicates that the concentration of the calibrator and the quality control product is obviously reduced, namely, the androstenedione molecule in the calibrator and the quality control product is aggregated or adsorbed to the wall of a plastic tube or a silica gel film or a rubber plug;
(2) comparative example 32 and example 38 demonstrate that testosterone molecules without modification and without the addition of surfactant to the dilution have some effect on the stability of the product;
(3) comparative example 33 and example 39 demonstrate that estradiol molecules without modification and without the addition of surfactant to the diluent have some effect on product stability;
(4) comparative example 34 and example 310 demonstrate that progesterone molecules without modification and without the addition of surfactants in the dilution have some effect on the stability of the product;
(5) comparative example 35 and example 311 demonstrate that cortisol molecules without modification and without the addition of surfactant to the dilution have some effect on the stability of the product;
(6) example 32 sets a comparison on the modified substance group site of example 31, highlighting that the preferred site is the carbon atom at the 6 th position of the steroid parent nucleus, which indicates that the androstenedione molecule is modified, and different modified sites also affect the aggregation of the androstenedione molecule in the system or prevent the androstenedione molecule from being adsorbed on the tube wall of the plastic tube or the silica gel film or the rubber plug;
(7) example 33 sets a comparison on the modified species site of example 31, highlighting that the preferred species is hydroxyl, which indicates that modifying androstenedione molecules, different modified groups will also affect the aggregation of androstenedione molecules in the system or prevent adsorption onto the tube wall of a plastic tube or onto a silicone film or a rubber plug;
(8) example 34 optimizes the surfactant type and concentration of the diluent based on example 31, and improves hydrophilicity and dispersibility comprehensively, which indicates that modifying molecules with poor hydrophilicity and adding a certain concentration of surfactant to the diluent can improve aggregation of androstenedione molecules in the system or prevent adsorption to promote synergy;
(9) the comparison of the concentration conditions of the surfactants in examples 34, 35 and 36 shows that the preferred concentration is 1%, which indicates that the surfactants with different concentrations can also influence the aggregation of androstenedione molecules in the system or prevent the androstenedione molecules from being adsorbed on the tube wall of a plastic tube or a silica gel film or a rubber plug, and when the concentration of tween-20 is 1%, the effect is better than that of 0.05% or 0.3%;
the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A steroid derivative characterized by: the compound contains a cyclopentane-polyhydrophenanthrene mother nucleus, and at least one carbon position of the cyclopentane-polyhydrophenanthrene mother nucleus is substituted with a hydrophilic group; the cyclopentane polyhydrophenanthrene mother nucleus is provided by at least one steroid hormone selected from androgen, estrogen, progestogen and corticoid; the steroid derivative is at least one of the following molecular structural formulas:
2. the application of a steroid derivative is characterized in that: the steroid derivative according to claim 1 as an antigen of a steroid hormone for use in the detection of the steroid hormone.
3. A detection agent for detecting a steroid hormone, characterized in that: the steroid hormone antigen preservative solution comprises a preservative solution and a steroid hormone antigen dissolved in the preservative solution, wherein the steroid hormone antigen is the steroid derivative according to claim 1, or the preservative solution comprises a buffer solution and a surfactant dissolved in the buffer solution.
4. The detection agent according to claim 3, characterized in that: the detection agent is used as a calibrator and a quality control product for detecting steroid hormones.
5. The detection agent according to claim 3, characterized in that: the concentration of the surfactant is 0.05-3% w/v.
6. The detection agent according to claim 3, characterized in that: the surfactant comprises at least one of an anionic surfactant and a nonionic surfactant; and/or
The buffer solution comprises at least one of phosphate buffer solution, acetate buffer solution, citrate buffer solution, borate buffer solution, Tris hydrochloric acid buffer solution and carbonate buffer solution.
7. The detection agent according to claim 3, characterized in that: the anionic surfactant comprises at least one of long-chain alkyl carboxylate, long-chain alkyl sulfonate, long-chain alkyl sulfate and long-chain alkyl phosphate;
the nonionic surfactant comprises at least one of polyoxyethylene ether surfactant and polyoxyethylene ester surfactant.
8. A kit for detecting a steroid hormone, comprising: comprising as steroid hormone antigen the steroid derivative according to claim 1, or comprising the detection agent according to any one of claims 3 to 7.
9. Use of the detection agent according to any one of claims 3 to 7 or the kit according to claim 8 for the clinical detection of steroid hormones.
10. The use according to claim 9, wherein the detection agent is used as a calibrator or quality control agent for clinical testing of steroid hormones.
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