CN109157662B - Human serum albumin-adriamycin cross-linked substance nano-particles and application thereof - Google Patents

Human serum albumin-adriamycin cross-linked substance nano-particles and application thereof Download PDF

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CN109157662B
CN109157662B CN201810575098.1A CN201810575098A CN109157662B CN 109157662 B CN109157662 B CN 109157662B CN 201810575098 A CN201810575098 A CN 201810575098A CN 109157662 B CN109157662 B CN 109157662B
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adriamycin
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林坚
许诺
陈龙
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0056—Peptides, proteins, polyamino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The invention relates to a human serum albumin-adriamycin cross-linked substance and application thereof, the human serum albumin-adriamycin cross-linked substance HSA-DOX synthesized by a micromolecule cross-linking technology can form nano particles, the HSA-DOX nano particles can selectively kill tumor cells and inhibit lymph node metastasis of tumors, and can be used for targeted imaging and targeted therapy of the tumors. Compared with uncrosslinked adriamycin, HSA-DOX of the invention can obviously enhance the tumor treatment effect and reduce the tumor volume.

Description

Human serum albumin-adriamycin cross-linked substance nano-particles and application thereof
Technical Field
The invention belongs to the field of medicines and biotechnology, in particular relates to a nano anti-cancer medicine, and especially relates to a human serum albumin-adriamycin cross-linked substance and an application thereof in treating tumors.
Background
Tumors are still a common disease and frequently encountered disease which seriously threaten human health, and are one of the main causes of death. Chemotherapy is a treatment mode that utilizes cytotoxic drugs to kill tumor cells, inhibit the growth and reproduction of tumor cells and promote the differentiation of tumor cells, and is a systemic treatment means. However, in clinical treatment, chemotherapy treatment is a co-worker in killing tumor cells, and normal cells and immune cells are killed together. Among them, doxorubicin is one of the most commonly used and important drugs.
Clinically used adriamycin, also called doxorubicin, is an important chemotherapeutic drug for treating tumors, but the wide clinical application of the adriamycin is limited due to the generated biological toxicity. Because the adriamycin A does not have tumor targeting, tumor tissues and normal tissues can be killed and killed simultaneously in the chemotherapy process, and serious side effects can be generated by using the adriamycin A for a long time, so that the heart, the liver, the brain and the kidney are damaged.
Disclosure of Invention
Based on the problems in the prior art, the invention uses the human serum albumin to crosslink the adriamycin, enhances the targeting property to the tumor by the human serum albumin, and reduces the toxic and side effects of the adriamycin. The invention unexpectedly discovers that the human serum albumin cross-linked adriamycin can selectively target breast cancer cells, can be used for treating breast cancer, and can also be used for breast cancer living body imaging detection after being marked. In addition, human serum albumin cross-linked doxorubicin also has a higher tumor therapeutic effect and a better safety profile than doxorubicin (not cross-linked) at the same active dose.
Specifically, in one aspect, the invention provides the use of a human serum albumin-doxorubicin cross-linked substance in the preparation of a tumor detection agent, wherein the human serum albumin-doxorubicin cross-linked substance is a nanoparticle formed by cross-linking doxorubicin molecules on albumin based on a small molecule cross-linking technology.
The invention discloses an application of a human serum albumin-adriamycin cross-linked substance in preparing a tumor detection agent, wherein the human serum albumin-adriamycin is marked, and the tumor detection agent is a living body imaging agent.
The application of the invention, wherein the tumor is breast cancer, and the marker is Cy5.5 marker.
In a second aspect, the present invention provides a use of a human serum albumin-doxorubicin cross-linked complex in the preparation of a drug for treating tumor, wherein the human serum albumin-doxorubicin cross-linked complex is a nanoparticle formed by cross-linking doxorubicin molecules on albumin based on a small molecule cross-linking technology.
The invention relates to an application of a human serum albumin-adriamycin cross-linked substance in preparing a medicament for treating tumors, wherein the tumors are breast cancers.
The invention discloses application of a human serum albumin-adriamycin cross-linked substance in preparing a medicament for treating tumors, wherein the medicament for treating tumors is a medicament for selectively killing breast cancer cells.
The invention discloses application of a human serum albumin-adriamycin cross-linked substance in preparing a medicament for treating tumors, wherein the medicament for treating tumors is a medicament for inhibiting breast cancer cell lymph node metastasis.
In a third aspect, the invention provides a breast cancer treatment drug, which comprises human serum albumin-adriamycin cross-linked nanoparticles, wherein adriamycin molecules are cross-linked on human serum albumin through a small molecule cross-linking technology to form nanoparticles, and the average particle size of the nanoparticles is about 25 nm; the ratio of HSA to DOX was 1: 3.
In a fourth aspect, the present invention provides a method for preparing a cross-linked human serum albumin-doxorubicin conjugate, comprising:
(1) preactivating albumin, and reacting the albumin with SPDP to prepare albumin with pyridine dimercapto;
(2) reducing preactivated albumin, and reducing the preactivated albumin to prepare sulfhydryl activated albumin;
(3) and (3) crosslinking, namely slowly adding ALDOX into the sulfhydryl activated albumin prepared in the step (2) to obtain the human serum albumin-adriamycin conjugate.
The preparation method of the human serum albumin-adriamycin cross-linked substance is characterized in that the human serum albumin-adriamycin cross-linked substance is nano particles, and the average particle size is 25 nm; wherein the ratio of HSA to DOX is 1: 3.
Compared with the prior art, the technical scheme of the invention has the following advantages:
(1) the invention discovers the tumor targeting property of albumin, particularly the breast cancer cell targeting property, so that adriamycin is specifically conveyed to tumor tissues through a cross-linking technology, and after targeted enrichment of albumin cross-linked adriamycin medicine at tumor parts, adriamycin molecules are slowly released in a local acidic microenvironment of the tumor tissues and are delivered to tumor cell nuclei, thereby specifically killing tumor cells without influencing other normal tissues. Thereby enabling imaging and/or treatment of the tumor.
(2) The ternary complex of the human serum albumin, the adriamycin and the marker (such as Cy5.5) can treat tumors, can realize the targeted imaging of tumor cells, and specifically verifies the targeted imaging of breast cancer cells, and the imaging detection result of the ternary complex is consistent with the imaging result of Luciferase, thereby indicating the reliability and the accuracy of the ternary complex. In addition, for the diagnosis of breast cancer, the ternary complex can accurately diagnose whether the breast cancer cells have lymph node metastasis.
(3) Compared with adriamycin (uncrosslinked) with the same active dose, the human serum albumin-adriamycin cross-linked product has higher tumor treatment effect and better safety due to lower dosage and slow release effect.
(4) The cross-linked product of the human serum albumin-adriamycin obtained by the preparation method is nano-particles, so that the drug metabolism characteristic is improved due to the cross-linking of HSA, and the cross-linked product shows pH response characteristics due to the specific cross-linking agent and the cross-linking method. The human serum albumin-doxorubicin nanoparticles are stable under the near-neutral pH condition of normal body fluid, and can slowly release active DOX molecules under the low pH value acidic condition of a tumor microenvironment, so that the specificity of the HSA-DOX tumor is further enhanced.
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Various other advantages and benefits will become apparent to those of ordinary skill in the art upon reading the following detailed description of the preferred embodiments. The drawings are only for purposes of illustrating the preferred embodiments and are not to be construed as limiting the invention. Also, like reference numerals are used to refer to like parts throughout the drawings. In the drawings:
FIG. 1: human serum albumin-adriamycin cross-linked nano-particle size distribution
FIG. 2: standard curve of adriamycin absorbance and concentration
FIG. 3: tumor cell localization of HSA-DOX
FIG. 4: HSA-DOX selective killing of breast cancer cells
FIG. 5: HSA-DOX in vivo tumor targeting, 7h, 24h and 48h in vivo imaging graph, the control group on the left and the HSA-DOX experimental group on the right
FIG. 6: lymph node metastasis of HSA-DOX targeted tumors
FIG. 7: imaging graph of mouse animal experiment Luciferase
FIG. 8: tumor volume growth curve of transplanted tumor mice
FIG. 9: body weight change curve of transplanted tumor mouse
Detailed Description
Exemplary embodiments of the present disclosure will be described in more detail below with reference to the accompanying drawings. While exemplary embodiments of the present disclosure are shown in the drawings, it should be understood that the present disclosure may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art.
According to an embodiment of the present invention, the following examples are presented
Example 1 crosslinking of Albumin with Doxorubicin Using protein Small molecule crosslinking technology
Preparation method of HSA-DOX
5mg of albumin powder was weighed out and dissolved in 10mL of 1mM EDTA solution, pH7.5, and 8. mu.L of 500mM SPDP solution was added. Shaking the reaction at room temperature for 2h to react the SPDP with the amino group on the albumin, so as to form a coupling product of the albumin and the SPDP.
Figure BDA0001687333480000041
After the reaction, the reaction was ultrafiltered using a Millipore 10kD ultrafilter tube to remove unreacted free SPDP molecules and washed three times with EDTA solution. This was dissolved in 10mL of a 1mM EDTA solution (pH7.5), 6mg of DTT was added, and the reaction was stirred at room temperature for 1 hour.
After the reaction, the reaction product was dissolved in 7mL of a 1mM EDTA solution having a pH of 7.5, which was obtained by removing unreacted free DTT molecules by ultrafiltration using a Millipore 10kD ultrafiltration tube and washing three times with the EDTA solution. mu.L of a 100mM solution of AlDOX (Aldox from MedChemexpress, CAS No.:1361644-26-9) was added to 3mL of DMSO and mixed well. 3mL of the solution was slowly added to 7mL of the protein solution, and shaken during the addition, and the reaction was shaken overnight at room temperature. After the reaction, ultrafiltration was carried out using a Millipore 10kD ultrafiltration tube to remove unreacted free AlDOX molecules, and the product was stored at-20 ℃ after washing three times with deionized water.
Figure BDA0001687333480000042
Characterization of HSA-DOX
The prepared HSA-DOX was characterized by placing the HSA-DOX solution in a cuvette and measuring it with a dynamic light scattering instrument, and the results are shown in FIG. 1, demonstrating that HSA-DOX is a nanoparticle having a particle size of about 25nm (FIG. 1).
Doxorubicin was diluted to different concentrations and the absorbance thereof was measured by a microplate reader, and a standard curve of absorbance and concentration was plotted (fig. 2). Detecting the absorbance of the HSA-DOX to be 34923, and calculating the concentration of the DOX in the prepared HSA-DOX solution to be 67 mu M through a regression curve; meanwhile, the protein concentration in HSA-DOX is 1.9mg/mL as measured by A280 absorption, and the ratio of HSA to DOX is calculated to be about 1: 3.
HSA-DOX was placed in PBS at pH7.5 and 5.5 for 3h at room temperature, and then protein and free DOX molecules were separated by ultrafiltration. And (2) placing the protein solution after ultrafiltration in a microplate reader to measure DOX fluorescence intensity, and calculating the protein concentration and the DOX concentration to obtain the protein solution, wherein the ratio of HSA to DOX is still 1:3 under the condition of pH7.5, and the ratio of HSA to DOX is reduced to 1:0.5 under the condition of pH5.5, so that the HSA-DOX can be degraded to release DOX molecules under an acidic environment.
Example 2 Selective killing of tumor cells by Albumin-conjugated Adriamycin drug
HSA-DOX can enter tumor cells: HSA-DOX was added to the culture medium of adherently cultured MDA-MB-231 cells and incubated for 4h at 37 ℃ in an incubator with AlDOX alone as a control, and nuclei were stained with Hoechst33342 for 5 min. Co-localization of fluorescence from DOX (red) and Hoechst (blue) was observed under confocal microscopy (figure 3). Similar to the results of the AlDOX control group, HSA-DOX demonstrated that HSA-DOX released DOX in the acidic environment of tumor cells, so that DOX could enter the nucleus.
HSA-DOX selective killing of tumor cells: HSA-DOX was added to tumor cells (MDA-MB-231) and normal cells (HEK293) at different concentrations, such that the DOX concentrations were 0.4, 0.8, and 1.6. mu.M. After incubation at 37 ℃ for 24h, cell activity was measured with MTT (FIG. 4). The result shows that the killing capability to MDA-MB-231 cells is obviously improved along with the increase of the concentration of HSA-DOX, and the killing effect to HEK293 cells is not obvious, so that the HSA-DOX can be proved to have the effect of selectively killing tumor cells without influencing normal cells.
Example 3 verification of animal model Effect
1. Tumor targeting of HSA-DOX in vivo:
subcutaneous injection of 3X10 in Balb/c nude mice5MDA-MD-231 cells transformed with Luciferase. When the tumor volume was 5-10mm3, 100. mu.L of Cy5.5-labeled HSA-DOX was injected into the tail vein, and the fluorescence of Cy5.5 and Luciferase was imaged in a biopsy instrument 24h later (FIG. 5). The obvious co-localization of Cy5.5 and Luciferase fluorescence can be seen, and HSA-DOX can be enriched in tumor tissues and has good tumor targeting property.
2. HSA-DOX Targeted tumor lymph node metastasis:
5X105 MDA-MD-231 cells transfected with Luciferase were injected into the tail vein of Balb/c nude mice. After two weeks of culture, tumor cells produced lymph node metastasis, 100. mu.L of Cy5.5-labeled HSA-DOX was injected into the tail vein, and after 24 hours, the fluorescence of Cy5.5 and Luciferase was imaged on the thigh lymph nodes of nude mice in a live imager (FIG. 6), and the upper and lower limb lymph nodes of nude mice were removed for fluorescence imaging. Wherein Cy5.5 and Luciferase generate obvious co-localization, MDA-MB-231 tumor cell metastasis occurs in two of four dissected lymph nodes, namely, fluorescence of Cy5.5 also occurs in the lymph nodes with Luciferase fluorescence, and no obvious Cy5.5 fluorescence occurs in the lymph nodes without metastasis. HSA-DOX was shown to target not only tumor tissue but also lymph node metastasis of tumors.
3. Efficacy and safety of HSA-DOX for tumor therapy:
selecting 4-6 weeks nude mice, injecting 5x10 subcutaneously5The MDA-MB-231 cells containing Luciferase of Luciferase. After the tumor model has stable tumor formation and the tumor volume is 5-10mm3, the tumor is divided into three groups (control group, DOX group and HSA-DOX group) on average. Control group, DOX combination HSA-DOX group Each tail vein was injected with 100. mu.L of PBS solution, doxorubicin solution and HSA-DOX solution, respectively, so that the DOX concentrations were all 2 mg/kg. The tail vein was dosed once every three days and two weeks after dosing Luciferase was imaged on the tumors (fig. 7). The imaging result shows that the mouse tumor injected with HSA-DOX has lower fluorescence intensity, namely has obvious inhibition effect on the growth of the tumor. Meanwhile, the tumor volume of the mice was measured and calculated during the treatment (tumor length x width 2/2), and the body weight data of the mice were also recorded, and the results are shown in fig. 8 and 9. The above results indicate that AlDOX alone has no significant effect on tumor treatment, while HSA-DOX is able to significantly reduce tumor volume. In addition, the weight of the mice has no obvious change in the administration process, and the safety is proved to be good.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.

Claims (5)

1. The human serum albumin-adriamycin cross-linked substance is a nanoparticle formed by cross-linking adriamycin molecules on albumin based on a small molecule cross-linking technology; the nanoparticles have an average particle size of about 25 nm;
the tumor is breast cancer.
2. The use of the human serum albumin-doxorubicin conjugate according to claim 1 for the preparation of a tumor detection agent, wherein said human serum albumin-doxorubicin is labeled and said tumor detection agent is a live imaging agent.
3. Use according to claim 2, characterized in that the marker is the Cy5.5 marker.
4. The human serum albumin-adriamycin cross-linked substance is a nanoparticle formed by cross-linking adriamycin molecules on albumin based on a small molecule cross-linking technology; the nanoparticles have an average particle size of about 25 nm;
the tumor is breast cancer;
the medicine for treating the tumor is a medicine for selectively killing breast cancer cells or a medicine for inhibiting lymph node metastasis of the breast cancer cells.
5. A medicament for treating breast cancer comprises human serum albumin-adriamycin cross-linked nanoparticles, wherein adriamycin molecules are cross-linked on human serum albumin through a small molecule cross-linking technology to form nanoparticles, and the average particle size of the nanoparticles is about 25 nm; the ratio of HSA to DOX is 1: 3;
the preparation method of the human serum albumin-adriamycin cross-linked nanoparticle comprises the following steps:
(1) preactivating albumin, and reacting the albumin with SPDP to prepare albumin with pyridine dimercapto;
(2) reducing preactivated albumin, and reducing the preactivated albumin to prepare sulfhydryl activated albumin;
(3) and (3) crosslinking, namely slowly adding ALDOX into the sulfhydryl activated albumin prepared in the step (2) to obtain the human serum albumin-adriamycin conjugate.
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