Preparation for reducing ADC drug induced inflammation-related adverse reactions, and preparation method and application thereof

Abstract

The invention relates to a preparation for reducing inflammation-related adverse reactions induced by ADC drugs as well as a preparation method and application of the preparation. According to the invention, the process of inducing inflammation-related adverse reactions by ADC drugs is deeply analyzed, an induction mechanism is found, a triple mechanism of blocking of scavenger receptors such as MSR1, inhibition of a Ceramide lysosomal axis and reconstruction of an inflammation regression pathway is designed aiming at the induction mechanism, a compound capable of performing intervention is excavated, and an intervention preparation is further designed, so that the compound can be applied to the treatment of the inflammation-related adverse reactions. The ADC-induced inflammation-related adverse reactions can be intervened in the mechanism level, safety and curative effect are both considered, universality and clinical conversion value are achieved, and a new solution is provided for improvement of treatment compliance of ADC drugs and survival benefits of patients.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to formulations for reducing inflammation-related adverse reactions induced by ADC drugs, their preparation methods, and applications. Background Technology

[0002] Antibody-drug conjugates (ADCs) have become a significant advancement in cancer treatment in recent years. Leveraging the high selectivity of antibodies and the potent cytotoxic killing ability of their payloads, they have achieved breakthrough efficacy in the treatment of various solid tumors, including breast cancer, gastric cancer, and lung cancer. Among them, HER2-targeted ADCs, such as Trastuzumab deruxtecan (T-DXd, Enhertu), have not only demonstrated sustained and significant clinical benefits in HER2-high expression tumors but have also shown a survival-prolonging advantage in HER2-low expression breast cancer and NSCLC patients for the first time, thus expanding the spectrum of HER2-targeted therapies. Besides T-DXd, other ADCs, such as Trastuzumab emtansine (T-DM1), Trastuzumab duocarmazine (SYD985), and Brentuximab vedotin, have also shown positive efficacy in various tumor types and are gradually forming a differentiated indication pattern. Clinical and market data further confirm the rapid development and huge potential of ADCs: According to statistics, the global ADC market size reached US$12.8 billion in 2024, of which T-DXd sales reached US$3.54 billion, highlighting its outstanding clinical application prospects and commercial value.

[0003] However, with the widespread clinical application of ADCs, their inflammation-related adverse events (irAEs) have gradually attracted attention, especially drug-related interstitial lung disease (ILD), which is considered one of the most serious and potentially fatal toxicities. According to multiple international clinical trials and real-world testing data, the incidence of T-DXd-related ILD is approximately 10%–15%, exceeding 26% in patients with uterine carcinosarcoma or non-small cell lung cancer, and approaching 14% in breast cancer patients; further clinical studies indicate that 2–4% of patients die from severe ILD. In addition to ILD, ADCs can also cause multi-organ damage such as myocarditis, liver inflammation, and intestinal inflammation, significantly limiting their further application. Current clinical management mainly includes dose reduction, treatment interruption, drug discontinuation, corticosteroids, and supportive care. However, this strategy cannot fundamentally cure inflammation-related adverse events and may lead to further disease deterioration due to delayed or interrupted anti-tumor treatment. Therefore, how to effectively prevent and intervene in inflammation-related adverse reactions induced by ADC drugs is a key issue that needs to be addressed by existing technologies. Summary of the Invention

[0004] In response to the shortcomings of existing technologies and actual clinical needs, this invention provides the application of compounds in the preparation of formulations that reduce inflammation-related adverse reactions induced by ADC drugs, thereby overcoming the lack of effective strategies in existing technologies to address ADC drug-related inflammatory adverse reactions, and thus achieving effective relief and control of inflammatory damage.

[0005] To achieve the above objectives, the present invention adopts the following technical solution: In a first aspect, the present invention provides the use of compounds in the preparation of formulations that reduce inflammation-related adverse reactions induced by ADC drugs, said compounds comprising at least one of compounds that bind to or inhibit scavenger receptors, ceramide synthesis inhibitors, or pro-inflammatory remission compounds.

[0006] This invention provides an in-depth analysis of the process by which ADC drugs induce inflammation-related adverse reactions. It reveals that ADC drugs can be recognized and taken up by scavenger receptors (such as MSR1, also known as SR-A or CD204) on the surface of macrophages, subsequently triggering ceramide-dependent lysosomal instability, leading to the activation and release of cathepsin B (CTSB). Simultaneously, ADC treatment is accompanied by a reduction in inflammatory mediators, causing immune imbalance and persistent inflammation, thereby exacerbating inflammation-related adverse reactions, such as inducing lung injury and fibrosis. Based on these findings, this invention designs a triple mechanism of "MSR1 and other scavenger receptor blockade, Ceramide lysosomal axis inhibition, and inflammatory remission pathway reconstruction," and explores compounds capable of intervention to develop formulations that can reduce ADC drug-induced inflammation-related adverse reactions.

[0007] It is understood that the formulation may be a drug or a formulation for other purposes.

[0008] Optionally, the scavenger receptor includes MSR1.

[0009] Optionally, the compound that binds to or inhibits scavenger receptors includes at least one of a polysaccharide having a sulfated or sulfonated structure, a polyanionic ligand, or a phagocytosis / endocytosis inhibitor.

[0010] Optionally, the polysaccharide having a sulfated or sulfonated structure includes at least one of fucoidan, sulfated dextran, or heparin.

[0011] Optionally, the polyanionic ligand includes at least one of polyinosinic acid, acetylated low-density lipoprotein, or ferritin.

[0012] Optionally, the phagocytosis / endocytosis inhibitor includes at least one of Wortmannin, Cytochalasin D, Latrunculin A, LY294002, Chlorpromazine, Filipin, EIPA, Dynasore, or Pitstop 2.

[0013] Optionally, the ceramide synthesis inhibitor includes at least one of desipramine, imipramine, amitriptyline, clomipramine, nortriptyline, mitomycin, or furan toxin.

[0014] Optionally, the pro-inflammatory compound includes polyunsaturated fatty acids and / or lipid mediators (such as RvE, Maresins, or Protectins).

[0015] Optionally, the polyunsaturated fatty acid includes docosapentaenoic acid (DVA).

[0016] In a second aspect, the present invention provides an formulation for reducing inflammation-related adverse reactions induced by ADC drugs, the formulation comprising at least one of the compounds that bind or inhibit scavenger receptors as described in the first aspect, ceramide synthesis inhibitors, or pro-inflammatory remission compounds.

[0017] Optionally, the formulation further includes a pharmaceutically acceptable carrier on which the compound that binds or inhibits scavenger receptors, the ceramide synthesis inhibitor, and the pro-inflammatory depressant compound are loaded.

[0018] Optionally, the carrier includes a nanocarrier.

[0019] This invention utilizes a rational molecularly targeted design and synthesis strategy to construct a class of multifunctional modified nano-formulations. These nano-formulations are characterized by simple preparation, high stability, good safety, and strong targeting. Compared with existing single or symptomatic supportive treatments (such as pirfenidone PFD for treating pulmonary fibrosis), the nano-formulations of this invention can not only effectively alleviate inflammation-related adverse reactions caused by different ADC drugs, but also exert multiple interventional effects on other inflammatory damage induced by the same drug. Furthermore, this invention has demonstrated good therapeutic effects in various mouse and human primary cell and animal models, showing broad potential for clinical application.

[0020] Optionally, the nanocarrier includes a liposome carrier.

[0021] Optionally, the liposome carrier includes phospholipids, cholesterol, and cationic lipids.

[0022] Optionally, the compound that binds to or inhibits scavenger receptors is modified on the surface of the liposome carrier, and the ceramide synthesis inhibitor and the pro-inflammatory depressant compound are encapsulated in the liposome carrier.

[0023] Optionally, the preparation method of the formulation includes the following steps: (1) Dissolve the compound that binds to or inhibits scavenger receptors in deionized water or phosphate buffer and add an emulsifier to obtain an aqueous solution; (2) Ceramide synthesis inhibitors, anti-inflammatory compounds, phospholipids, cholesterol, and cationic lipids were mixed to obtain an oil phase solution; (3) Add the oil phase solution to the aqueous phase solution to obtain an emulsion system; (4) Remove the organic solvent from the emulsion system to obtain a nano solution; (5) The nano solution is subjected to ultrasonic treatment to obtain nanoparticles.

[0024] Optionally, the preparation method specifically includes: (1) Dissolve the compound that binds to or inhibits scavenger receptors in deionized water or phosphate buffer, add an emulsifier (such as HS-15 surfactant), and ultrasonically disperse to obtain an aqueous solution; (2) Dissolve the ceramide synthesis inhibitor and the pro-inflammatory compound together with cholesterol, phospholipids and cationic lipids in an organic solvent and stir until completely clear; (3) Add the oil phase solution to the aqueous phase solution, stir to form an emulsion, and further treat with ultrasound to obtain the emulsion system; (4) Remove the organic solvent in the emulsion system by rotary evaporation under reduced pressure or natural evaporation to obtain a nano solution; (5) The nano solution was subjected to ultrasonic treatment to self-assemble and obtain relatively uniform nanoparticles.

[0025] Optionally, the mass ratio of the compound that binds to or inhibits scavenger receptors to the emulsifier is 1:(4~100).

[0026] Optionally, the mass ratio of the ceramide synthesis inhibitor and the pro-inflammatory compound to cholesterol, phospholipids and cationic lipids is 1: (1~100): (1~100): (1~100): (1~100).

[0027] Optionally, the ADC drug includes an ADC drug that can be recognized or bound by scavenger receptors.

[0028] Optionally, ADC drugs that can be recognized or bound by scavenger receptors include ADC drugs containing Trastuzumab antibodies.

[0029] Compared with the prior art, the present invention has at least the following beneficial effects: This invention provides an in-depth analysis of the process by which ADC drugs induce inflammation-related adverse reactions, discovers the induction mechanism, and designs a triple mechanism targeting the inducing mechanism: "blockade of scavenger receptors such as MSR1, inhibition of the Ceramide lysosomal axis, and reconstruction of the inflammation resolution pathway." It also identifies compounds that can be used for intervention and further designs interventional formulations that can intervene in ADC-induced inflammation-related adverse reactions at the mechanism level, taking into account both safety and efficacy. This invention has universality and clinical translational value, providing a new solution for improving treatment adherence and patient survival benefits of ADC drugs. Attached Figure Description

[0030] Figure 1 This is a schematic diagram of the structure of lipid-based nanoparticles.

[0031] Figure 2 This is a schematic diagram illustrating the working principle of lipid-based nanoparticles.

[0032] Figure 3This image shows the results of observing Caspase-1 activation in three-dimensional lung organoids using confocal microscopy. The scale bar is 100 μm.

[0033] Figure 4 The image shows the results of IL-1β detection using the ELISA method.

[0034] Figure 5 The image shows the cryo-electron microscopy results of lipid-based nanoparticles FDDN, with a scale bar of 100 nm.

[0035] Figure 6 The figure shows the stability characterization results of lipid-based nanoparticles FDDN.

[0036] Figure 7 The figure shows the competitive inhibition effect of lipid-based nanoparticles FDDN on the binding of T-DXd and MSR1.

[0037] Figure 8 This is a diagram showing the in vivo fluorescence imaging results at the whole-body level in mice.

[0038] Figure 9 This is an image showing the results of in vitro fluorescence imaging of the major organs of a mouse.

[0039] Figure 10 Graphs showing the anti-inflammatory effects of different lipid nanoparticles.

[0040] Figure 11 The results show the effect of FDDN in alleviating the T-DXd-induced inflammatory response in a cell model. In Figure A, the results are observed by confocal microscopy. In T-DXd-treated macrophages, the fluorescence signals of CTSB (red) and activated Caspase-1 (green) are significantly enhanced. Scale bar = 100 μm. Figure B shows the results of ELISA detection of IL-1β secretion level in cell supernatant.

[0041] Figure 12 The figures show the results of FDDN alleviating T-DXd-induced inflammation and profibrotic response in a three-dimensional lung organoid model. Figure A shows the fluorescence signals of CTSB (red) and activated Caspase-1 (green) in the three-dimensional lung organoid after T-DXd treatment, detected by confocal microscopy, with a scale bar of 100 μm. Figure B shows the IL-1β level in the organoid supernatant detected by ELISA. Figure C shows the TGF-β1 level in the supernatant detected by ELISA.

[0042] Figure 13A Immunofluorescence staining of MSR1 in lung tissues of mice in different treatment groups (FDDN or pirfenidone PFD, 7.5 mg / kg) and MSR1... + The image shows the quantitative analysis results of macrophages. Blue represents the cell nucleus, and green represents MSR1.

[0043] Figure 13B This is a graph showing the ELISA results of ceramide levels in bronchoalveolar lavage fluid (BALF).

[0044] Figure 13C The image shows the results of immunofluorescence staining and quantitative signal analysis of ALOX5AP in lung tissue sections. Blue represents cell nuclei, and red represents ALOX5AP.

[0045] Figure 13D The image shows the ELISA results of the content of the pro-inflammatory mediator RvD1 (RvD1) in BALF.

[0046] Figure 13E The figure shows the results of quantitative analysis of inflammatory factors IL-1β and TGF-β1 in BALF.

[0047] Figure 13F This image shows the immunofluorescence staining results of α-SMA, a marker of myofibroblast activation, in lung tissue. Blue represents the cell nucleus, and red represents α-SMA.

[0048] Figure 14 The figures show the efficacy of FDDN nanoparticles targeting MSR1 in alleviating T-DXd-induced pulmonary fibrosis in a mouse model. Figure A shows semi-quantitative analysis of α-SMA expression based on histopathology; Figure B shows lung imaging and histological examination results, including representative lung CT images, H&E staining, and Masson's trichrome staining; Figure C shows quantitative analysis of collagen deposition based on MT staining images. Figure 15A Flow cytometry results of human primary BALF macrophage model treated with FDDN nanoparticles.

[0049] Figure 15B Figure 1 shows the results of flow cytometry quantitative analysis of human primary BALF macrophage model treated with FDDN nanoparticles.

[0050] Figure 15C Figure 1 shows the ELISA results of a human primary BALF macrophage model treated with FDDN nanoparticles.

[0051] Figure 15D The image shows the release of CTSB in a human primary BALF macrophage model treated with FDDN nanoparticles; blue represents the cell nucleus and red represents CTSB.

[0052] Figure 15E Figure showing the IL-1β level in a human primary BALF macrophage model treated with FDDN nanoparticles.

[0053] Figure 15FFigure showing the RvD1 level in a human primary BALF macrophage model treated with FDDN nanoparticles.

[0054] Figure 16A This image shows the H&E staining results of the major organs of a mouse.

[0055] Figure 16B The graph shows the results of quantitative analysis of the content of the plasma cardiac creatine kinase isoenzyme MB (CK-MB).

[0056] Figure 16C The graph shows the results of quantitative analysis of aspartate aminotransferase (AST) content.

[0057] Figure 16D The graph shows the results of quantitative analysis of alanine aminotransferase (ALT) content.

[0058] Figure 17 The figure shows the results of quantitative analysis of IL-1β secretion in THP-1-derived macrophages under SYD985 or T-DM1 treatment, with or without FDDN intervention.

[0059] Figure 18 The figure shows the cytotoxicity assessment results of THP-1-derived macrophages under SYD985 or T-DM1 treatment with or without FDDN intervention. Detailed Implementation

[0060] The technical solution of the present invention will be further described below with reference to the accompanying drawings and specific embodiments. It should be noted that these embodiments are only used to demonstrate the feasibility and representative technical effects of the present invention, and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention is subject to the claims. Although only some representative compounds and model systems were used in the embodiments (such as T-DXd, SYD985, T-DM1 and other ADCs; fucoidan as an MSR1 inhibitor; Wortmannin as a phagocytic inhibitor; Desipramine as a ceramide inhibitor; docosapentaenoic acid as a pro-inflammatory remission compound, etc.), these embodiments have covered and verified the core technical idea of ​​the present invention: by regulating the scavenger receptor pathway, the ceramide synthesis circuit and the inflammation remission pathway, the upstream, key and mobile nodes of the ADC-induced inflammatory response can be controlled.

[0061] More importantly, the various active compounds involved in this invention (including other ADCs that can be recognized or bound by scavenger receptors as listed in the claims, other MSR1-related ligands, phagocytic regulators, ceramide metabolism regulators, unsaturated fatty acids and their derivatives) exhibit high correlation and functional convergence in terms of mechanism of action, target consistency, biological structure, and receptor activity profile. For example: ADCs and their analogues that have the same or similar scavenger receptor recognition domains can induce abnormal uptake and inflammatory responses through MSR1 or related SR family pathways. Lipid-mediated inflammatory amplification pathways (such as ceramide production, CTSB activation, and lysosomal stress) are common mechanisms by which ADCs induce inflammation-related toxicity, independent of specific antibody or payload types. The signal nodes targeted by various inhibitors (Wortmannin, Desipramine, CA-074, etc.) are broad-spectrum inflammatory amplification links, and those skilled in the art can reasonably infer from their mechanisms other structurally and functionally similar compounds listed in the claims.

[0062] Unsaturated fatty acid compounds (such as EPA / DPA / DHA) and their derivatives have consistent biological functions in intracellular lipid turnover, inflammation reduction, and membrane structure stabilization, suggesting that their regulation of ADC-related inflammation is predictable. Based on this, the core inventiveness of this invention lies in proposing a universal regulatory strategy centered around the scavenger receptor-lipid metabolism-lysosomal inflammation axis, applicable to multiple classes of ADC drugs and related structural analogs. The specific compounds verified in the embodiments of this invention are merely representative examples, while other molecules listed in the claims, due to their consistent structural characteristics, receptor binding profiles, biological metabolic pathways, or inflammatory regulatory mechanisms, have technical effects that are theoretically predictable for those skilled in the art and can be applied to the overall technical framework constructed by this invention.

[0063] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased from legitimate channels.

[0064] This invention focuses on inflammation-related adverse reactions induced by ADC drugs, deeply analyzing the mechanisms by which ADC drugs induce these adverse reactions and intervening around key pathological links. Specifically, it was found that ADC drugs can be recognized and taken up by scavenger receptors (such as MSR1) on the surface of macrophages, thereby triggering ceramide-dependent lysosomal instability, leading to the activation and release of cathepsin B. Simultaneously, ADC treatment is accompanied by a reduction in inflammatory mediators, causing immune imbalance and persistent inflammation, thus exacerbating inflammation-related adverse reactions, such as inducing lung injury and fibrosis.

[0065] Based on the above findings, this invention designs a triple strategy of "MSR1 receptor blocking, ceramide-lysosomal axis inhibition, and inflammatory regression pathway reconstruction," which can intervene in ADC-induced inflammation-related adverse reactions at the mechanistic level, thereby providing a new technical path for improving the safety and sustainable application of ADC therapy. Specifically, a series of drug screenings are conducted ( Figure 2 Based on overall experimental results and clinical translation prospects, fucoidan (Fuco), desipramine (Desi), and docosapentaenoic acid (DPA) were used as functional modules for subsequent nanomedicine design. To achieve precise in vivo immune regulation, inhalable lipid-based nanoparticles (Fucoidan-Desipramine-DPA Nanoparticles, hereinafter referred to as "FDDN") were constructed, with the structural schematic shown in Figure [Figure number missing]. Figure 1 As shown in the figure, the nanoparticles include a liposome carrier, an MSR1-specific blocking module, a ceramide-lysosome axis blocking module, and an inflammation resolution signal reconstruction module.

[0066] The MSR1-specific blocking module includes: modifying the surface of a liposome carrier with fucoidan or other scavenger receptor inhibitors to selectively bind to the macrophage scavenger receptor MSR1; by competitively occupying the MSR1 binding site, effectively reducing the abnormal recognition and uptake of ADCs (such as Trastuzumab antibody for HER2 targeting) by MSR1; thereby inhibiting the abnormal phagocytic response of inflammatory cells and reducing the risk of inflammation initiation.

[0067] The ceramide-lysosome axis blocking module includes: encapsulating desipramine or its structural analogues (such as imipramine, amitriptyline, clomipramine, nortriptyline, etc.) or other known ceramide synthesis inhibitors (such as miriocin, fumonisin B1) in a liposome carrier; by blocking ceramide-driven lysosomal instability, reducing cell stress-induced death and amplified inflammatory responses; thereby inhibiting the sustained activation of downstream inflammatory signaling pathways.

[0068] The inflammation resolution signal reconstruction module includes: loading polyunsaturated fatty acids (such as docosapentaenoic acid) or other pro-inflammatory resolution mediators / precursors into nanoparticles; promoting the generation of anti-inflammatory mediators by enhancing the arachidonic acid-5-lipoxygenase-activated protein (ALOX5AP)-dependent inflammation resolution pathway; helping to restore lung tissue homeostasis and promoting natural repair in the later stages of inflammation.

[0069] Specifically, taking HER2-targeted ADC drugs as an example, the schematic diagram of FDDN's working process is as follows: Figure 2 As shown, the FDDN nanoparticles modified with fucose (FC) can competitively interfere with the binding of trastuzumab to MSR1, thereby preventing abnormal macrophage uptake; even if some ADC enters the cell and activates the ceramide pathway, the desipramine loaded on the nanoparticles can block ADC-induced ceramide production; even if a small amount of ceramide is still induced, the DPA loaded on the nanoparticles can reactivate the ALOX5AP-dependent inflammation resolution signaling pathway, promote inflammation resolution, and thus delay or alleviate the occurrence and development of ADC-related interstitial lung injury (ILD).

[0070] The liposome carrier refers to an artificially prepared nanoscale spherical vesicle structure composed of phospholipids, cholesterol, and surfactants. In this invention, it can be constructed using lung-compatible components such as dipalmitoylphosphatidylcholine (DPPC), cholesterol (Cholesterol), and cationic lipid DOTAP, which not only ensures structural stability but also endows it with good mucus penetration ability and enables continuous and controllable local release into the lungs.

[0071] Specifically, in addition to using fucoidan as a surface modifier, other polysaccharides with sulfated or sulfonated structures, such as dextran sulfate, heparin, and its derivatives, can also exert similar blocking effects in the MSR1-specific blocking module. Furthermore, polyanionic ligands such as polyinosinic acid (PolyI), acetylated low-density lipoprotein (AcLDL), ferritin, as well as monoclonal antibodies or Fab fragments and small molecule competitive inhibitors targeting MSR1 can all be selected. Further, common phagocytosis / endocytosis inhibitors (such as Wortmannin, Cytochalasin D, Latrunculin A, LY294002, Chlorpromazine, Filipin, EIPA, Dynasore, or Pitstop 2), and gene editing or gene silencing technologies (siRNA / shRNA interference with MSR1 expression or CRISPR / Cas9 knockout of MSR1) can all serve as feasible alternatives to the MSR1 blocking module.

[0072] In this invention, fucoidan refers to a class of polysaccharides containing fucose and sulfate groups. It is understood that fucoidan from different sources, with different molecular weights, different degrees of sulfation, or reasonable variations in sugar chain structure, as well as structural analogs, derivatives, or pharmaceutically acceptable salt forms thereof that maintain their sulfated fucose backbone characteristics and scavenger receptor binding ability, can all serve as compounds that bind to or inhibit scavenger receptors and are applicable to the technical solutions of this invention. For example, it can be purchased from MedChemExpress, USA, catalog number HY-132179.

[0073] In addition to desipramine, other tricyclic compounds of the same class, such as imipramine, amitriptyline, clomipramine, and nortriptyline, can also be used in the ceramide-lysosome axis blocking module. Other ceramide synthesis inhibitors (such as mitomycin and fumonisin B1) can be further substituted. On the other hand, lysosomal stabilizers or protease inhibitors (such as CA-074Me, E-64, leupeptin, and bafilomycin A1) and antioxidants (such as NAC and GSH) can also achieve similar protective effects. Gene-level intervention is also feasible; for example, siRNA / shRNA or CRISPR / Cas9 can target and regulate related synthesis and activation genes, thereby blocking this inflammatory signaling axis.

[0074] In the inflammation resolution signal reconstruction module, in addition to DPA (docosapentaenoic acid), other lipid mediators that promote decomposition (such as RvE, Maresins, Protectins, etc.) or their biological precursors can be used as substitutes. The expression of ALOX5AP, ALOX5, and related synthases can also be enhanced through mRNA delivery to promote the generation of anti-inflammatory mediators and drive the reconstruction of post-inflammatory homeostasis.

[0075] In the preparation of the liposome carrier, performance can be optimized by adjusting the ratio of phospholipids and cationic lipids compatible with lung surfactants, such as the classic formulation of DPPC:POPG:Cholesterol = 7:2:1, or combinations such as DPPC:DPPG:Cholesterol or DPPC:DSPC:POPG:Cholesterol. The preparation methods for nanomedicines are not limited to solvent miscibility methods; they can also be achieved using thin-film hydration, solvent injection, double emulsion, microfluidics, precipitation, high-pressure homogenization, spray drying, or freeze-drying.

[0076] This invention also allows for the control of nanoparticle size, morphology, surface charge, or structural modification to achieve better lung distribution and anti-inflammatory effects. Furthermore, the ratio of the active pharmaceutical ingredient to the lipid component can be flexibly adjusted; for example, reducing the dosage of the active drug and increasing the proportion of phospholipid components can improve safety while ensuring efficacy.

[0077] In addition to liposome carriers, the active ingredients of this invention can also be delivered by other biocompatible nanocarriers, such as polymer nanomicelles, dendritic macromolecules, solid lipid nanoparticles, lipid-polymer hybrid nanoparticles, etc.

[0078] This invention's technical solution is not only applicable to inflammation-related adverse reactions caused by HER2-targeted ADCs (such as T-DXd), but can also be extended to adverse reactions induced by other non-HER2-targeted ADC drugs that can be recognized or bound by scavenger receptors. Furthermore, it can be validated in non-rodent animal models (such as monkeys, ferrets, and pigs). Further, it has theoretical feasibility in other diseases with inflammation as the main pathological feature, such as myocarditis, enteritis, and other multi-organ inflammatory damage, as well as chronic inflammatory diseases such as liver fibrosis and kidney fibrosis; however, in specific applications, the dosage form may need to be adjusted accordingly.

[0079] Methods for preparing nanoparticles include: 1) Aqueous phase preparation: Dissolve the compound that binds to the scavenger receptor in deionized water or phosphate buffer, add an emulsifier (such as about 20 mg of HS-15, or other surfactants depending on the system), and disperse by ultrasonication to obtain a uniform and transparent aqueous solution; 2) Oil phase preparation: Ceramide synthesis inhibitors and pro-inflammatory depressant compounds are dissolved together with cholesterol, lung surfactant-compatible phospholipids (such as DPPC, DSPC, etc., the types can be expanded) and lung-targeting cationic lipids (such as DOTAP, DOTMA, etc., the types can be expanded) in an organic solvent (such as about 2.5 mL of ethanol, chloroform or dichloromethane), and stirred until completely clear; 3) Emulsion formation: The oil phase is slowly added to the aqueous phase and magnetically stirred for about 1 hour to form an emulsion. The emulsion is then further processed by ultrasonic testing with a probe to obtain a homogeneous and stable emulsion system. 4) Removal of organic solvents: Organic solvents are gradually removed by rotary evaporation under reduced pressure or natural evaporation to obtain a nano-solution with good hydrophilicity; 5) Particle optimization and control: The solution was further self-assembled by ultrasonication in a water bath. By adjusting the ultrasonication time (e.g., about 5 minutes) and energy (about 8W), stable nanoparticles with a particle size of about 145.94 ± 2.86 nm, a PDI of 0.18 ± 0.03, a potential of -33.37 ± 0.14 mV, and an encapsulation efficiency of about 58.68 ± 2.03% could be obtained.

[0080] The encapsulation efficiency mainly refers to the encapsulation efficiency of DPA in the nanosystem, and its main detection process involves the following steps: Sampling: Take 100~200 µL of the nano-dispersion into a brown centrifuge tube; Membrane disruption / total lipid extraction: Add 3 mL of chloroform:methanol = 2:1 (v / v, +0.01% BHT), vortex vigorously for 1 min; then sonicate in a water bath for 2-3 min. Phase separation: Add 0.2 mL of 1 M HCl + 0.8 mL of water (to acidify the system to pH≈2, dissociating DPA). - ↔DOTAP + After gently shaking, centrifuge at 3000 g for 5 min. Collect the organic phase (lower layer), then re-extract it once with 1 mL of chloroform and combine the two phases. Dry it under nitrogen (≤40℃, protected from light). Dissolve the injection solution: Add 1.0 mL of acetonitrile:methanol = 9:1 (+0.1% acetic acid) to dissolve, filter at 0.22 µm, and detect by HPLC-UV (254 nm); Quantitative analysis: Quantitative analysis was performed using the external standard / internal standard method with peak area ratio (Analyte / IS) - concentration.

[0081] Example 1 This embodiment tests the intervention effects of different inhibitors on T-DXd-induced inflammation.

[0082] To partially simulate the lung microenvironment, THP-1 macrophages, BEAS-2B cells, and HELF cells differentiated from phorbol PMA (10 ng / mL, 12 h) were mixed at a ratio of 1:8:1 and seeded in ultra-low adsorption 96-well round-bottom culture plates, and three-dimensional lung organoids were formed using the hanging drop method. After 3 days of culture, the cells were treated with T-DXd (100 nM) for 24 h, with or without different inhibitors: fucoidan (HY-132179, Fuco, for blocking MSR1, 1 μg / mL), phagocytic inhibitor Wortmannin (WM, 0.1 μM), ceramide synthesis inhibitor desipramine (Desi, 2 μM), CTSB inhibitor CA-074 (10 μM), and the unsaturated fatty acid docosapentaenoic acid (DPA) (5 μg / mL). A control group (Ctrl) was cultured in medium without any inhibitors. Confocal microscopy was used to observe the activation of Caspase-1 in spheroids. The supernatant from spheroid culture was collected, and the content of interleukin-1β (IL-1β) was detected using ELISA; its concentration was calculated using a corresponding standard curve.

[0083] The results are as follows Figure 3 and Figure 4 As shown, Figure 3 The image shows the results of confocal microscopy observation of Caspase-1 activation in three-dimensional lung organoids. Blue represents the cell nucleus and green represents Caspase-1. The results show that the above inhibitors can all intervene in T-DXd-induced Caspase-1 activation, such as by reducing the green fluorescence signal. Figure 4 The graph shows the IL-1β content results, indicating that different interventions all alleviated T-DXd-induced IL-1β release. Based on the overall experimental results, Fuco, Desi, and DPA can be selected as functional modules for subsequent nanomedicine design.

[0084] Example 2 This embodiment prepares lipid-based nanoparticles.

[0085] Fucoidan-Desi-DPA nanoparticles (FDDN) were prepared using a modified single-emulsion solvent evaporation method. The specific preparation process is as follows: The aqueous phase was prepared by dissolving approximately 30 mg of polyethylene glycol 15-hydroxystearate (Solutol HS-15) and approximately 20 mg of fucoidan in 8 mL of deionized water; the organic phase was prepared by co-dissolving desipramine (approximately 5 mg), DPA (approximately 20 mg), DPPC (approximately 20 mg), cholesterol (approximately 10 mg), (2,3-dioleoyl-propyl)-trimethylammonium chloride (DOTAP, approximately 15 mg), and distearate-phosphatidylethanolamine-polyethylene glycol (DSPE-PEG, approximately 5 mg) in 2 mL of anhydrous ethanol. The organic phase was slowly added to the aqueous phase under magnetic stirring, followed by short-term probe sonication, and nanoparticles were obtained by rotary evaporation. The morphology of nanoparticles (1 mg / mL) was observed using cryo-electron microscopy (Cryo-EM, FEI Talos). The hydrated particle size, polydispersity index (PDI), and zeta potential of nanoparticles (0.05 mg / mL) were determined using dynamic light scattering (DLS) at 25 °C. The nanoparticles were stored at 4 °C for 3 months, and their particle size and PDI were periodically measured to assess stability.

[0086] Experimental results show that FDDN nanoparticle formulations are all in a uniformly dispersed state. Figure 5 The particle size is approximately 145 nm (145.94±2.86), the PDI is less than 0.2 (0.18±0.03), and the zeta potential is consistently negative, approximately -35 mV (-33.37±0.14). Notably, FDDN can be stored for at least 90 days under suitable conditions. Figure 6).

[0087] Example 3 This embodiment tests the bonding strength of the prepared FDDN.

[0088] The binding affinity between T-DXd and MSR1 was quantitatively analyzed using ELISA. Recombinant MSR1 protein was coated into the wells of ELISA plates, blocked, and then different concentrations of T-DXd or mixtures of T-DXd with FDDN nanoparticles or fucose were added. The plates were incubated at room temperature for 2 h. A T-DXd-only treatment served as the control group. Subsequently, HRP-labeled secondary antibody and TMB chromogenic substrate were added, and absorbance was measured at 450 nm. EC50 was calculated using a four-parameter logistic regression model. 50 value.

[0089] Results obtained by competitive ELISA assay are as follows: Figure 7 As shown, FDDN (red, EC) 50 Approximately 1500 nM) and Fuco (blue, EC) 50 The 1200 nM (approximately 1200 nM) significantly inhibited the binding ability of T-DXd to MSR1, while the control group (gray, EC) 50 The binding level (approximately 100 nM) was unaffected. These results indicate that FDDN can effectively and competitively bind to MSR1.

[0090] Example 4 This embodiment tests the targeting ability and anti-inflammatory effect of FDDN.

[0091] The lung-targeting ability of FDDN was evaluated via intratracheal administration. Dil-labeled FDDN (7.5 mg / kg) was administered to C57BL / 6 mice via endotracheal injection using a microneedler. Four hours after administration, in vivo fluorescence imaging was performed using the IVIS Spectrum imaging system. Subsequently, lung, liver, kidney, spleen, and heart were harvested for ex vivo imaging, and the fluorescence intensity of lung tissue was quantitatively analyzed. To assess the co-localization of nanoparticles with lung macrophages, immunofluorescence staining was performed on lung tissue. The distribution characteristics of Dil-labeled FDDN in lung tissue were observed using confocal microscopy with anti-MSR1 and anti-T-DXd antibodies.

[0092] Results of whole-body in vivo fluorescence imaging and ex vivo fluorescence imaging of major organs in mice are as follows: Figure 8 As shown, FDDN is preferentially enriched in the lungs.

[0093] Mouse lung tissue was collected, sections were prepared and stained, and the immunofluorescence imaging results of the lung tissue sections are as follows: Figure 9 As shown, FDDN (green) and MSR1 +Macrophages (red) showed significant colocalization, confirming their ability to achieve targeted delivery to specific macrophage subsets.

[0094] In addition, single-drug and dual-drug nanoparticles were prepared according to the preparation method in Example 2, differing only in drug composition. These included FDSN (nanoparticles encapsulating Fuco and Desipramine), FDPN (nanoparticles encapsulating Fuco and DPA), DSDPN (nanoparticles encapsulating Desipramine and DPA), FN (nanoparticles encapsulating Fuco), DSN (nanoparticles encapsulating Desipramine), or DPN (nanoparticles encapsulating DPA). FDDN, FDSN, FDPN, DSDPN, FN, DSN, or DPN (all 1 μg / mL) were incubated with three-dimensional lung organoids for 6 hours, followed by stimulation with T-DXd (100 nM). A control group (Ctrl) was used, treated only with the culture medium. The IL-1β level in the culture supernatant was detected by ELISA to assess the anti-inflammatory capabilities of different nanoparticles. Compared with single-function or dual-function nanoparticles, FDDN integrating a triple-function module showed a more significant anti-inflammatory effect in a three-dimensional lung organoid model, specifically manifested in a significant reduction in IL-1β levels in the supernatant. Figure 10 ).

[0095] THP-1 cells were pre-incubated with FDDN (1 μg / mL) for 6 h, followed by stimulation with T-DXd (100 nM). A control group (Ctrl) was used, treated only with culture medium. CTSB activity and subcellular distribution were detected using Magic Red® dye (which is specifically cleaved by cathepsin B (CTSB) and produces red fluorescence). Results are as follows: Figure 11 As shown, T-DXd-treated macrophages exhibited CTSB release into the cytoplasm, manifesting as diffuse fluorescence; however, after the combined addition of FDDN, this diffuse fluorescence was significantly weakened, with the fluorescence mainly showing a punctate distribution, suggesting that the integrity of the lysosomal membrane was restored. Figure 11 (Figure A). Simultaneously, the activation level of caspase-1 was assessed using the FAM FLICA caspase-1 detection kit (which specifically labels active caspase-1 in live cells with the fluorescent inhibitor probe FAM-YVAD-FMK). In T-DXd-treated macrophages, the fluorescence signal of activated caspase-1 (green) was significantly enhanced, indicating the activation of inflammasomes; after combined FDDN treatment, the activation level of this inflammasome was significantly reduced (…). Figure 11(Figure A). ELISA was used to detect the secretion level of IL-1β in cell supernatant, and the results further verified the inhibitory effect of FDDN on T-DXd-induced inflammatory response. Figure 11 (Figure B in the middle)

[0096] Example 5 This embodiment tests the effect of FDDN in relieving inflammation and fibrosis caused by T-DXd.

[0097] After pre-incubating FDDN (1 μg / mL) with three-dimensional lung organoids for 6 h, the cells were stimulated with T-DXd (100 nM). CTSB activity and subcellular distribution were detected using Magic Red® dye. Simultaneously, caspase-1 activation levels were assessed using the FAM FLICA caspase-1 assay kit. Results are as follows: Figure 12 As shown, FDDN can significantly attenuate the activation of inflammasomes induced by T-DXd ( Figure 12 (Figure A). Further analysis using ELISA revealed that FDDN effectively inhibited T-DXd-induced inflammation. Figure 12 (Figure B) and the pro-fibrotic signaling pathway ( Figure 12 (Figure C in the middle)

[0098] Male C57BL / 6 human HER2 transgenic mice (B-hHER2, strain number 110812, BioMice) aged 6-8 weeks were selected. To simulate the clinical T-DXd administration regimen, mice were injected with T-DXd (10 mg / kg) via the tail vein on days 1 and 22, and observed for 6 weeks. Control mice were injected with an equal volume of sterile saline. Treatment mice were administered FDDN (7.5 mg / kg / mouse) via a microneedle via the trachea on days 1-5 and 22-26, while the positive control group received pirfenidone (PFD) using the same administration regimen. To dynamically assess lung structure and fibrotic remodeling in mice, small animal micro-CT scans were performed at baseline (before administration) and at the experimental endpoint. Before scanning, mice were anesthetized with 1.5-2% isoflurane, and imaging was performed using a Quantum FX micro-CT system (PerkinElmer). Imaging data were analyzed in a blinded manner by two independent researchers to assess radiographic changes such as pulmonary fibrosis, consolidation, and structural disorder. Based on advances in imaging, mice were sacrificed on day 43. After sacrifice, the lungs were lavaged three times via endotracheal intubation (1 mL sterile PBS each time), and bronchoalveolar lavage fluid (BALF) was collected. The supernatant of the first lavage fluid was collected after centrifugation at 1000 rpm, 4°C for 10 min, aliquoted, and stored at -80°C for subsequent analysis. The levels of IL-1β, TGF-β1, and lipid mediators ceramide and RvD1 in BALF were detected by ELISA. Lung tissue was fixed in 4% paraformaldehyde, embedded in paraffin, and sectioned for H&E staining and Masson's trichrome staining to assess the inflammatory response and degree of fibrosis. Fibrosis burden was quantified by calculating the percentage of collagen-positive area. Furthermore, multiplex immunofluorescence staining was used to detect the expression levels of MSR1, CCL8, ALOX5AP, and α-SMA to assess the activation status of inflammatory macrophages, the integrity of inflammatory resolution pathways, and the transdifferentiation of fibroblasts into myofibroblasts.

[0099] Experimental results show that T-DXd treatment of MSR1 in the lungs + The number of macrophages increased by approximately 3.2-fold, and FDDN could restore them to control levels (P < 0.0001). Figure 13A Meanwhile, ceramide, which is associated with lysosomal damage and inflammasome activation, was increased by approximately 2.8-fold in T-DXd-treated lungs, while FDDN was significantly reduced (P = 0.0154). Figure 13B Furthermore, T-DXd treatment significantly suppressed ALOX5AP expression by approximately 90% ( ). Figure 13C And reduce RvD1 levels by approximately 80% ( Figure 13DT-DXd treatment in mice resulted in a pro-fibrotic and pro-inflammatory cytokine environment in BALF, with TGF-β1 and IL-1β showing only partial improvement. Figure 13E The levels of IL-1β were significantly elevated. FDDN effectively restored both to control levels, while PFD selectively inhibited only TGF-β1 and had limited effect on IL-1β, suggesting that the immunomodulatory effect of PFD is incomplete. α-SMA immunofluorescence staining showed ( Figure 13F T-DXd treatment extensively activates myofibroblasts in the lungs; FDDN can reduce α-SMA + Fibroblast area recovered to near baseline levels, myofibroblast activation was almost completely inhibited, while PFD decreased by only about 30%. Figure 14 (Figure A in the middle) Figure 14 Image B shows the results of lung imaging and histological examination: representative lung CT images, H&E staining, and Masson trichrome staining (MT). Figure 14 Figure C shows the quantitative analysis of collagen deposition based on MT staining images, demonstrating the mitigating effect of FDDN on T-DXd-induced fibrosis.

[0100] To evaluate the immunomodulatory effects of FDDN under clinically relevant conditions, primary human alveolar macrophages (AMs) isolated from bronchoalveolar lavage fluid (BALF) of male donors at Peking University First Hospital were selected. The relevant ethical approvals were obtained from the Biomedical Research Ethics Committee of Peking University First Hospital (Approval No.: 2022-603-002). The collected cells were cultured at 5 × 10⁻⁶ cells / day. 5 Cells were seeded per well in 6-well plates and cultured overnight at 37°C and 5% CO2. Cells were then treated with T-DXd (100 nM) alone or in combination with FDDN (1 μg / mL). Control groups included a blank control group and a T-DXd+PFD (1 μg / mL) treatment group. After treatment, cells were collected for flow cytometry and immunofluorescence analysis. Culture supernatant was also collected to detect ceramide, IL-1β, and RvD1 levels. For flow cytometry, cells were incubated on ice in PBS buffer containing 2% FBS with fluorescently labeled anti-human CD11b and MSR1 antibodies for 30 min. CTSB release was observed using a BD LSRFortessa flow cytometer and an immunofluorescence and high-content imaging system.

[0101] The flow cytometry results are shown in Figure 16. Under different treatment conditions, the subsets of BALF primary cells that simultaneously express MSR1 and CD11b changed significantly. Figure 15A Quantitative analysis showed that FDDN can effectively reduce MSR1. + CD11b +The proportion of macrophages in total BALF cells ( Figure 15B This suggests that it has an interventional role in inflammatory phenotype reprogramming. ELISA analysis showed that T-DXd induced a significant accumulation of ceramides in BALF macrophages (…). Figure 15C FDDN treatment significantly inhibited this process, indicating that it can block the MSR1-related lipid signaling pathway. FDDN also inhibited T-DXd-induced CTSB release ( Figure 15D In human primary alveolar macrophage culture supernatant, FDDN effectively reduced IL-1β secretion levels. Figure 15E This indicates that it can inhibit the inflammatory cascade response. FDDN treatment also restored the level of the pro-inflammatory mediator RvD1 (…). Figure 15F This indicates that it not only inhibits pro-inflammatory signals but also enhances endogenous inflammation resolution and tissue repair pathways, thereby achieving bidirectional regulation in the human BALF macrophage system.

[0102] Example 6 This embodiment tests the security of FDDN.

[0103] To assess the safety of FDDN, the general condition, weight, and food intake of mice were continuously monitored throughout the aforementioned animal experimental period. Serum was collected on day 43 to detect biochemical indicators such as plasma cardiac creatine kinase isoenzyme (CK-MB), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Simultaneously, lung, liver, kidney, spleen, and heart tissues were collected for HE staining to evaluate the histological safety of major organs. The untreated group served as the control group. HE staining showed that FDDN was well tolerated, with no significant damage to major organs in mice, and it was able to alleviate T-DXd-induced liver injury. Figure 16A In addition, CK-MB ( Figure 16B ), AST ( Figure 16C ) and ALT Figure 16D No increase was observed in AST and ALT levels, further validating the safety of FDDN. Furthermore, FDDN was found to alleviate T-DXd-related liver function impairment, as evidenced by significantly lower AST and ALT levels in the FDDN combination therapy group compared to the T-DXd monotherapy control group.

[0104] Example 7 This embodiment tests the effect of FDDN on other Trastuzumab-related ADCs.

[0105] Further analysis was conducted on ILD-related ADCs, including Trastuzumab duocarmazine (SYD985, approved for metastatic breast cancer) and Trastuzumab emtansine (T-DM1, a DM1-linked cytotoxic drug). The specific procedure was as follows: THP-1 cells were pre-incubated with FDDN (1 μg / mL) for 6 h, followed by stimulation with SYD985 and T-DM1 (100 nM). The culture medium-only treatment group served as the control (Ctrl) and blank group. The secretion level of IL-1β in the culture supernatant was further detected by ELISA, and cytotoxicity was assessed using the Cell Counting Kit-8 (CCK-8) reagent.

[0106] Experimental results are as follows Figure 17 and Figure 18 As shown, in macrophages, treatment with either SYD985 or T-DM1 alone (100 nM) induced significant IL-1β secretion and cytotoxicity, suggesting innate immune activation. Notably, FDDN pretreatment (1 μg / mL, 6 h) significantly attenuated this inflammatory response and cytotoxicity, further confirming the broad-spectrum properties of FDDN.

[0107] In summary, this invention provides an in-depth analysis of the process by which ADC drugs induce inflammation-related adverse reactions, identifies the induction mechanism, and designs a triple mechanism targeting the inducing mechanism: "blockade of MSR1 and other receptors, inhibition of the Ceramide lysosomal axis, and reconstruction of the inflammation resolution pathway." It also identifies compounds that can be used for intervention and further designs interventional formulations that can intervene in ADC-induced inflammation-related adverse reactions at the mechanistic level, balancing safety and efficacy. This approach has universality and clinical translational value, providing a new solution for improving treatment adherence and patient survival benefits of ADC drugs.

[0108] The applicant declares that the above description is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention fall within the protection and disclosure scope of the present invention.

Claims

1. The use of the compound in the preparation of formulations that reduce inflammation-related adverse reactions induced by ADC drugs, characterized in that, The compounds include at least one of compounds that bind to or inhibit scavenger receptors, ceramide synthesis inhibitors, or pro-inflammatory compounds.

2. The application according to claim 1, characterized in that, The scavenger receptors include MSR1; Optionally, the compound that binds to or inhibits scavenger receptors includes at least one of polysaccharides having a sulfated or sulfonated structure, polyanionic ligands, or phagocytosis / endocytosis inhibitors. Optionally, the polysaccharide having a sulfated or sulfonated structure includes at least one of fucoidan, sulfated dextran, or heparin; Optionally, the polyanionic ligand includes at least one of polyinosinic acid, acetylated low-density lipoprotein, or ferritin; Optionally, the phagocytosis / endocytosis inhibitor includes at least one of Wortmannin, Cytochalasin D, Latrunculin A, LY294002, Chlorpromazine, Filipin, EIPA, Dynasore, or Pitstop 2.

3. The application according to claim 1 or 2, characterized in that, The ceramide synthesis inhibitors include at least one of desipramine, imipramine, amitriptyline, clomipramine, nortriptyline, mitomycin, or furan toxin.

4. The application according to claim 1 or 2, characterized in that, The pro-inflammatory compound includes at least one of polyunsaturated fatty acids and / or lipid mediators; Optionally, the polyunsaturated fatty acid includes docosapentaenoic acid (DVA).

5. A formulation for reducing inflammation-related adverse reactions induced by ADC drugs, characterized in that, The formulation comprises at least one of the compounds that bind to or inhibit scavenger receptors as described in any one of claims 1-4, ceramide synthesis inhibitors, or pro-inflammatory depressants.

6. The formulation for reducing inflammation-related adverse reactions induced by ADC drugs according to claim 5, characterized in that, The formulation further includes a pharmaceutically acceptable carrier on which the compound that binds or inhibits scavenger receptors, the ceramide synthesis inhibitor, and the pro-inflammatory depressant compound are loaded.

7. The formulation for reducing inflammation-related adverse reactions induced by ADC drugs according to claim 6, characterized in that, The carrier includes a nanocarrier; Optionally, the nanocarrier includes a liposome carrier; Optionally, the liposome carrier includes phospholipids, cholesterol, and cationic lipids.

8. The formulation for reducing inflammation-related adverse reactions induced by ADC drugs according to claim 7, characterized in that, The compound that binds to or inhibits scavenger receptors is modified on the surface of the liposome carrier, and the ceramide synthesis inhibitor and the pro-inflammatory depressant compound are encapsulated in the liposome carrier.

9. The formulation for reducing inflammation-related adverse reactions induced by ADC drugs according to claim 7, characterized in that, The preparation method of the formulation includes the following steps: (1) Dissolve the compound that binds to or inhibits scavenger receptors in deionized water or phosphate buffer and add an emulsifier to obtain an aqueous solution; (2) Ceramide synthesis inhibitors, anti-inflammatory compounds, phospholipids, cholesterol, and cationic lipids were mixed to obtain an oil phase solution; (3) Add the oil phase solution to the aqueous phase solution to obtain an emulsion system; (4) Remove the organic solvent from the emulsion system to obtain a nano solution; (5) The nano solution is subjected to ultrasonic treatment to obtain nanoparticles.

10. The formulation for reducing inflammation-related adverse reactions induced by ADC drugs according to any one of claims 7-9, characterized in that, The ADC drug includes ADC drugs that can be recognized or bound by scavenger receptors; Optionally, ADC drugs that can be recognized or bound by scavenger receptors include ADC drugs containing Trastuzumab antibodies.

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