Bone-targeted nano-particles as well as preparation method and application thereof
By preparing bone-targeted nanoparticles, curcumin, icariin and alendronate sodium were integrated into a single nanocarrier, and the problems of low bioavailability and systemic side effects of existing drugs were solved, and comprehensive treatment and targeted delivery of osteoporosis were achieved.
Patent Information
- Application Number
- CN202510835382.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-20
- Publication Date
- 2025-08-15
AI Technical Summary
The existing osteoporosis treatment drugs have low bioavailability and systemic distribution leads to side effects, making it difficult to fully regulate the complex pathological process of osteoporosis.
Bone-targeted nanoparticles were prepared, curcumin, icariin and alendronate were integrated into a single nanocarrier, and the synergistic effect of multiple pharmacological effects was achieved through the bone targeting of alendronate and the core-shell structure design of the nanoparticles.
It increases the concentration of drugs in bone lesions, reduces systemic side effects, realizes comprehensive treatment of osteoporosis, enhances the therapeutic effect and improves the bioavailability of drugs.
Smart Images
Figure CN120478289A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of biomaterials, and in particular to bone-targeted nanoparticles and a preparation method and application thereof. Background Art
[0002] Osteoporosis is a systemic skeletal disease characterized by decreased bone mass and deterioration of bone microarchitecture. This pathological condition significantly increases bone brittleness and predisposes to fractures. This not only severely impairs patients' quality of life but also imposes a heavy economic burden on society. With the accelerating aging of the global population, the prevalence of osteoporosis continues to rise, making it a major public health issue that demands urgent resolution. Currently, clinically used drugs for the treatment of osteoporosis primarily include bisphosphonates (such as alendronate), selective estrogen receptor modulators (SERMs), parathyroid hormone analogs, and RANKL (Receptor Activator of Nuclear Factor-κB Ligand) inhibitors. Bisphosphonates are widely used clinically due to their significant efficacy in inhibiting osteoclast activity and reducing bone resorption. However, traditional bisphosphonates, such as alendronate, have significant limitations: oral bioavailability is extremely low, typically less than 1%, and they are prone to adverse reactions such as gastrointestinal irritation. Intravenous administration leads to systemic distribution of the drug, which can adversely affect non-target tissues, such as complications such as osteonecrosis of the jaw. Furthermore, most existing drugs target only a single pathological component of osteoporosis, such as simply inhibiting bone resorption, failing to fully address the complex pathophysiology of osteoporosis, which includes insufficient bone formation, excessive bone resorption, and the accompanying inflammatory response. Summary of the Invention
[0003] The purpose of the present invention is to provide a bone-targeted nanoparticle and its preparation method and application, which can integrate multiple active ingredients with different mechanisms of action into a single nanocarrier to achieve synergistic enhancement and targeted delivery.
[0004] In order to achieve the above object, the technical solution adopted by the present invention is as follows: In a first aspect, the present invention discloses a method for preparing bone-targeted nanoparticles, comprising: preparing curcumin organic solution, icariin organic solution, alendronate sodium solution and DSPE-PEG-NHS solution; Under stirring conditions, the icariin organic solution is added dropwise to the curcumin organic solution, and after the addition is completed, the stirring reaction is continued to self-assemble to form a curcumin-icariin intermediate; dispersing the curcumin-icariin intermediate in deionized water to obtain a dispersion; The sodium alendronate solution and the DSPE-PEG-NHS solution were added to the dispersion, stirred for a preset reaction time, and then dialyzed to obtain bone-targeted nanoparticles.
[0005] Furthermore, the preparation of the curcumin-icariin intermediate specifically includes: Under stirring conditions, the icariin organic solution is added dropwise to the curcumin organic solution; After the dropwise addition is completed, the reaction is stirred at room temperature for 12 to 72 hours to obtain an intermediate solution; The intermediate solution is added dropwise to deionized water, and after the addition is completed, the mixture is stirred and reacted at room temperature for 24 to 72 hours to obtain a suspension comprising a curcumin-icariin complex; The suspension is centrifuged, the supernatant is discarded, and the precipitate is collected to obtain a curcumin-icariin intermediate.
[0006] Furthermore, the method further comprises: after collecting the precipitate, freeze-drying the collected precipitate to remove water, thereby obtaining a solid product of the curcumin-icariin intermediate.
[0007] Furthermore, the preparation of curcumin organic solution and icariin organic solution specifically includes: dissolving curcumin in an organic solvent to obtain a curcumin organic solution; dissolving icariin in an organic solvent to obtain an icariin organic solution; The organic solvent is at least one of dimethyl sulfoxide, dimethyl sulfoxide, ethanol, methanol, acetone, dimethylformamide, tetrahydrofuran, dioxane, acetonitrile and N-methylpyrrolidone; The molar ratio of the icariin to the curcumin is 1-3:1.
[0008] Furthermore, the preparation of the alendronate sodium solution and the DSPE-PEG-NHS solution specifically includes: dissolving alendronate sodium in deionized water to obtain an alendronate sodium solution; Dissolve DSPE-PEG-NHS in deionized water to obtain a DSPE-PEG-NHS solution; The weight ratio of the alendronate sodium, DSPE-PEG-NHS and curcumin-icariin intermediate is 1.3-4.2:4:1-3.
[0009] In a second aspect, the present invention discloses a bone-targeted nanoparticle, which is prepared using the above-mentioned method for preparing bone-targeted nanoparticles, and includes a core and a shell coated on the core; the core is a hydrophobic complex formed by self-assembly of a curcumin-icariin intermediate and the hydrophobic chain of DSPE in DSPE-PEG-NHS through hydrophobic interaction; the shell is a hydrophilic polymer formed by outward extension of the PEG chain in DSPE-PEG-NHS, and sodium alendronate is loaded on the hydrophilic polymer.
[0010] Furthermore, the alendronate sodium is exposed on the surface or near-surface region of the bone-targeting nanoparticles in a non-covalently bound or partially embedded manner.
[0011] In a third aspect, the present invention discloses a use of bone-targeted nanoparticles prepared by the above-mentioned method for preparing bone-targeted nanoparticles in the preparation of drugs for treating or improving osteoporosis.
[0012] The present invention has the following unexpected beneficial effects: 1. The nanoparticles produced by the present invention are simultaneously loaded with curcumin, icariin, and alendronate. Alendronate can specifically deliver the nanoparticles to bone lesions. Curcumin and icariin, through their multiple mechanisms of anti-inflammatory and antioxidant effects, promote osteogenesis, and inhibit osteoclastogenesis, synergistically enhance the effects with alendronate, more comprehensively regulating bone metabolism and achieving comprehensive treatment for osteoporosis.
[0013] 2. The present invention uses sodium alendronate as the alendronate. Due to the sodium alendronate loaded on the surface or near-surface region of the bone-targeted nanoparticles, the bone-targeted nanoparticles have a specific affinity for bone hydroxyapatite. This ensures that the bone-targeted nanoparticles can be efficiently enriched in bone tissue after circulation in the body, particularly at osteoporosis lesions, helping to increase the drug concentration at the target site. Furthermore, sodium alendronate, a classic anti-osteoporosis drug, can inhibit osteoclast activity and reduce bone loss. By incorporating sodium alendronate into the nanoparticles, its targeting ability is utilized while also exerting its pharmacological effects.
[0014] 3. The bone-targeted nanoparticles described herein exhibit a core-shell structure. The curcumin-icariin intermediate and the hydrophobic chains of DSPE in DSPE-PEG-NHS self-assemble through hydrophobic interactions to form a hydrophobic complex that acts as a core encapsulated within the shell. This effectively addresses the poor water solubility and low bioavailability of curcumin and icariin, improving their in vivo stability and bioavailability. Furthermore, the introduction of DSPE-PEG-NHS, particularly the PEG chains, effectively prolongs the nanoparticles' circulation time in the blood, reducing clearance by the reticuloendothelial system (RES), further promoting targeted delivery.
[0015] 4. The bone-targeted nanoparticles prepared by the present invention have uniform particle size, good dispersibility, good stability and biocompatibility under physiological conditions, and reduce the toxic and side effects of drugs. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] In order to more clearly illustrate the specific implementation of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the implementation or prior art description. Obviously, the drawings described below are only some embodiments of the present invention.
[0017] Figure 1 The figure shows a flow chart of the method for preparing bone-targeted nanoparticles according to an embodiment of the present invention.
[0018] Figure 2 TEM images of the bone-targeting nanoparticles according to the embodiments of the present invention are shown. DETAILED DESCRIPTION
[0019] The following describes the embodiments of the present invention with reference to the accompanying drawings and preferred embodiments. Those skilled in the art will readily appreciate the other advantages and benefits of the present invention from the disclosure herein. The present invention may also be implemented or applied through various other specific embodiments, and the various details in this specification may be modified or altered based on different viewpoints and applications without departing from the spirit of the present invention. It should be understood that the preferred embodiments are intended only to illustrate the present invention and are not intended to limit the scope of protection of the present invention.
[0020] In one embodiment, the present invention discloses a method for preparing bone-targeted nanoparticles, comprising the following steps: S1, prepare curcumin organic solution, icariin organic solution, alendronate sodium solution and DSPE-PEG-NHS solution.
[0021] S2, under stirring conditions, adding the icariin organic solution dropwise to the curcumin organic solution, and continuing to stir the reaction after the addition is completed to self-assemble to form a curcumin-icariin intermediate.
[0022] S3, dispersing the curcumin-icariin intermediate in deionized water to obtain a dispersion.
[0023] S4, adding the sodium alendronate solution and the DSPE-PEG-NHS solution to the dispersion, stirring and reacting for a preset time, and then performing dialysis treatment to obtain bone-targeted nanoparticles.
[0024] The nanoparticles prepared by the present invention are simultaneously loaded with curcumin, icariin and sodium alendronate. The sodium alendronate can specifically deliver the nanoparticles to the site of bone lesions. Curcumin and icariin produce synergistic effects with sodium alendronate through their multiple mechanisms of anti-inflammation, anti-oxidation, promotion of osteogenesis and inhibition of osteoclastosis, thereby more comprehensively regulating the balance of bone metabolism and achieving comprehensive treatment of osteoporosis.
[0025] Curcumin, one of the core active ingredients in bone-targeted nanoparticles, possesses significant anti-inflammatory and antioxidant properties. Studies have shown that it can inhibit osteoclast differentiation and activity and promote osteoblast proliferation and differentiation, thereby playing a positive role in bone metabolic homeostasis. In the prepared bone-targeted nanoparticles, curcumin is primarily encapsulated in the hydrophobic core region, overcoming its inherent limitations of poor water solubility and low bioavailability.
[0026] Epimedium glycoside, another important active ingredient in bone-targeted nanoparticles, effectively promotes the proliferation and differentiation of osteoblasts and inhibits osteoclast activity, directly improving osteoporosis. Similar to curcumin, icariin is primarily encapsulated within the hydrophobic core of bone-targeted nanoparticles to enhance its solubility and bioavailability.
[0027] On the one hand, alendronate sodium acts as a bone-targeting ligand with an extremely high affinity for the bone mineral hydroxyapatite. The alendronate sodium molecule possesses a unique bisphosphonate structure that strongly chelates calcium ions on the surface of hydroxyapatite crystals, the primary inorganic component of bone. When bone-targeted nanoparticles enter the body's circulation via intravenous injection, surface-exposed or integrated alendronate sodium can specifically bind to the bone surface, particularly areas of active bone metabolism and resorption, thereby achieving precise targeted delivery of the nanoparticles to the bone. On the other hand, alendronate sodium, as a classic anti-osteoporosis drug, can itself inhibit osteoclast activity and reduce bone loss. By integrating it into bone-targeted nanoparticles, its targeting ability is utilized while also exerting its pharmacological effects, reducing its systemic side effects through targeted delivery.
[0028] DSPE (1,2-Distearoyl-sn-glycero-3-phosphorylethanolamine) is a phospholipid whose hydrophobic fatty acid chain, namely stearoyl, constitutes the hydrophobic core of bone-targeted nanoparticles, providing a favorable environment for the encapsulation of curcumin and icariin.
[0029] PEG (Polyethylene glycol) is hydrophilic and forms a hydrophilic "crown" on the surface of nanoparticles, which can effectively reduce the nonspecific adsorption of bone-targeted nanoparticles in the body, such as plasma protein adsorption, and reduce the clearance by the reticuloendothelial system (RES), thereby significantly prolonging the time bone-targeted nanoparticles remain in the blood circulation and providing ample circulation opportunities for bone targeting.
[0030] NHS (N-Hydroxy succinimide) is an active ester that can react with amine groups.
[0031] In the preparation method of the present invention, DSPE-PEG-NHS mainly acts as a self-assembling material and participates in non-covalent or weak covalent interactions during the formation of bone-targeted nanoparticles.
[0032] As a preferred embodiment of the present invention, the preparation of the curcumin-icariin intermediate specifically includes: Under stirring conditions, the icariin organic solution is added dropwise to the curcumin organic solution; After the dropwise addition is completed, the reaction is stirred at room temperature for 12 to 72 hours to obtain an intermediate solution; The intermediate solution is added dropwise to deionized water, and after the addition is completed, the mixture is stirred and reacted at room temperature for 24 to 72 hours to obtain a suspension comprising a curcumin-icariin complex; The suspension is centrifuged, the supernatant is discarded, and the precipitate is collected to obtain a curcumin-icariin intermediate.
[0033] Curcumin and icariin form a stable complex in an organic solvent through hydrogen bonding and π-π stacking. Long reaction times of 12 to 72 hours and 24 to 72 hours respectively allow the molecules ample time for kinetic alignment, thus avoiding structural defects in the complex caused by incomplete reaction. If the reaction time is too short, some icariin molecules may not bind to curcumin, resulting in an increase in free components in the intermediate and affecting the uniformity of subsequent nanoparticles. Furthermore, longer reaction times can shift the reaction equilibrium toward complex formation, reducing the amount of unreacted raw materials remaining. Through thermodynamic control, the probability of byproduct formation can be reduced, thereby improving the purity of the intermediate.
[0034] As a preferred embodiment of the present invention, the method further comprises: after collecting the precipitate, freeze-drying the collected precipitate to remove moisture, thereby obtaining a solid product of the curcumin-icariin intermediate.
[0035] Curcumin and icariin are both natural polyphenolic compounds that are susceptible to oxidation, decomposition, or structural isomerization at high temperatures. During the freeze-drying process, the material temperature is maintained between -40°C and 0°C, avoiding the degradation caused by traditional drying (above 60°C). Furthermore, freeze-drying achieves water sublimation at low temperatures, preserving the integrity of intermolecular interactions and ensuring the structural stability of the intermediates.
[0036] In conventional drying (such as spray drying), rapid solvent evaporation increases the surface tension of nanoparticles, leading to aggregation or particle size growth. Freeze-drying, through a "freezing followed by sublimation" mechanism, secures the particles within the ice crystal framework, forming a porous, loose structure after drying, preventing irreversible aggregation between particles.
[0037] As a preferred embodiment of the present invention, the preparation of curcumin organic solution and icariin organic solution specifically includes: Curcumin is dissolved in an organic solvent to obtain a curcumin organic solution; icariin is dissolved in an organic solvent to obtain an icariin organic solution; the organic solvent is at least one of dimethyl sulfoxide, dimethyl sulfoxide, ethanol, methanol, acetone, dimethylformamide, tetrahydrofuran, dioxane, acetonitrile and N-methylpyrrolidone.
[0038] Curcumin (a polar molecule containing phenolic hydroxyl groups and a β-diketone structure) and icariin (a flavonoid glycoside containing a sugar-based polar group) are more soluble in polar organic solvents. For example, dimethyl sulfoxide (DMSO), due to its strong polarity and hydrogen bonding ability, can dissolve curcumin and icariin, avoiding uneven reactions caused by incomplete dissolution of the raw materials. While alcoholic solvents such as ethanol and methanol have slightly lower solubility, their concentration can be adjusted to optimize the solubility balance while also reducing solvent toxicity. Furthermore, polar solvents promote π-π stacking and hydrogen bonding between curcumin and icariin, accelerating the self-assembly of the complex.
[0039] The molar ratio of the icariin to the curcumin is 1 to 3:1. When the molar ratio is less than 1:1, insufficient icariin causes curcumin to self-aggregate to form stacked dimers, reducing the purity of the complex. When the molar ratio is greater than 3:1, excess icariin may exist in a free state in the precipitate, requiring additional purification steps.
[0040] As a preferred embodiment of the present invention, the preparation of the alendronate sodium solution and the DSPE-PEG-NHS solution specifically includes: dissolving alendronate sodium in deionized water to obtain an alendronate sodium solution; Dissolve DSPE-PEG-NHS in deionized water to obtain a DSPE-PEG-NHS solution; The weight ratio of the alendronate sodium, DSPE-PEG-NHS and curcumin-icariin intermediate is 1.3-4.2:4:1-3.
[0041] A weight ratio of 1.3-4.2:1-3 ensures an optimal DSPE-PEG-NHS density on the surface of bone-targeted nanoparticles. Too dense a density impairs targeted binding, while too sparse a density prevents effective particle stabilization. This ensures efficient reaction between the NHS groups and the curcumin-icariin intermediate, optimizing the complex's physicochemical properties. This ensures sufficient binding sites between sodium alendronate and the curcumin-icariin intermediate, enabling the complex to target bone tissue, improving drug accumulation at bone lesions and minimizing toxic side effects associated with systemic distribution. Furthermore, this appropriate ratio prevents excessive sodium alendronate from destabilizing the complex, or insufficient alendronate from weakening the targeting effect.
[0042] The bone-targeting properties of alendronate combined with the long-circulating properties of DSPE-PEG-NHS enable precise delivery of the curcumin-icariin intermediate to bone tissue, making it particularly suitable for the treatment of bone-related diseases (such as osteoporosis and bone tumors), thereby increasing local drug concentration and reducing dosage and systemic toxicity. A deionized water system and a reasonable weight ratio promote the formation of a stable nanocomposite between the intermediate, alendronate, and DSPE-PEG-NHS, preventing particle aggregation or drug leakage caused by imbalanced component ratios and ensuring the stability of the formulation during storage and administration.
[0043] The following analysis and explanation are combined with specific examples.
[0044] A method for preparing bone-targeted nanoparticles comprises the following steps: S1, prepare curcumin organic solution, icariin organic solution, alendronate sodium solution and DSPE-PEG-NHS solution.
[0045] Accurately weigh 5 mg of curcumin, 18.35 mg of icariin, 6.5 mg of alendronate sodium, and 20 mg of DSPE-PEG-NHS.
[0046] 5 mg of curcumin was dissolved in 5 mL of dimethyl sulfoxide (DMSO) to obtain a curcumin organic solution.
[0047] 18.35 mg of icariin was dissolved in 5 mL of dimethyl sulfoxide (DMSO) to obtain an icariin organic solution.
[0048] 6.5 mg of alendronate sodium was dissolved in 2 mL of deionized water to obtain an alendronate sodium solution.
[0049] 20 mg of DSPE-PEG-NHS was dissolved in 2 mL of deionized water to obtain a DSPE-PEG-NHS solution.
[0050] S2, under stirring, adding the icariin organic solution dropwise to the curcumin organic solution, and continuing to stir the reaction after the addition is complete to self-assemble and form a curcumin-icariin intermediate. Specifically, under continuous stirring at a stirring speed of 500 rpm, the icariin organic solution is slowly added dropwise to the curcumin organic solution at a dropping rate of 1 mL / min. The stirring reaction is continued at room temperature for 12 hours to obtain an intermediate solution.
[0051] Prepare a container filled with 100 mL of deionized water and begin stirring at 500 rpm. Slowly add the intermediate solution dropwise to the deionized water at a rate of 0.5 mL / min to promote nanoparticle formation. Continue stirring at room temperature for 24 hours to allow for complete precipitation or self-assembly to form a suspension.
[0052] The suspension was centrifuged at 5000 G for 10 minutes, the supernatant was discarded, and the formed precipitate was collected.
[0053] The collected precipitate is freeze-dried to remove moisture, thereby obtaining a solid product of a curcumin-icariin intermediate.
[0054] S3, dispersing the curcumin-icariin intermediate in deionized water to obtain a dispersion. Specifically, 10 mg of the curcumin-icariin intermediate was weighed and dispersed in 1 mL of deionized water, and ultrasonically treated for 10 minutes to obtain a dispersion.
[0055] S4, adding the sodium alendronate solution and the DSPE-PEG-NHS solution to the dispersion, setting the stirring speed to 500 rpm, and stirring the mixture at room temperature for 24 h.
[0056] The reaction mixture was dialyzed to produce bone-targeted nanoparticles. Specifically, the resulting mixture was transferred to a dialysis bag with a molecular weight cutoff of 10 kDa, which was then placed in a sufficient amount of deionized water for dialysis. The dialysis process lasted for three days, with the dialysate replaced with fresh deionized water every eight hours to effectively remove unreacted small molecules and free components.
[0057] After dialysis is complete, the bone-targeted nanoparticle suspension is removed from the dialysis bag. This is a purified aqueous solution of bone-targeted nanoparticles containing curcumin, icariin, and alendronate. Depending on the needs, the bone-targeted nanoparticle suspension can be used directly in subsequent applications or further processed, such as freeze-drying, to obtain a solid powder.
[0058] In one embodiment, the present invention discloses a bone-targeted nanoparticle, which is prepared by the preparation method of bone-targeted nanoparticles described in any of the above embodiments, and includes a core and a shell coated on the core; the core is a hydrophobic complex formed by self-assembly of a curcumin-icariin intermediate and the hydrophobic chain of DSPE in DSPE-PEG-NHS through hydrophobic interaction; the shell is a hydrophilic polymer formed by the outward extension of the PEG chain in DSPE-PEG-NHS, and sodium alendronate is loaded on the hydrophilic polymer.
[0059] The bone-targeted nanoparticles produced by the present invention exhibit a core-shell structure. The hydrophobic complex formed by the self-assembly of the curcumin-icariin intermediate and the hydrophobic chains of DSPE in DSPE-PEG-NHS through hydrophobic interactions serves as the core encapsulated within the shell. This effectively addresses the poor water solubility and low bioavailability of curcumin and icariin, improving their in vivo stability and bioavailability. Furthermore, the introduction of DSPE-PEG-NHS, particularly the PEG chains, effectively prolongs the nanoparticles' circulation time in the blood, reducing clearance by the reticuloendothelial system (RES), further promoting targeted delivery.
[0060] After determination, see Figure 2 As shown, the bone-targeted nanoparticles prepared by the present invention have uniform particle size and good dispersibility. They also have good stability and biocompatibility under physiological conditions, reducing the toxic side effects of drugs.
[0061] The bone-targeted nanoparticles of the present invention achieve effective treatment or improvement of osteoporosis through multiple synergistic mechanisms, specifically: 1) Targeted enrichment to improve efficacy: Bone-targeted nanoparticles are specifically enriched in bone lesions through the mediation of alendronate sodium, allowing curcumin, icariin and alendronate sodium to reach higher therapeutic concentrations locally in the bones, thereby significantly improving the therapeutic effect of the drugs.
[0062] 2) Multi-target synergistic therapy: Alendronate sodium directly inhibits osteoclast activity and reduces bone resorption, which is a fundamental role in anti-osteoporosis. Curcumin and icariin, two natural active ingredients, possess multiple pharmacological effects, including anti-inflammatory and antioxidant effects, promoting osteoblast proliferation and differentiation, and inhibiting osteoclast activity. Curcumin and icariin not only directly promote bone formation and inhibit bone resorption, but also improve the bone microenvironment by modulating inflammatory responses and oxidative stress, creating favorable conditions for bone repair.
[0063] Synergistic Effects: Alendronate primarily inhibits bone resorption, while curcumin and icariin act simultaneously on both bone resorption and formation, and also have anti-inflammatory properties. The three agents work synergistically in bone-targeted nanoparticles, achieving a more comprehensive and effective intervention for osteoporosis, addressing the shortcomings of single agents.
[0064] 3) Reduce systemic toxic side effects: Through targeted delivery, the distribution of drugs in non-target organs is reduced, thereby significantly reducing the systemic side effects such as gastrointestinal irritation, hepatotoxicity and kidney toxicity that may be caused by free alendronate sodium, thereby improving the safety of treatment.
[0065] 4) Improved drug bioavailability: Nanocarriers solve the problems of poor water solubility and low bioavailability of curcumin and icariin, ensuring that these active ingredients can effectively exert their pharmacological effects.
[0066] As a preferred embodiment of the present invention, the alendronate sodium is exposed on the surface or near-surface region of the bone-targeting nanoparticles in a non-covalently bound or partially embedded manner.
[0067] Non-covalent binding (such as electrostatic interactions and van der Waals forces) does not disrupt the chemical structure of alendronate sodium, maintaining its biological activity. Furthermore, the reversibility of non-covalent bonds allows alendronate sodium to remain stable in the bloodstream. However, upon reaching the local microenvironment of bone tissue (e.g., acidic pH, enzymatic hydrolysis), it can be released responsively to the environment, achieving targeted controlled release and preventing premature drug release or accumulation. Furthermore, non-covalent binding does not require complex chemical reactions such as cross-linking or coupling; instead, it combines alendronate with nanoparticles through physical adsorption or intermolecular forces, simplifying preparation and avoiding the effects of chemical modification on alendronate sodium's activity.
[0068] Alendronate sodium is partially embedded on the surface of bone-targeted nanoparticles, rather than being completely free. This prevents rapid clearance or degradation in the bloodstream while retaining its ability to bind to the bone matrix through near-surface exposure. This arrangement balances the stability and targeting functionality of the bone-targeted nanoparticles. Furthermore, the partial embedding approach allows for controllable embedding by adjusting the nanoparticle formulation, facilitating process optimization and large-scale production.
[0069] In one embodiment, the present invention discloses a use of bone-targeted nanoparticles prepared by the method for preparing bone-targeted nanoparticles described in any of the above embodiments in preparing a drug for treating or improving osteoporosis.
[0070] The above embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Any equivalent substitution or modification made by those skilled in the art based on the present invention is within the protection scope of the present invention.
Claims
1. A method for preparing bone-targeted nanoparticles, characterized in that: include: preparing curcumin organic solution, icariin organic solution, alendronate sodium solution and DSPE-PEG-NHS solution; Under stirring conditions, the icariin organic solution is added dropwise to the curcumin organic solution, and after the addition is completed, the stirring reaction is continued to self-assemble to form a curcumin-icariin intermediate; dispersing the curcumin-icariin intermediate in deionized water to obtain a dispersion; The sodium alendronate solution and the DSPE-PEG-NHS solution were added to the dispersion, stirred for a preset reaction time, and then dialyzed to obtain bone-targeted nanoparticles.
2. The method for preparing bone-targeted nanoparticles according to claim 1, wherein: The preparation of the curcumin-icariin intermediate specifically includes: Under stirring conditions, the icariin organic solution is added dropwise to the curcumin organic solution; After the dropwise addition is completed, the reaction is stirred at room temperature for 12 to 72 hours to obtain an intermediate solution; The intermediate solution is added dropwise to deionized water, and after the addition is completed, the mixture is stirred and reacted at room temperature for 24 to 72 hours to obtain a suspension comprising a curcumin-icariin complex; The suspension is centrifuged, the supernatant is discarded, and the precipitate is collected to obtain a curcumin-icariin intermediate.
3. The method for preparing bone-targeted nanoparticles according to claim 1, characterized in that: Also includes: After collecting the precipitate, the collected precipitate is freeze-dried to remove moisture, thereby obtaining a solid product of the curcumin-icariin intermediate.
4. The method for preparing bone-targeted nanoparticles according to claim 1, wherein: The preparation of curcumin organic solution and icariin organic solution specifically includes: dissolving curcumin in an organic solvent to obtain a curcumin organic solution; dissolving icariin in an organic solvent to obtain an icariin organic solution; The organic solvent is at least one of dimethyl sulfoxide, dimethyl sulfoxide, ethanol, methanol, acetone, dimethylformamide, tetrahydrofuran, dioxane, acetonitrile and N-methylpyrrolidone; The molar ratio of the icariin to the curcumin is 1-3:
1.
5. The method for preparing bone-targeted nanoparticles according to claim 1, characterized in that: The preparation of alendronate sodium solution and DSPE-PEG-NHS solution specifically includes: dissolving alendronate sodium in deionized water to obtain an alendronate sodium solution; Dissolve DSPE-PEG-NHS in deionized water to obtain a DSPE-PEG-NHS solution; The weight ratio of the alendronate sodium, DSPE-PEG-NHS and curcumin-icariin intermediate is 1.3-4.2:4:1-3.
6. A bone-targeted nanoparticle, characterized in that: Prepared by the preparation method of bone-targeted nanoparticles according to any one of claims 1 to 5, comprising a core and a shell coated on the core; The core is a hydrophobic complex formed by self-assembly of the curcumin-icariin intermediate and the hydrophobic chain of DSPE in DSPE-PEG-NHS through hydrophobic interaction; The shell is a hydrophilic polymer formed by outward extension of the PEG chain in DSPE-PEG-NHS, and sodium alendronate is loaded on the hydrophilic polymer.
7. The bone-targeting nanoparticle according to claim 6, characterized in that: The alendronate sodium is exposed on the surface or near-surface area of the bone-targeting nanoparticles in a non-covalently bound or partially embedded manner.
8. Use of bone-targeted nanoparticles prepared by the method for preparing bone-targeted nanoparticles according to any one of claims 1 to 5 in preparing a drug for treating or improving osteoporosis.