Drug delivery carrier of hybrid silicon dioxide coating as well as preparation method and application of drug delivery carrier
By forming a silicon dioxide layer on poly(lactic acid-glycolic acid) nanoparticles to form SiLGA NPs, the problems of short half-life of enzyme therapy and uncontrolled nanoparticle release are solved, and the retention of enzyme activity and stability of drug delivery are achieved.
Patent Information
- Application Number
- CN202510049652.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-13
- Publication Date
- 2025-05-23
AI Technical Summary
In the prior art, enzyme therapy is susceptible to immune clearance, has a short half-life and requires frequent administration. At the same time, the nanoparticles are hydrolyzed and decomposed after delivery, resulting in uncontrolled cargo release.
The enzyme was coated in poly(lactic acid-glycolic acid) nanoparticles using water-oil-water double emulsion technology, and deposited on its surface to form a silicon dioxide layer to form SiLGA NPs.
Through the formation of the silica layer, SiLGA NPs can better retain the enzyme activity, extend the half-life of the enzyme, avoid the sudden release of goods, and achieve more stable drug delivery.
Smart Images
Figure CN120022252A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of biomedicine technology, in particular to a hybrid silicon dioxide coated drug delivery carrier and a preparation method and application thereof. Background Art
[0002] Active enzymes offer attractive therapeutic strategies for many diseases, including cancer. More specifically, amino acid depletion therapy (AADT) is a promising strategy that typically uses active enzymes to target metabolic processes that tumor cells rely on for survival, growth, and proliferation. The active enzymes of AADT (e.g., asparaginase, arginine deiminase, arginase, methioninase, cysteine enzymes, etc.) deprive cancer cells of the amino acids they need for growth, and immune responses to exogenous enzymes often result in a short elimination half-life, which limits the clinical implementation of these therapies.
[0003] The attachment of polyethylene glycol (PEG) to active drugs or drug delivery vehicles is a strategy to improve the half-life of therapeutic molecules, including enzymes, and PEGylation protects enzymes from antibodies and proteases in vivo. However, the immune system can produce antibodies against PEG with repeated dosing, thereby reducing the long-term efficacy of PEGylated drugs. In addition, a large proportion of the population is now exposed to PEGylated liposomes during vaccination, which increases anti-PEG antibodies. Patient sensitization to PEGylated formulations can complicate treatment regimens, so new enzyme delivery methods are urgently needed.
[0004] Some cancer cells are critically dependent on non-essential biomolecules for survival, growth, and proliferation. Enzyme-based therapeutics can eliminate these biomolecules to specifically target tumor cells. However, enzyme therapies are susceptible to immune clearance, have a short half-life, and require frequent dosing. Encapsulation of therapeutic cargo in biocompatible and biodegradable poly(lactic-co-glycolic acid) nanoparticles (PLGANPs) is a controlled release strategy. However, PLGA NPs exhibit burst cargo release shortly after delivery or when they decompose via hydrolysis when introduced into an aqueous environment.
[0005] Nanoparticles offer a high surface area to volume ratio and loading efficiency to increase the half-life of enzymes after delivery. PLGA NPs break down into natural byproducts of human metabolism (lactic and glycolic acids), and PLGA hydrolysis promotes the release of enzyme cargo, which can begin hours after injection. Although the rate of hydrolytic degradation can be tuned to some extent by varying the molecular weight and monomer ratio of PLGA, dose dumping associated with the characteristic burst release of enzyme cargo from PLGA NPs remains a problem for controlled release.
[0006] Modified chitosan and others have been shown to help reduce the burst release of cargo from PLGA NPs, however burst release remains a major limitation for long-term controlled cargo delivery. Therefore, the present inventors designed a hybrid silica-coated drug delivery vehicle that can better retain enzyme activity. Summary of the invention
[0007] The purpose of the present invention is to overcome the shortcomings and deficiencies of the prior art and to provide a drug delivery carrier of a hybrid silica coating and a preparation method and application thereof. The technical solution adopted by the present invention is as follows:
[0008] In a first aspect, a hybrid silica-coated drug delivery carrier is provided, wherein the drug delivery carrier is a poly(lactic acid-glycolic acid) nanoparticle having a silica layer deposited on the surface.
[0009] In a second aspect, a method for preparing the hybrid silica-coated drug delivery carrier is provided, comprising the following steps:
[0010] S1. Enzymes were encapsulated in poly(lactic-co-glycolic acid) nanoparticles, i.e., PLGANPs, using water-oil-water double emulsion technology;
[0011] S2. Depositing a silicon dioxide layer on the poly (lactic acid-glycolic acid) nanoparticles to obtain SiLGA NPs.
[0012] Step S1 specifically comprises connecting the active enzyme suspended in the first aqueous phase W1 with the PLGA dissolved in the oil, i.e., the O phase, and emulsifying the W1 / O interface to produce nanodroplets suspended in the oil, i.e., emulsion 1; connecting the emulsion 1 with the second aqueous phase W2, and emulsifying at the O / W2 interface to produce an aqueous suspension of oil-phase nanoparticles, i.e., emulsion 2, encapsulating the enzyme in the water core, and evaporating the oil phase to form an aqueous suspension of PLGA NPs with active enzymes.
[0013] Step S2 specifically comprises forming a silicon dioxide layer on the surface of PLGA NPs by sol-gel polycondensation of silicic acid.
[0014] In a third aspect, a pharmaceutical preparation is provided, which comprises the above-mentioned hybrid silica-coated drug delivery carrier.
[0015] The beneficial effects of the present invention are as follows: the present invention provides a hybrid silica-coated PLGA (SiLGA) NPs as a feasible drug delivery carrier, which has a diameter of less than 200 nm, a metastable Zeta potential, and high loading efficiency and content; compared with PLGA NPs not coated with silica coating, SiLGA NPs retain enzyme activity to a greater extent, and the encapsulated enzyme retains good activity and catalyzes the diffusion of small molecule substrates through the porous silica layer. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, without paying creative labor, other drawings obtained based on these drawings still belong to the scope of the present invention.
[0017] Figure 1 is the transmission electron microscopy image of PLGA NPs;
[0018] Figure 2 Transmission electron microscopy image of SiLGA NPs;
[0019] Figure 3 The percentage of penicillinase activity retained in the unencapsulated and encapsulated (PLGA, SiLGA) forms after treatment with protease PK. DETAILED DESCRIPTION
[0020] In order to make the objectives, technical solutions and advantages of the present invention more clear, the present invention will be further described in detail below in conjunction with embodiments and drawings.
[0021] Example
[0022] 1. Synthesis of PLGA NPs
[0023] Polyvinyl alcohol (PVA) The RG 504H) solution (aqueous phase 2) was heated to room temperature, and 300 μL of water was dropped into the oil phase while mixing under low vortex, and the resulting solution was vortex mixed under high pressure for 1 min to form the first emulsion (emulsion 1); emulsion 1 was ultrasonically treated at 20 kHz, 500 W.
[0024] Then, emulsion 1 was immediately added dropwise to 18 mL of aqueous phase 2 while stirring at 300 rpm to form a second emulsion (emulsion 2). Emulsion 2 was then placed in ice water and ultrasonicated at 20 kHz and 500 W. Emulsion 2 was sealed with a Parafilm. TM The lid was closed, air was exhausted with a syringe tip, and the mixture was stirred at 200 rpm at room temperature overnight to produce solid PLGA NPs.
[0025] 2. Synthesis of SiLGA NPs
[0026] PLGA NPs (1.5 mL) were added to 30 mL PBS (0.1X) and mixed thoroughly, and the remaining PLGA NPs were stored at 4°C; 74 μL TMOS (tetramethyl orthosilicate, purum, ≥98% (GC) was added to 500 μL HCl (0.1 mM) and mixed thoroughly to form silicic acid. The PLGA NPs suspension was then vortexed and 450 μL silicic acid was added dropwise. The suspension was thoroughly vortexed at high temperature and shaken at 4°C overnight to allow the silicic acid to condense into silica on the surface of the PLGA NPs. Finally, about 13 mL of ultrapure water was added to the SiLGA NPs, centrifuged at 3900 rpm for 15 min, and the supernatant was collected at 4°C to obtain SiLGANPs.
[0027] In summary, the present invention uses water-oil-water double emulsion technology to obtain protein-loaded PLGA NPs, and then synthesizes SiLGA NPs with a silica coating. The active enzyme suspended in the aqueous phase (W1) is connected to the PLGA (O) dissolved in the oil. Emulsification at the W1 / O interface produces nanodroplets suspended in the oil (emulsion 1). Emulsion 1 is connected to the second aqueous phase (W2). Emulsification at the O / W2 interface produces an aqueous suspension of oil-phase NPs (emulsion 2), which wraps the enzyme in the water core. The evaporation of the oil phase forms an aqueous suspension of PLGA NPs with active enzyme cargo. Subsequently, the sol-gel polycondensation of silicic acid forms a silica layer around the PLGA NPs.
[0028] PLGA NPs served as scaffolds, on which a uniform silica layer was deposited to form SiLGA NPs. PLGA NPs and SiLGA NPs were characterized by transmission electron microscopy.
[0029] The above disclosure is only the preferred embodiment of the present invention, which certainly cannot be used to limit the scope of the present invention. Therefore, equivalent changes made according to the claims of the present invention are still within the scope of the present invention.
Claims
1. A hybrid silica-coated drug delivery carrier, characterized in that: The drug delivery carrier is polylactic acid-glycolic acid nanoparticles with a silicon dioxide layer deposited on the surface.
2. The method for preparing a hybrid silica-coated drug delivery carrier according to claim 1, characterized in that: The following steps are involved: S1. Enzymes were encapsulated in polylactic-co-glycolic acid nanoparticles, i.e., PLGA NPs, using water-oil-water double emulsion technology; S2. Depositing a silicon dioxide layer on the polylactic acid-glycolic acid nanoparticles to obtain SiLGA NPs.
3. The method for preparing a drug delivery carrier of a hybrid silica coating according to claim 2, characterized in that: Step S1 specifically comprises connecting the active enzyme suspended in the first aqueous phase W1 with the PLGA dissolved in the oil, i.e., the O phase, and emulsifying the W1 / O interface to produce nanodroplets suspended in the oil, i.e., emulsion 1; Emulsion 1 is connected to the second aqueous phase W2, and emulsifies at the O / W2 interface to produce an aqueous suspension of oil-phase nanoparticles, i.e., emulsion 2, which encapsulates the enzyme in the water core, and the evaporation of the oil phase forms an aqueous suspension of PLGA NPs with active enzymes.
4. The method for preparing a drug delivery carrier of a hybrid silica coating according to claim 2, characterized in that: Step S2 specifically comprises forming a silicon dioxide layer on the surface of PLGA NPs by sol-gel polycondensation of silicic acid.
5. A pharmaceutical preparation comprising the drug delivery carrier of the hybrid silica coating according to claim 1.