Research status of new drug delivery system for apatinib

Apatinib (Apa) is a small molecule targeted tumor therapy drug. Its main anti-tumor mechanism is to highly selectively bind and inhibit vascular endothelial cell growth factor receptor 2 (VEGFR-2), thereby reducing Tumor cell microvessel density, inhibit angiogenesis and tumor cell growth. Apa has a good therapeutic effect on a variety of tumors, can reverse the multidrug resistance of tumor cells, and improve the therapeutic effect of chemotherapy drugs. In addition, Apa can also be used for the treatment of neovascular eye diseases. The currently marketed oral preparation is apatinib mesylate tablets, which have a large clinical dosage and many side effects. In order to reduce the dosage, improve the efficacy, and reduce the toxic and side effects, the new dosage form of Apa has become a research hotspot.

1. Nanoparticles

Nanoparticles can dissolve or encapsulate drugs in them, or physically adsorb them on their surface, and have the characteristics of high drug loading, high encapsulation efficiency and controllable drug release. Prepare Apa nanoparticles with human serum albumin (HSA) as the carrier material, and use polyethylene glycol (PEG) modified HSA (HSA-PEG) as the nanoparticle backbone to encapsulate Apa to prepare Apa-HSA-PEG nanoparticles And study its inhibitory effect on retinal vascular permeability mediated by human retinal epithelial cells vascular endothelial cell growth factor (VEGF) and its blocking effect on diabetes-induced retinal vascular leakage. In vitro paracellular permeability and transendothelial cell resistance measurement results show that Apa-HSA-PEG nanoparticles have a significant inhibitory effect on the increased permeability of human retinal microvascular endothelial cells induced by VEGF; streptozotocin-induced diabetes model In vivo experiments in mice showed that intravitreal injection of Apa-HSA-PEG nanoparticles can significantly inhibit diabetes-induced retinal vascular leakage. Apa-HSA-PEG nanoparticles can effectively inhibit VEGF-induced blood vessel formation, migration and proliferation of human endothelial cells.

2. Micelles

Micelles are aggregate particles formed by self-assembly of surfactants or amphiphilic block copolymers in aqueous solution after the concentration exceeds a certain critical value. The polymer micelle formed by the amphiphilic block copolymer has a "core-shell" structure and is a new type of drug carrier with great development potential. Take advantage of Apa as a tumor cell multidrug resistance (MDR) inhibitor to construct a photosensitive reactive oxygen free radical (ROS)-responsive polymer micelle with protoporphyrin as the photosensitizer, and co-carry Apa and doxorubicin Bistar (DOX), the micelles use acetylated chondroitin sulfate covalently linked to protoporphyrin through ester bonds as the backbone, acetylated chondroitin sulfate as the hydrophilic block, and protoporphyrin as the hydrophobic block. Through hydrophobic interaction and π-π stacking, Apa and DOX are encapsulated in the core of micelles formed by protoporphyrin. When the micelle system is irradiated with 635 nm infrared light, protoporphyrin undergoes photoelectric conversion to generate a large amount of ROS, which further triggers the decomposition and assembly of micelles, thereby releasing co-loaded drugs. The released Apa can competitively inhibit the P-glycoprotein drug pump of drug-resistant tumor cells, allowing DOX to escape the recognition of P-glycoprotein, thereby reversing the MDR of tumor cells.

3. Liposome

Liposomes are bilayer closed vesicles composed of lipids (such as LECITHIN and cholesterol). The hollow inside is a hydrophilic cavity that can be loaded with hydrophilic drugs; there is a hydrophobic cavity between the bilayers and the thickness is about 4 nm, can embed hydrophobic drugs. Liposomes have a biomembrane-like structure, high histocompatibility, high cell affinity, low toxicity, biodegradability and slow release. They are a good drug delivery carrier. Studies have combined Apa-loaded liposomes with other chemotherapeutic drugs (such as docetaxel) to treat colon cancer. While oral Apa liposomes, local injection of FIBRIN glue delivers docetaxel micelles. Hexamate and methoxy polyethylene glycol-polycaprolactone (MPEG-PCL) block copolymer self-assemble to form micelles, which are then mixed with fibrin glue. Results In the animal tumor model established by subcutaneously inoculating colon cancer CT26 cells in Balb/c mice, compared with intratumoral injection of fibrin glue alone to deliver docetaxel micelles, oral Apa liposomes combined with intratumoral injection of fibrin The solution of gel delivery of docetaxel micelles shows stronger anti-tumor activity, which can promote tumor cell apoptosis, inhibit their proliferation, and reduce tumor cell angiogenesis.

4. Hydrogel

Hydrogel is a good drug controlled release carrier. It is a gel formed by swelling in Water with a three-dimensional network structure of synthetic or natural polymer through physical or chemical cross-linking. It contains a large amount of Water can also be loaded with medicines, with good biocompatibility. Nude mice were subcutaneously inoculated with human liver cancer HepG2 cells to establish a mouse subcutaneous tumor model. Magnetic resonance imaging (MRI), histomorphology and immunohistochemistry were used to evaluate the effect of intratumoral injection of Apa-loaded gadolinium-PEG hydrogel in the treatment of liver cancer. . The results showed that compared with the Apa naked drug group and the unloaded gadolinium-PEG hydrogel group, the Apa-loaded gadolinium-PEG hydrogel group had a larger tumor tissue necrosis area, CD34 single-chain penetrating protein and VEGFR-2 The expression of Apa is less, and the average optical density and microvessel density of VEGFR-2 are significantly reduced, indicating that the gadolinium-PEG hydrogel helps to improve the efficacy of Apa.

5. Superfine fiber

The ultrafine fibers prepared by electrostatic spinning technology have the characteristics of small diameter and large specific surface area, and can be used as a new type of drug controlled release carrier to increase the dissolution rate of drugs in water and improve the bioavailability of drugs. Some scholars use polylactic acid (PLA) as the matrix material and use microfluid electrospinning technology to develop a programmed drug-releasing microfiber (DOX-PM+AP@F) implanted with DOX micelles and Apa. The drug delivery device, the DOX-loaded micelle skeleton is composed of 3-aminophenylboronic acid (PBA) modified PEG-PCL block copolymer, and the DOX-loaded micelles and free DOX-containing glycerin aqueous solution are used as the aqueous phase, and the Apa-containing 30 %PLA dimethyl carbonate (DMC) solution is the oil phase. After electrospinning, the DOX-loaded micelles and free DOX are wrapped in the cavity inside the ultrafine fibers, and the Apa is evenly dispersed in the PLA matrix. The encapsulation efficiency of the two drugs in the ultrafine fibers prepared by the method can reach 99%. The superfine fiber can achieve programmed drug release during the degradation process, that is, rapid release of DOX micelles and slow release of Apa. The slowly released Apa can continuously inhibit the P glycoprotein drug pump of MCF-7/ADR resistant tumor cells, thereby increasing the accumulation of DOX in the cells. The DOX-PM+AP@F drug-carrying device has a good anti-tumor cell MDR effect in vivo. It was implanted in MCF-7/ADR tumor-bearing mice subcutaneously near the tumor site after DOX-PM+AP@F 21 d, DOX The tumor volume of mice in the PM+AP@F group was about 400.3 mm3, while the tumor volume of mice in the fiber group carrying DOX alone was about 1 070 mm3; and on the 40th day of dosing, the DOX-PM+AP@F group The survival rate of tumor-bearing mice can reach more than 80%, which is significantly higher than the fiber group carrying DOX alone; Western blotting results show that DOX-PM+AP@F can up-regulate the pro-apoptotic factor Bax and down-regulate the anti-apoptotic factor The expression of Bcl-2 enhances the activity of Caspase 3/9 (Caspase-3/9) to promote tumor cell apoptosis.

6. Lipid nanobubbles

Lipid nanobubbles are drug carriers with inert gas as the core and phospholipids as the shell, which can be loaded with drugs through electrostatic adsorption, encapsulation in the bubble and non-covalent binding of biotin-avidin. Among them, the drug loading mode wrapped in the bubble is relatively stable, and the drug loading and the encapsulation rate are relatively high. Some scholars have prepared a lipid nanobubbles loaded with Apa and used liver cancer glypican 3 (GPC3) for targeted modification. The Apa is wrapped between the phospholipid layer and the interlayer of perfluoropropane inert gas. The sealing rate can reach up to 68%. The targeting factor GPC3 is encapsulated on the surface of lipid nanobubbles through biotin-avidin interaction, which can significantly improve the ability of lipid nanobubbles to adhere to human liver cancer HepG2 cells; in vitro cell test results show that GPC3 encapsulating Apa targets The combined action of lipid nanobubbles and ultrasound can significantly increase the inhibitory effect of Apa on tumor cell proliferation and block more tumor cells in G1 phase.

The current research and development hotspots of Apa's new drug delivery systems include nanoparticles, micelles, liposomes, hydrogels, ultra-fine fibers and lipid nanobubbles, etc. These new drug delivery systems can improve the water solubility and focus of Apa The concentration of the drug significantly enhances the role of the drug in inhibiting tumor growth and reversing the MDR of tumor cells, and helps reduce drug toxicity. However, most of the research on these new drug delivery systems of Apa is still in the basic research stage of cells and animal models, and there are still many problems to be solved in clinical application. Therefore, the quality control and safety evaluation of the new drug delivery system still require further attention from related scholars. In-depth research and development of safer and more effective new Apa dosage forms is still the direction of future efforts.