Apatinib (Apa) is a small-molecule targeted antitumor therapeutic drug that exerts its primary antitumor effect through highly selective binding and inhibition of Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2), thereby reducing the microvascular density of tumor cells, inhibiting angiogenesis, and suppressing tumor cell growth. Apa demonstrates favorable therapeutic outcomes against various types of tumors, with the ability to reverse multi-drug resistance in tumor cells and enhance the efficacy of chemotherapeutic drugs. Additionally, Apa can be applied in the treatment of neovascular ocular diseases. Currently, the marketed oral formulation is Apatinib Mesylate Tablets, which, despite its clinical effectiveness, requires a relatively high dosage and is associated with numerous side effects. Consequently, the development of novel Apa formulations has emerged as a research focus aimed at reducing dosage, enhancing efficacy, and mitigating adverse reactions.

1. Nanoparticles

Nanoparticles can dissolve or encapsulate drugs within their structure or physically adsorb them on their surface, exhibiting characteristics such as high drug loading capacity, high encapsulation efficiency, and controlled drug release. Using human serum albumin (HSA) as the carrier material, Apa nanoparticles can be prepared. Specifically, polyethylene glycol (PEG)-modified HSA (HSA-PEG) serves as the nanoparticle scaffold to encapsulate Apa, resulting in Apa-HSA-PEG nanoparticles. These nanoparticles are studied for their inhibitory effects on vascular endothelial growth factor (VEGF)-mediated retinal vascular permeability in human retinal epithelial cells and their blocking effects on diabetes-induced retinal vascular leakage. In vitro assays of paracellular permeability and transendothelial electrical resistance have demonstrated that Apa-HSA-PEG nanoparticles significantly inhibit the VEGF-induced increase in permeability of human retinal microvascular endothelial cells. In vivo experiments using streptozotocin-induced diabetic model mice have shown that intravitreal injection of Apa-HSA-PEG nanoparticles can markedly suppress diabetes-induced retinal vascular leakage. Furthermore, Apa-HSA-PEG nanoparticles effectively inhibit VEGF-induced angiogenesis, migration, and proliferation of human endothelial cells.

2.Micelles

Micelles are aggregates formed spontaneously by surfactants or amphiphilic block copolymers in aqueous solutions when their concentration exceeds a critical threshold. Polymeric micelles composed of amphiphilic block copolymers possess a "core-shell" structure, making them a promising new drug carrier with significant development potential. Leveraging Apa's advantage as an inhibitor of multidrug resistance (MDR) in tumor cells, a photosensitive polymer micelle responsive to reactive oxygen species (ROS) was constructed using protoporphyrin as the photosensitizer. This micelle co-loads Apa and doxorubicin (DOX), utilizing acetylated chondroitin sulfate covalently linked to protoporphyrin via ester bonds as the scaffold. Here, acetylated chondroitin sulfate serves as the hydrophilic block, while protoporphyrin functions as the hydrophobic block, encapsulating Apa and DOX within the micelle core through hydrophobic interactions and π-π stacking. Upon irradiation with 635 nm infrared light, the protoporphyrin undergoes photoelectric conversion, generating a substantial amount of ROS, which subsequently triggers the disassembly of the micelle, releasing the co-loaded drugs. The released Apa competitively inhibits the P-glycoprotein drug pump in resistant tumor cells, enabling DOX to evade recognition by P-glycoprotein, thereby reversing the MDR phenotype in tumor cells.

3.Liposomes

Liposomes are enclosed vesicles composed of lipid bilayers (such as phosphatidylcholine and cholesterol). The interior of these vesicles forms a hydrophilic cavity capable of loading hydrophilic drugs, while the space between the lipid bilayers constitutes a hydrophobic cavity with a thickness of approximately 4 nm, allowing for the encapsulation of hydrophobic drugs. Liposomes possess a structure similar to biological membranes, exhibiting high tissue compatibility, high cellular affinity, [low immunogenicity (as the original text had a placeholder "low" which could refer to multiple properties, but low immunogenicity is a common characteristic of liposomes)], biodegradability, and sustained-release properties, making them an excellent drug delivery vehicle. Studies have investigated the combination of Apa-loaded liposomes with other chemotherapeutic drugs (e.g., docetaxel) for the treatment of colon cancer. In this approach, Apa liposomes are administered orally, while docetaxel micelles self-assembled from docetaxel and methoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) block copolymers are delivered locally via fibrin glue injection. Results from an animal tumor model established by subcutaneous injection of CT26 colon cancer cells into Balb/c mice showed that the combination therapy of oral Apa liposomes with intratumoral injection of fibrin glue-delivered docetaxel micelles exhibited stronger antitumor activity compared to intratumoral injection of fibrin glue-delivered docetaxel micelles alone. This combined treatment promoted tumor cell apoptosis, inhibited proliferation, and reduced angiogenesis in tumor cells.

4.Hydrogels

Hydrogels are excellent drug controlled-release carriers, comprising synthetic or natural polymeric materials that form a three-dimensional network structure through physical or chemical crosslinking. When swollen in water, they form a gel that contains a large amount of water and can encapsulate drugs, exhibiting good biocompatibility. To evaluate the efficacy of Apa-loaded gadolinium-PEG hydrogels for intratumoral injection in treating liver cancer, a mouse subcutaneous tumor model was established by inoculating human hepatoma HepG2 cells into nude mice. The therapeutic effects were assessed using magnetic resonance imaging (MRI), histomorphology, and immunohistochemistry. The results showed that compared to the Apa-alone group and the unloaded gadolinium-PEG hydrogel group, the Apa-loaded gadolinium-PEG hydrogel group exhibited a larger area of necrotic tumor tissue, reduced expression levels of CD34 transmembrane glycoprotein and VEGFR-2, and significantly decreased mean optical density and microvessel density of VEGFR-2. These findings indicate that gadolinium-PEG hydrogels can enhance the efficacy of Apa in treating liver cancer.

5. Ultrafine Fibers

Ultrafine fibers prepared through electrostatic spinning technology possess characteristics such as small diameter and large specific surface area, making them a novel drug controlled-release carrier that can increase the dissolution rate of drugs in water and enhance their bioavailability. Researchers have developed a programmed drug release ultrafine fiber (DOX-PM+AP@F) implantable drug delivery device co-loaded with DOX micelles and Apa, using polylactic acid (PLA) as the matrix material and a microfluidic electrostatic spinning technique. The DOX-loaded micelle scaffold is composed of PEG-PCL block copolymers modified with 3-aminophenylboronic acid (PBA), where an aqueous solution of DOX micelles and free DOX in glycerol serves as the aqueous phase, and a 30% PLA dimethyl carbonate (DMC) solution containing Apa serves as the oil phase. After electrostatic spinning, the DOX micelles and free DOX are encapsulated within the cavities inside the ultrafine fibers, while Apa is uniformly dispersed in the PLA matrix. This method achieves encapsulation efficiencies of both drugs in the ultrafine fibers up to 99%. The ultrafine fibers enable programmed drug release during degradation, with rapid release of DOX micelles followed by slow release of Apa. The sustained release of Apa can continuously inhibit the P-glycoprotein drug efflux pump in MCF-7/ADR drug-resistant tumor cells, thereby increasing the accumulation of DOX within the cells. The DOX-PM+AP@F drug delivery device demonstrates excellent in vivo anti-tumor MDR effects. When DOX-PM+AP@F was implanted near the tumor site in MCF-7/ADR tumor-bearing mice, the tumor volume in the DOX-PM+AP@F group was approximately 400.3 mm3 after 21 days, compared to approximately 1070 mm3 in the mice treated with DOX-loaded fibers alone. Furthermore, on day 40 post-treatment, the survival rate of tumor-bearing mice in the DOX-PM+AP@F group exceeded 80%, significantly higher than that of the DOX-loaded fiber group. Western blotting results indicated that DOX-PM+AP@F promoted tumor cell apoptosis by upregulating the expression of the pro-apoptotic factor Bax, downregulating the anti-apoptotic factor Bcl-2, and enhancing the activity of caspase-3/9.

6.Lipid Nanobubbles

Lipid nanobubbles are drug carriers consisting of an inert gas core and a phospholipid shell, capable of loading drugs through electrostatic adsorption, intra-bubble encapsulation, and non-covalent biotin-avidin binding. Among these methods, intra-bubble encapsulation is relatively stable and offers higher drug loading and encapsulation efficiency. Researchers have developed Apa-loaded lipid nanobubbles that are targeted with glypican-3 (GPC3), a protein overexpressed in liver cancer. Apa is encapsulated within the interlayer between the phospholipid layer and the perfluoropropane inert gas core, achieving a maximum encapsulation efficiency of 68%. The targeting factor GPC3 is attached to the surface of the lipid nanobubbles via biotin-avidin interaction, significantly enhancing their ability to adhere to human hepatoma HepG2 cells. In vitro cellular experiments revealed that the combination of GPC3-targeted Apa-loaded lipid nanobubbles and ultrasound significantly enhanced the inhibitory effect of Apa on tumor cell proliferation and arrested more tumor cells in the G1 phase of the cell cycle.

Current research hotspots in Apa's novel drug delivery systems encompass nanoparticles, micelles, liposomes, hydrogels, ultrafine fibers, and lipid nanobubbles. These innovative delivery systems all enhance Apa's water solubility and drug concentration at the disease site, significantly boosting its efficacy in inhibiting tumor growth, reversing multidrug resistance (MDR) in tumor cells, and contributing to reduced drug toxicity. However, much of the research on these novel Apa delivery systems remains at the fundamental level, using cell and animal models. Transitioning these systems into clinical applications presents numerous challenges that need to be addressed. Consequently, scholars must continue to prioritize quality control and safety evaluation of these novel delivery systems. The ongoing pursuit of safer and more effective Apa formulations remains a critical direction for future research and development.

Reference Materials

Chen Jiarong, Xie Li, Zhao Hongjian, Hu Xin, Liu Rong. "Research Progress on Novel Drug Delivery Systems for Apatinib." Chinese Pharmacy, 2020, 31(12): 1528-1532.

Sun Peipei, Zhang Long, Zhang Tai, et al. "Efficacy Analysis of Single-Agent Apatinib in the Treatment of Advanced Colorectal Cancer Patients with Failure of Second-Line or Above Chemotherapy." Journal of Clinical Oncology, 2017, 22(7): 646-649.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.