Regorafenib loaded self-assembled lipid-based nanocarrier for colorectal cancer treatment via lymphatic absorption

Oral chemotherapy can improve life quality of patients. Approximately 70 oral small-molecule protein kinase inhibitors, including regorafenib, lapatinib, and sorafenib, have been used for oral chemotherapy in the past few decades [1]; however, the chemotherapeutic effect of these drugs is still limited by poor bioavailability due to their poor water solubility, poor epithelial permeability, pre-systemic metabolism and undesirable biodistribution of the drug [2]. Advanced formulations are needed to optimize these pharmacokinetic properties and improve therapeutic efficacy [3].

Colorectal cancer is considered to be the most common malignant cancer, causing nearly 900 000 deaths annually [4]. The prognosis of colorectal cancer (CRC) is unsatisfactory, especially for patients with metastatic lesions [5]. Regorafenib (Stivarga®, REG) is the first approved small-molecule multi-kinase inhibitor for the treatment of metastatic colorectal cancer (MCC) and metastatic gastrointestinal stromal tumors (GIST). REG blocks the activity of protein kinases involved in the regulation of tumor angiogenesis, oncogenesis, and the tumor microenvironment [6], [7]. According to the Biopharmaceutical Classification System (BCS), REG can be classified as a BCS IV drug with the low solubility (< 5 μg/mL), poor biomembrane permeability (apparent permeability coefficient (Papp) < 5.0×10-6 cm/s) [8], [9]. The first-pass metabolism, poor in vivo circulation and biodistribution also compromise the therapeutic outcome of REG and induce potential side effects, such as hepatic toxicity [10], [11]. The oral bioavailability of commercial tablets based on solid dispersion technology is approximately 10% and is strongly influenced by food due to incomplete intestinal absorption, although pharmaceutical salt and polymorphic hydrate have also been used to improve oral absorption [12]. Therefore, the pharmacokinetic properties of REG need to be optimized to achieve more effective therapeutic effects.

Oral absorption of anticancer drugs through the intestinal lymphatic system has advantages over oral absorption through the portal blood [13]. Drugs can be transported through the intestinal lymphatic system to the circulation without first being metabolized by the liver, resulting in improved bioavailability [14]. In addition, intestinal lymphatic transport is more effective for chemotherapeutics because lymphatic drainage is the primary route for the metastasis of tumor cells [15], [16], [17], [18].

In recent years, there has been growing interest in drug delivery using self-assembled lipid-based nanoparticles, which consist of a combination of lipids with cholesterol and safe surfactants [19]. These lipid-based nanoparticles can either mediate the transfer of lipids and loaded drugs from the intestine to the tissues for lipid storage and metabolism and the tissues that express lipoprotein receptors [20]. The lipid nanoparticles can also accumulate in specific cell types by binding to receptors such as low-density lipoproteins. Notably, these receptors are overexpressed in cancer cells, so the use of lipid drug carriers facilitates drug delivery to the cancer cells and improves chemotherapy efficacy [21], [22].

The chylomicron pathway is the primary pathway for absorption of lipids from the intestine into the lymphatic system. Chylomicrons are lipoprotein particles synthesized by enterocyte and composed of triglycerides, phospholipids, cholesterol, and apolipoproteins (mainly apolipoprotein B-48) [23]. The synthesized chylomicrons are transported to the intestinal lymph, and then enter the systemic blood circulation through the thoracic duct, thereby avoiding the first metabolism by the liver. Lipophilic glyceride-rich chylomicrons allow lipophilic drugs to be incorporated into and transported along with chylomicrons into the lymphatic system. However, only a few highly lipophilic drugs (log P > 5) with a solubility in long-chain triglycerides greater than 50 mg/g are expected to be absorbed via the chylomicron pathway, so partitioning of the drug to the synthesized chylomicrons is a limiting step for the drug absorption through the intestinal lymphatic system [24], [25].

In this study, to improve oral absorption and the anti-colorectal cancer efficacy of REG through lymphatic absorption, we developed a self-assembled lipid-based nanocarrier (SALN) containing REG. The SALN consists of phospholipids (Lipoid E80), cholesterol, glycerol tributyrate, diethylene glycol monoethyl ether, and Solutol HS-15. REG is soluble in the mixture of GT and MCT, and both excipients are commonly used in lipid-based formulations for poorly soluble drugs. The phospholipid and cholesterol could stabilize the drug in the oil phase and improve the drug loading capacity and nanoparticle formation [26], [27]. The amphiphilic polymer Solutol HS-15 was an excellent stabilizer for SALN, which could increase the drug loading capacity, and improve the drug permeability across cell layers [28], [29]. These ingredients could be self-assembled as nanocarriers that mimic the post-digestive micelles formed by the action of pancreatic enzymes in the intestine [30], [31]. Studies have shown that the post-digestive micelles stimulate the secretion of triglyceride-enriched lipoproteins which play an important role in the assembly and secretion of chylomicrons [31], [32], [33]. We hypothesized that the SALN would be suitable for loading hydrophobic drugs, ready for internalization by enterocytes, and could ride the chylomicron transport pathway in the enterocyte to facilitate intestinal lymphatic absorption of the drug. We expected that the SALN could improve the bioavailability of REG and optimize the pharmacokinetics to achieve a more effective therapeutic response against colorectal cancer.

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