Cyclodextrin-Based Host-Guest Complexes Loaded with Regorafenib for Colorectal Cancer Treatment

Cyclodextrins (CDs) are cyclic oligosaccharides composed of glucose units connected via α-1,4-glycosidic bonds. Their unique structure, which forms a hydrophobic central cavity and hydrophilic exterior, allows them to form host-guest complexes with various molecules.

Regorafenib is a multi-target kinase inhibitor approved for the treatment of metastatic colorectal cancer (mCRC) and other malignancies. It targets several key kinases involved in angiogenesis (VEGFR), oncogenic signaling (RAF, RET), and tumor microenvironment regulation. Despite its effectiveness, regorafenib faces significant challenges in clinical application due to its poor aqueous solubility and low bioavailability, which hinder its therapeutic efficacy.

To address these limitations, researchers have explored various formulations that improve regorafenib's pharmacokinetic properties. Among these, cyclodextrin-based formulations have emerged as a promising solution, capable of enhancing both the solubility and stability of regorafenib ^[1].

In Vitro and In Vivo Efficacy of Cyclodextrin-Loaded Regorafenib

• In Vitro Results

In vitro studies have demonstrated that cyclodextrin-loaded regorafenib complexes exhibit enhanced cytotoxicity against colorectal cancer cells. For instance, cell proliferation assays using CT26 CRC cell lines show that the complexes significantly inhibit cell growth compared to free regorafenib. The increased solubility and stability of the drug in the complex contribute to higher intracellular drug concentrations, thereby increasing the drug's efficacy.

Additionally, flow cytometry and immunohistochemical analyses confirm that these complexes induce apoptosis in CRC cells by modulating key signaling pathways, including the P38 MAPK pathway, which is crucial for cell survival and inflammation.

• In Vivo Results

In vivo studies using CT26 xenograft mouse models further support the therapeutic potential of cyclodextrin-regorafenib complexes. Treatment with the complexes results in significant tumor growth inhibition compared to free regorafenib, suggesting that the encapsulation enhances the drug's delivery to the tumor site. Key findings include:

• Reduced tumor size
• Enhanced tumor oxygenation
• Increased Drug Accumulation at Tumor Sites

Mechanistic Insights

Mechanistic studies suggest that the enhanced anti-tumor effects of the cyclodextrin-regorafenib complex are mediated through multiple pathways, including the inhibition of angiogenesis and the activation of tumor-associated macrophages (TAMs). By targeting the P38 MAPK signaling axis in TAMs, the complex promotes an anti-inflammatory response, which contributes to its overall therapeutic effect.

Clinical Implications and Future Directions

The promising in vitro and in vivo results indicate that cyclodextrin-regorafenib complexes offer a novel and effective strategy for colorectal cancer treatment. By improving the solubility, stability, and tumor-targeting properties of regorafenib, these complexes overcome the drug's limitations, potentially improving patient outcomes in clinical settings.

Future research should focus on optimizing the formulation of cyclodextrin-regorafenib complexes for human use, including the development of scalable production methods and long-term stability studies. Additionally, clinical trials are needed to evaluate the safety and efficacy of these complexes in cancer patients, particularly in combination with other targeted therapies or immunotherapies.

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