Cetuximab Conjugated with Octreotide and Entrapped Calcium Alginate-beads for Targeting Somatostatin Receptors

Abstract

There is a need to formulate oral cetuximab (CTX) for targeting colorectal cancer, which is reported to express somatostatin receptors (SSTRs). Therefore, coating CTX with a somatostatin analogue such as octreotide (OCT) is beneficial. Alginate was used to coat CTX to facilitate delivery to the gastrointestinal tract (GIT). This study aimed to deliver CTX conjugated with OCT in the form of microparticles as a GIT-targeted SSTR therapy. Both CTX and OCT were conjugated using a solvent evaporation method and the conjugated CTX-OCT was then loaded onto Ca-alginate-beads (CTX-OCT-Alg), which were characterized for drug interactions using differential scanning calorimetry (DSC), and Fourier transform infrared spectra (FTIR). Moreover, the morphology of formulated beads was examined using a scanning electron microscope (SEM). The drug content and release profile were studied using UV spectroscopy. Finally, in vitro cytotoxicity of all compounds was evaluated. The results showed homogenous conjugated CTX-OCT with a diameter of 0.4 mm. DSC showed a delay in the OCT peak that appeared after 200 °C due to small polymer interaction that shifted the OCT peak. Moreover, FTIR showed no prominent interaction. SEM showed clear empty cavities in the plain Ca-alginate-beads, while CTX-OCT-Alg showed occupied beads without cavities. CTX-OCT-Alg had a negligible release in 0.1 N HCl, while the CTX-OCT was completely released after 300 min in phosphate buffer pH 7.4. All formulations showed good antiproliferative activity compared with free drugs. The formulated CTX-OCT-Alg are a promising platform for targeting colorectal cancer through Git.Oral dosage forms of medications are generally a convenient dosage form for drug delivery 1,2 . However, one of the main challenges in drug delivery is to overcome gastric barriers and preventing the drug release in the stomach 3 . There was a huge increase in the development of orally delivered anti-cancer agents in the past 10 years, as a quarter of all available anti-cancer drugs are now administered orally 4 . Colorectal cancer is one of the most common forms of malignancy and the fourth most common contributor to cancer mortalities 5 . Moreover, targeting specific cells in cancer therapy provides an advantageous way to treat cancer directly 6-10 . For example, the release of drug in the colon and drug particles can be driven by octreotide (OCT) and bind to somatostatin receptors (SSTRs), which are a component of ligand-mediated targeting 8 . The inhibition effect of somatostatin (SST) analogues on tumor cells is one effective approach to cancer therapy. Moreover, SST and its analogues have open Scientific RepoRtS | (2020) 10:4736 | https://doi.org/10.1038/s41598-020-61605-y www.nature.com/scientificreports www.nature.com/scientificreports/ shown proliferative inhibition of colon cancer cell lines 11 . There are five subtypes of SSTRs expressed in colorectal cancer, and SSTR1 is the most prevalent compared to the others 12 .Cetuximab (CTX) is a recombinant monoclonal antibody drug used in the...

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