V. Palanirajan, M. Abdelmahmoud, A. Maki, S-C Cheah
Keywords: cancer, everolimus, cyclodextrin, Inclusive complex, capsules
Summary:In this research project, we developed the enteric capsules filled with a new class of potential anticancer complex designed by molecular modelling tasks and silico analyzing techniques. This would be utilized to improve the efficacy of everolimus to treat colorectal cancer (CRC). The CRC is the third most diagnosed malignancy and the fourth leading cause of metastatic CRC (mCRC) deaths in the world, and it is to increase in intensity by 2.2 million new cases and 1.1 million cancer deaths by 2030.(1) Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), showed efficacy in patients with mCRC cancers in Phase I trials. Further, the Phase II studies had concluded that everolimus in combination with other targeted agents molecularly confirmed the dysregulation of the PI3K/Akt/mTOR pathway. (2) In this project, everolimus nanocomposite were prepared by using FDA approved excipients and drugs such as recombinant human keratinocyte growth factor (rHuKGF), everolimus, cyclodextrin and lactose. Our initial molecular modelling and in silico studies revealed that rHuKGF molecules binds to the FGFR2b (1NUN, RCSB PDB) receptor and inward human colon carcinoma cell line (Caco-2) cells, cyclodextrin molecules bind to fibroblast growth factor (FGF), inhibiting FGF oligomerization while the everolimus goes inside the cells and acts as mTOR inhibitor. Based on this preliminary investigation, the rHuKGF incorporated everolimus:cyclodextrin inclusive complex nanocomposites (E-Nps) were prepared by common solvent evaporation and lyophilization method. The prepared E-Nps were tested by using RTCA xCELLigence technology and the results revealed that when the Caco-2 are treated with E-Nps the antiproliferative, effect of the mTOR inhibitor everolimus has dramatically improved. (3) Further, the E-Nps was mixed with lactose (diluents) and filled in the enteric capsules. The in-vitro disintegration and dissolution studies were performed to evaluate the release of everolimus in a buffer solution having pH of the small intestine. The disintegration studies revealed that enteric coated capsules disintegrate fast in above pH 5.5 solutions. In-vitro release study showed the ability of enteric capsules to prevent the release of everolimus in pH 1.2 and allow it to release in pH higher than 5.5. Based on this report, prepared enteric capsules containing E-Nps can be effectively used to treat the mCRC patients. Funding This project (Ref: FRGS/2/2014/SKK02/UCSI/02/1) is supported by Department of Higher Education, Ministry of Education Malaysia, under the Fundamental Research Grant Scheme (FRGS) Malaysia. Reference 1. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66(4):683-91. 2. Ng K, Tabernero J, Hwang J, Bajetta E, Sharma S, Del Prete SA, et al. Phase II study of everolimus in patients with metastatic colorectal adenocarcinoma previously treated with bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens. Clinical cancer research : an official journal of the American Association for Cancer Research. 2013;19(14):3987-95. 3. Maki MAA, Kumar PV, Cheah S-C, Siew Wei Y, Al-Nema M, Bayazeid O, et al. Molecular Modeling-Based Delivery System Enhances Everolimus-Induced Apoptosis in Caco-2 Cells. ACS Omega. 2019;4(5):8767-77.