Abstract
Antimitotics are important anticancer agents and include the natural alkaloid prodrug colchicine (COL). However, a major challenge of using COL as an anticancer drug is its cytotoxicity. We developed a novel drug delivery system (DDS) for COL using mesoporous silica nanoparticles (MSNs). The MSNs were functionalized with phosphonate groups, loaded with COL, and coated with folic acid chitosan-glycine complex. The resulting nanoformulation, called MSNsPCOL/CG-FA, was tested for action against cancer and normal cell lines. The anticancer effect was highly enhanced for MSNsPCOL/CG-FA compared to COL. In the case of HCT116 cells, 100% inhibition was achieved. The efficiency of MSNsPCOL/CG-FA ranked in this order: HCT116 (colon cancer) > HepG2 (liver cancer) > PC3 (prostate cancer). MSNsPCOL/CG-FA exhibited low cytotoxicity (4%) compared to COL (~60%) in BJ1 normal cells. The mechanism of action was studied in detail for HCT116 cells and found to be primarily intrinsic apoptosis caused by an enhanced antimitotic effect. Furthermore, a contribution of genetic regulation (metastasis-associated lung adenocarcinoma transcript 1 (MALAT 1), and microRNA (mir-205)) and immunotherapy effects (angiopoietin-2 (Ang-2 protein) and programmed cell death protein 1 (PD-1) was found. Therefore, this study shows enhanced anticancer effects and reduced cytotoxicity of COL with targeted delivery compared to free COL and is a novel method of developing cancer immunotherapy using a low-cost small-molecule natural prodrug.
Highlights
Colchicine (COL) is a natural alkaloid compound derived mainly from the medicinal plantColchicum automnale and has been used in the clinic for treating gout and familial Mediterranean fever.COL has shown some benefit in primary biliary cirrhosis [1], amyloidosis [2], and condyloma acuminate treatments [3]
We propose that the action for MSNsPCOL/CG-folic acid (FA) is the release of COL
The drug delivery systems (DDSs) was fabricated by loading COL into spherical mesoporous silica nanoparticles and their subsequent modification with phosphonate groups
Summary
Colchicine (COL) is a natural alkaloid compound derived mainly from the medicinal plantColchicum automnale and has been used in the clinic for treating gout and familial Mediterranean fever.COL has shown some benefit in primary biliary cirrhosis [1], amyloidosis [2], and condyloma acuminate treatments [3]. COL is an antimitotic drug, which interferes strongly with cell division by affecting microtubule assembly and disassembly during mitosis. Most of the antimitotic drugs are toxic anticancer agents, which preferentially kill cancer cells, as they divide much faster than normal cells. The major challenge for COL is its toxicity, which causes severe side effects to patients [4]. Despite COL not yet being used clinically for cancer therapy because of its toxicity to normal cells, it is used as a lead compound in generating potent anticancer agents [5,6,7,8,9]. To reduce the side effects of COL on normal cells, many types of research have included analogs of COL [10,11] and combination treatments with other drugs [12]. Gupta and Dudani [13]
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