Targeted Nano-Drug Delivery of Colchicine against Colon Cancer Cells by Means of Mesoporous Silica Nanoparticles

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.

<p>Virucidal Action Against Avian Influenza H5N1 Virus and Immunomodulatory Effects of Nanoformulations Consisting of Mesoporous Silica Nanoparticles Loaded with Natural Prodrugs</p>

“…MSNs have been studied as a versatile drug delivery vehicle in in vitro and in vivo studies for various diseases. [29][30][31][32][33] They can be administered via injection (intravenous, hypodermic, or intramuscular) or orally and are eliminated through the urine and feces. 34 MSNs have been used to enhance the solubility, targeting ability, and therapeutic activity with a combination of two or more drugs for dual therapeutic efficiency.…”

Role of Natural Bioactive Compounds in the Rise and Fall of Cancers

“…The ethyl acetate fraction of the crude extract of Streptomyces sp. MUM256, isolated from mangrove soil in Malaysia, and the cyclic dipeptides contained whose ability to induce cell cycle arrest and apoptosis was demonstrated by Tan et al [23] in colon cancer cells; -Manoalide, an antibiotic sesterterpenoid isolated from the marine sponge Luffariella variabilis, which preferentially inhibits the proliferation of oral cancer cells inducing apoptosis and DNA damages via oxidative stresses, such as intracellular ROS and MitoSOX/MitoMP [24]; -λ-carrageenan, a family of linear sulfated polysaccharides, proven to enhance the effect of radiotherapy by suppressing the survival and invasiveness of different cancer cell lines in vitro and in vivo through the Rac GTPase-activating protein 1 pathway [25]; -Ethanol, which was found to trigger a pro-survival autophagic response following the induction of oxidative and endoplasmic reticulum stress in colon cancer cells, and the activation of Nrf2 and HO-1 also leading to the acquisition of a more aggressive phenotype [26]; -Colchicine, an alkaloid present in the medicinal plant Colchicum autumnale, whose enhanced anticancer effects and reduced cytotoxicity on colon cancer cells when delivered in the nanoformulated form was reported by AbouAitah et al [27].…”

“…The other articles and reviews addressed further cancer-related issues relevant to types of compounds of a different nature, specifically: The methanolic extract of Malva pseudolavatera leaves, which showed a promising selective anti-proliferative and pro-apoptotic effect on acute myeloid leukemia cell lines, determining PARP cleavage, cytochrome-c release, Bax/Bcl-2 ratio increase and ROS overproduction [ 19 ]; Eicosapentaenoic acid, an ω-3 polyunsaturated fatty acid, which played a protective role, both alone and in combination with angiotensin-converting enzyme inhibitors, in attenuating adipocyte-induced proinflammatory cytokine expression and the migration of breast cancer cells in an in vitro model of obesity-induced breast cancer [ 20 ]; Fucoidan, a sulphated polysaccharide derived from brown seaweed, whose combination with gemcitabine determined an enhanced pro-apoptotic and cell cycle-inhibitory activity on selected uterine carcinosarcoma and stromal sarcoma cell lines [ 21 ]; Nicotin, whose mechanisms underlying the promotion of melanoma cell proliferation and migration mediated through α9-nAChR-initiated carcinogenic signaling and PD-L1 expression were reported by Nguyen et al [ 22 ]; The ethyl acetate fraction of the crude extract of Streptomyces sp. MUM256, isolated from mangrove soil in Malaysia, and the cyclic dipeptides contained whose ability to induce cell cycle arrest and apoptosis was demonstrated by Tan et al [ 23 ] in colon cancer cells; Manoalide, an antibiotic sesterterpenoid isolated from the marine sponge Luffariella variabilis , which preferentially inhibits the proliferation of oral cancer cells inducing apoptosis and DNA damages via oxidative stresses, such as intracellular ROS and MitoSOX/MitoMP [ 24 ]; λ-carrageenan, a family of linear sulfated polysaccharides, proven to enhance the effect of radiotherapy by suppressing the survival and invasiveness of different cancer cell lines in vitro and in vivo through the Rac GTPase-activating protein 1 pathway [ 25 ]; Ethanol, which was found to trigger a pro-survival autophagic response following the induction of oxidative and endoplasmic reticulum stress in colon cancer cells, and the activation of Nrf2 and HO-1 also leading to the acquisition of a more aggressive phenotype [ 26 ]; Colchicine, an alkaloid present in the medicinal plant Colchicum autumnale , whose enhanced anticancer effects and reduced cytotoxicity on colon cancer cells when delivered in the nanoformulated form was reported by AbouAitah et al [ 27 ]. …”

Friend or Foe? An Unrecognized Role of Uric Acid in Cancer Development and the Potential Anticancer Effects of Uric Acid-lowering Drugs

“…A study has also shown that colchicine induces cell death by apoptosis, and inhibits the invasion and migration of cancer cells by reducing extracellular matrix (ECM) degradation through downregulating MMP9 and the urokinase-type activator system 70 . Actually, in some studies, colchicine in the form of nanoparticles has been used as an anticancer drug to inhibit colon and liver cancer cells 71 , 72 .…”