Abstract
BackgroundThere is an obvious correlation between ulcerative colitis and colorectal cancer, and the risk of colorectal cancer in patients with ulcerative colitis is increasing. Therefore, the combination therapy of anti-inflammatory and anti-tumor drugs may show promising to inhibit colon cancer. 5-aminosalicylic acid (5-ASA) with anti-inflammatory function is effective for maintaining remission in patients with ulcerative colitis and may also reduce colorectal cancer risk. Histone deacetylase (HDAC) plays an essential role in the progression of colon cancer. Butyric acid (BA) is a kind of HDAC inhibitor and thus shows tumor suppression to colon cancer. However, the volatile and corrosive nature of BA presents challenges in practical application. In addition, its clinical application is limited due to its non-targeting ability and low bioavailability. We aimed to synthesize a novel dual-prodrug of 5-ASA and BA, referred as BBA, to synergistically inhibit colon cancer. Further, based on the fact that folate receptor (FR) is over-expressed in most solid tumors and it has been identified to be a cancer stem cell surface marker in colon cancer, we took folate as the targeting ligand and used carboxymethyl-β-cyclodextrin (CM-β-CD) to carry BBA and thus prepared a novel inclusion complex of BBA/FA-PEG-CM-β-CD.ResultsIt was found that BBA/FA-PEG-CM-β-CD showed significant inhibition in cell proliferation against colon cancer cells SW620. It showed a pro-longed in vivo circulation and mainly accumulated in tumor tissue. More importantly, BBA/FA-PEG-CM-β-CD gave great tumor suppression effect against nude mice bearing SW620 xenografts.ConclusionsTherefore, BBA/FA-PEG-CM-β-CD may have clinical potential in colon cancer therapy.Graphical
Highlights
Colon cancer is a common malignant tumor of the digestive tract that tends to occur at the junction of the rectum and sigmoid colon
Peaks due to vibrations of the conjugated overlapped with the hydroxyl group (O–H) bond and C = O bond was detected around 3416 cm−1 and 1599 cm−1 in the spectra of CM-β-CD (d). These results further proved that folic acid (FA)-Polyethylene glycol (PEG)-CM-β-CD was successfully synthesized
No significant difference in the average body weight was observed among the treatment groups except 5-FU, in which the tested mice treated with 5-FU significantly decreased by 4.46% (P < 0.05). These results demonstrated that butylaminyl benzoic acid (BBA)/FA-PEGCM-β-CD showed no toxicity to normal mice
Summary
Colon cancer is a common malignant tumor of the digestive tract that tends to occur at the junction of the rectum and sigmoid colon. The treatment of colon cancer mainly includes surgery and drug treatment [5, 6]. Studies have shown an obvious correlation between ulcerative colitis and colorectal cancer, and the risk of colorectal cancer in patients with ulcerative colitis is increasing [13, 14]. We took the combination therapy of anti-tumor drug and anti-inflammatory drug to inhibit synergistically colon cancer and improve the therapeutic efficacy [16]. There is an obvious correlation between ulcerative colitis and colorectal cancer, and the risk of colorectal cancer in patients with ulcerative colitis is increasing. The combination therapy of anti-inflammatory and anti-tumor drugs may show promising to inhibit colon cancer. 5-aminosalicylic acid (5-ASA) with anti-inflammatory function is effective for maintaining remission in patients with ulcerative colitis and may reduce colorectal cancer risk. Based on the fact that folate receptor (FR) is over-expressed in most solid tumors and it has been identified to be a cancer stem cell surface marker in colon cancer, we took folate as the targeting ligand and used carboxymethyl-β-cyclodextrin (CM-β-CD) to carry BBA and prepared a novel inclusion complex of BBA/FA-PEG-CM-β-CD
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