Targeted drug delivery to the colon has attracted the attention of many researchers owing to its tremendous advantages over systemic drug administration, including increased drug potency and efficacy and reduced adverse drug reactions [
1,
2]. Colonic drug delivery systems have been used to treat a plethora of bowel diseases encompassing colorectal carcinoma, ulcerative colitis, diverticulitis, Crohn’s disease, and irritable bowel syndrome [
3,
4,
5]. Colon-specific drug delivery has long been used to enhance therapeutic effectiveness by reducing unwanted absorption in other regions of the gastrointestinal tract, guaranteeing that the whole drug dose is specifically delivered to the site of interest in the colon [
6,
7]. Most colon-targeted drug delivery systems are either responsive to the pH of the colon or to enzymes produced by intestinal microbiota [
8,
9,
10]. For instance, metronidazole, which is used for treatment of bowel infection, was formulated in a tablet containing pH-sensitive polymers consisting of Eudragit E, Eudragit L, and alginate in order to delay the release of metronidazole and achieve a once daily formulation [
11]. In this study, metronidazole release was sustained for 12 h; however, a percentage of the drug was released in acidic medium (simulated gastric fluid). Moreover, a combined time-dependent and pH-sensitive multilayer system was composed of an outer layer consisting of a pH-sensitive polymer that degrades at pH greater than 5, a middle layer containing swellable HPMC polymer, and an inner layer composed of enteric coating material [
12]. The system has shown colon targeting capability, as demonstrated by in vivo rat experiments. Additionally, chitosan nanoparticles have been loaded with the immunosuppressive drug tacrolimus for inflammatory bowel disease targeting [
13]. The nanoparticles were coated with a pH-sensitive Eudragit S 100 polymer and hyaluronic acid as a targeting ligand for CD44 receptors expressed by leukocytes at the site of inflamed intestine, and the results showed significant reduction in the inflammatory mediators produced by macrophages. Colon-specific drug delivery has also been utilized for the treatment of colorectal carcinoma diseases by specifically delivering chemotherapeutic agents to the colon using polymeric carriers [
14]. For example, alginate microparticles were coated with Eudragit S 100 for colon-targeted delivery of 5-fluorouracil (FU), which is a chemotherapeutic agent used for treatment of colorectal cancer [
15]. The release studies have shown almost zero drug release in the first 4 h in simulated gastric fluid; additionally, the release of the drug was sustained for 20 h, indicating the suitability of this system for colon-specific delivery of anti-cancer agents. Several drug chemical modification techniques have been employed to specifically deliver drugs to the colon, such as using prodrugs, which are pharmacologically inactive substances; however, they are activated when they reach the colon [
16,
17]. For instance, azo-based compounds composed of azo groups covalently attached to anti-inflammatory drugs used for irritable bowel diseases have been utilized for colon targeting of these drugs, where the resultant prodrugs become specifically active in the colon due to the reducing effect of azoreductase produced by gut microbiota cleaving the bond and release the drug to the site of interest [
18]. Nagpal et al. synthesized an azo-based prodrug of 5-amino salicylic acid by chemically conjugating
l-histidine to 5-amino salicylic acid via azo linkage, where the drug release was minimal in simulated gastric fluid and only 14 percent of the drug released in simulated intestinal fluid without the bacterial azoreductase. However, more than 85 drugs were released in a medium consisting of rat faeces, which contains intestinal microbiota, indicating azoreductase-responsive drug release in the colon [
19]. Another example is conjugating
l-alanine to 5-salicylic acid for colon targeting, and the results demonstrated that the prodrug was specifically in the gut microbiota of the rabbit via oral and intercaecal routes, indicating successful colon-specific delivery [
20]. Moreover, colonic drug delivery is not only used for localized treatment of gut diseases, but also for oral delivery of protein therapeutics, which are acid labile and enzyme degradable, to protect these therapeutics from the harsh gastrointestinal conditions preceding the absorption process [
21]. For example, uricase, an enzyme responsible for breaking down urate crystals accumulated in body joints, was encapsulated into alginate/pectin microparticles for the treatment of gout [
22]. These microparticles were coated with a pH-responsive polymer (Eudragit S-100) to protect the protein (uricase) from degradation by gastric enzymes, where this system displayed enhanced colonic absorption when the drug was combined with bile salts. It has also been reported that aloe vera (
A. vera) gel was employed for insulin delivery to the colon to prevent its gastrointestinal degradation [
23]. In this study, ex vivo experiments demonstrated that insulin absorption was maximally promoted at the colon region compared to the ilium and jejunum, indicating effective colon targeting using
A. vera. Moreover, recent advances have focused on oral delivery of human insulin using mucus penetrating PLGA-nanoparticles, which successfully protect insulin from the acidic environment of simulated gastric fluid and enhance its absorption across intestinal epithelial cells [
24]. Most previous studies have demonstrated the importance of colon-specific drug delivery systems; however, they involved multi-step processes for the synthesis of drug delivery carriers. Therefore, this research aims to design a new one-pot formulation composed of methacrylate derivatives for the delivery of FU in order to treat colorectal carcinoma. This polymer has the capability to retain a drug and prolong its release to enable site-specific drug delivery to the colon only. The synthetic procedure can also be readily scaled up for continuous manufacturing.