pectins and Colorectal-Neoplasms

Increasing incidents of colorectal cancer have shifted researchers' attention to the production and improvement of anti-cancer drugs by the scientific investigation of vast pool of synthetic, biological and natural products. Thymoquinone and thymohydroquinone are considered the ideal compounds for the cancer therapy as they are economically and environmental friendly and have less toxicity level to the survival and diseased model up to increased dosage level. For colorectal cancer, researches are shifting towards the oral drug delivery instead of injection, as administering drugs through oral route shows maximum absorption of drugs, improves patient life quality and is cost-effective. Naturally occurring polysaccharides as oral drug carriers, such as pectin, have the ability to break down completely in colon, making it suitable for targeted drug delivery against cancer cells. Pectin with polymeric base is an efficient nano drug carrier. The current study reviews the delivery of thymoquinone/thymohydroquinone through pectin nano carriers to treat colorectal cancer.

Topics: Administration, Oral; Antineoplastic Agents, Phytogenic; Benzoquinones; Colorectal Neoplasms; Drug Carriers; Humans; Hydrogen-Ion Concentration; Nanoparticles; Nigella sativa; Pectins; Phytotherapy; Thymol; Thymus Plant

Dietary fibre (DF) is widely considered to protect against cancer, especially colorectal cancer. However, a large prospective epidemiological study has shown no apparent effect of DF intake on the development of colorectal cancer. We suggest that this may be because the term DF represents a wide range of materials, some able to protect, but some able to enhance carcinogenesis. This is consistent with data from animal carcinogenesis experiments. Most of the DF in western diets is in the form of plant cell walls, but these vary in their composition and it is unlikely that all types are protective. The few data available indicate that plant cell walls containing suberin or lignin may be the most protective, although they are present in only small amounts in food plants. DFs are also added to foods. These include components obtained from plant cell walls, such as pectins, as well as soluble DFs from other sources. In general, animal carcinogenesis experiments indicate that soluble DFs do not protect and some may enhance carcinogenesis. Few human intervention studies have been done on DF or sources of DF, with the exception of wheat bran, a good source of DF, which has been shown to protect. Possible mechanisms whereby DF may enhance carcinogenesis are discussed. In addition to DFs, resistant starches and non-digestible oligosaccharides are added to foods; these, like DF, escape digestion in the small intestine. However, so far only a few animal carcinogenesis experiments have been reported using these materials, and no human intervention studies. We believe caution should be exercised in the addition of such materials to food.

Topics: Animals; Bile Acids and Salts; Cell Division; Cell Wall; Cellulose; Colorectal Neoplasms; Cytoskeleton; Diet; Dietary Fiber; Edible Grain; Female; Humans; Lignin; Lipids; Male; Membrane Lipids; Mice; Mice, Inbred BALB C; Neoplasms; Oligosaccharides; Pectins; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Rats, Wistar; Surveys and Questionnaires

Mucoadhesive drug delivery systems (DDS) may promote safer chemotherapy for colorectal cancer (CRC) by maximizing local drug distribution and residence time. Carbohydrate polymers, e.g. pectin (P) and chitosan (CS), are potential biomaterials for CRC-targeted DDS due to their gelling ability, mucoadhesive property, colonic digestibility, and anticancer activity. Polymer mucoadhesion is augmentable by thiolation, e.g. pectin to thiolated pectin (TP). Meanwhile, P-CS polyelectrolyte complex has been shown to improve structural stability. Herein, we fabricated, characterized, and evaluated 5-fluorouracil-loaded primary DDS combining TP and CS as a composite (TPCF) through triple crosslinking actions (calcium pectinate, polyelectrolyte complex, disulfide). Combination of these crosslinking yields superior mucoadhesion property relative to single- or dual-crosslinked counterparts, with comparable drug release profile and drug compatibility. PCF and TPCF exhibited targeted cytotoxicity towards HT29 CRC cells with milder cytotoxicity towards HEK293 normal cells. In conclusion, TP-CS composites are promising next-generation mucoadhesive and selectively cytotoxic biomaterials for CRC-targeted DDS.

Topics: Biocompatible Materials; Chitosan; Colorectal Neoplasms; Drug Delivery Systems; HEK293 Cells; Humans; Pectins; Polyelectrolytes

Hydrogels represent a key element in the development of in vitro tumor models, by mimicking the typical 3D tumor architecture in a physicochemical manner and allowing the study of tumor mechanisms. Here we developed a thermo-sensitive, natural polymer-based hydrogel, where chitosan and pectin were mixed and, after a weak base-induced chitosan gelation, a stable semi-Interpenetrating Polymer Network formed. This resulted thermo-responsive at 37 °C, injectable at room temperature, stable up to 6 weeks in vitro, permeable to small/medium-sized molecules (3 to 70 kDa) and suitable for cell-encapsulation. Tunable mechanical and permeability properties were obtained by varying the polymer content. Optimized formulations successfully supported the formation and growth of human colorectal cancer spheroids up to 44 days of culture. The spheroid dimension and density were influenced by the semi-IPN stiffness and permeability. These encouraging results would allow the implementation of faithful tumor models for the study and development of personalized oncological treatments.

Topics: Chitosan; Colorectal Neoplasms; HCT116 Cells; Humans; Hydrogels; Pectins

Topics: Animals; Antineoplastic Agents; Biological Availability; Cell Death; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Drug Carriers; Drug Liberation; Humans; Lipids; Male; Milk; Molecular Docking Simulation; Nanoparticles; Pectins; Rats; Rats, Wistar; Zebrafish

Large intestine cancer is one of the most relevant chronic diseases taking place at present. Despite therapies have evolved very positively, this pathology is still under deep investigation. One of the recent approaches is the prevention by natural compounds such as pectin. In this paper, we have assessed the impact of citrus pectin and modified citrus pectin on colorectal cancer in rats (Rattus norvegicus F344) to which azoxymethane and DSS were supplied. The lowest intake of food and body weight were detected in animals fed with citrus pectin, together with an increase in the caecum weight, probably due to the viscosity, water retention capacity and bulking properties of pectin. The most striking feature was that, neither citrus pectin nor modified citrus pectin gave rise to a tumorigenesis prevention. Moreover, in both, more than 50% of rats with cancer died, probably ascribed to a severe dysbiosis state in the gut, as shown by the metabolism and metagenomics studies carried out. This was related to a decrease of pH in caecum lumen and increase in acetate and lactic acid levels together with the absence of propionic and butyric acids. A relevant increase in Proteobacteria (Enterobacteriaceae) were thought to be one of the reasons for enteric infection that could have provoked the death of rats and the lack of cancer prevention. However, a reduction of blood glucose and triacylglycerides level and an increase of Bifidobacterium and Lactobacillaceae were found in animals that intake pectin, as compared to universal and modified citrus pectin feeding.

Topics: Acetates; Animals; Azoxymethane; Bifidobacterium; Blood Glucose; Body Weight; Butyrates; Carcinogenesis; Chromatography, High Pressure Liquid; Citrus; Colorectal Neoplasms; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Hydrogen-Ion Concentration; Lactic Acid; Lactobacillaceae; Male; Metagenomics; Pectins; Phylogeny; Propionates; Proteobacteria; Rats; Rats, Inbred F344; Triglycerides

The encapsulation of nanoparticles within microparticles designed for specific delivery to the colon is a relevant strategy to avoid premature degradation or release of nanoparticles during their passage through the stomach and upper gastrointestinal tract (GIT), allowing the targeted delivery of chemotherapeutics to the colon after oral administration. Here, we designed an oral multiparticulate system to achieve targeted release in the colon. In this sense, chitosan nanoparticles (CS NPs) encapsulated with 5-fluorouracil (5-FU) and incorporated into retrograded starch and pectin (RS/P) microparticles were developed and their in vivo distribution along the mouse GIT after oral administration was monitored using multispectral optical imaging. In vitro release studies revealed that the encapsulation of CS NPs into RS/P microparticles promoted greater control of 5-FU release rates, with a significant reduction (53%) in acid media that might replicate that found in the stomach following oral administration. The evaluation of the in vivo biodistribution of the CS NPs in mice showed a faster clearance in the distribution pattern along the mouse GIT, i.e., a shorter transit time of CS NPs compared to CS NPs-loaded RS/P microparticles. Additionally, CS NPs alone showed non-specific absorption into the blood-stream with associated kidney accumulation, while for the CS NPs-loaded RS/P microparticles no significant accumulation was observed in blood or major clearance organs. This suggests the specific degradability of RS/P by the colon microbiota appears to have been decisive in the higher protection of the CS NPs along the GIT until release in the colon, preventing unwanted absorption into the bloodstream and major organs following oral administration. Our findings represent a proof of concept for the use of RS/P microparticles as potential carriers for delivering drug-loaded nanoparticles to the colon and this work will contribute to the development of oral-systems for colorectal cancer therapy.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Chitosan; Colon; Colorectal Neoplasms; Drug Carriers; Drug Compounding; Drug Liberation; Female; Fluorouracil; Gastrointestinal Microbiome; Humans; Intestinal Absorption; Intestinal Mucosa; Mice; Models, Animal; Nanoparticles; Particle Size; Pectins; Proof of Concept Study; Starch; Tissue Distribution

The objective of this study was to investigate the in vitro cytotoxicity and in vivo anticancer efficacy of redox-responsive microbeads containing thiolated pectin-doxorubicin (DOX) conjugate. Oral microbeads were coated with an enteric polymer to protect the drug from release in the upper gastrointestinal (GI) tract and allow redox-triggered drug release in the colon. Morphology, particle size, drug content, and in vitro drug release behavior of the microbeads were characterized; in vitro cytotoxicity was tested on mouse colon carcinoma, human colorectal adenocarcinoma, and human bone osteosarcoma cell lines. In vivo anticancer efficacy of coated microbeads was examined in BALB/c mice with murine colon carcinoma. These coated microbeads significantly inhibited the growth of all cell lines. The in vivo study confirmed delivery of DOX to the colorectal tumor site, redox-responsiveness, and anticancer efficacy of coated microbeads. Coated microbeads also effectively inhibited primary tumor growth and suppressed tumor metastases without gross toxicity to the non-target tissue. No noticeable damage was found in mouse GI tissues, indicating lack of DOX toxicity. These novel coated microbeads containing thiolated pectin-DOX conjugate may be a promising vehicle for targeted clinical delivery of DOX to the colorectal cancer site by oral administration.

Topics: Adenocarcinoma; Animals; Antibiotics, Antineoplastic; Bone Neoplasms; Caco-2 Cells; Cell Proliferation; Colorectal Neoplasms; Delayed-Action Preparations; Doxorubicin; Drug Carriers; Drug Compounding; Drug Liberation; HT29 Cells; Humans; Male; Mice, Inbred BALB C; Osteosarcoma; Oxidation-Reduction; Pectins; Sulfhydryl Compounds; Technology, Pharmaceutical; Time Factors; Tumor Burden

This study was aimed to develop and evaluate p53 polyplex-loaded enteric-coated calcium pectinate microbeads for oral gene delivery as an effective novel alternative for colorectal cancer therapy. Mutation in p53 is the key event in colorectal cancer (CRC) and an important target for the treatment of CRC through gene therapy. Polymethacrylates-based non-viral vectors were evaluated for their ability to complex, protect and transfect p53 (wt) into colon cancer cell line. Polyplexes were formulated by complexation of cationic polymer with anionic pDNA at different N/P ratios. p53 polyplex-loaded calcium pectinate (CP) microbeads were prepared by ionotropic gelation of pectin with calcium chloride and coated with Eudragit® S100. In vitro release studies showed that enteric-coated CP microbeads protected the release of p53 polyplex in upper GIT with less than 10% release. In-vitro cell line studies and in vivo studies in rat showed that polymethacrylate carrier could transfect the pDNA effectively. Results of in vivo gene expression study further confirmed the ability of enteric-coated calcium pectinate microbeads to deliver pDNA specifically to rat colon. Conclusively, enteric-coated calcium pectinate microbeads released p53 polyplex specifically in colon and could serve as an effective alternative for CRC therapy.

Topics: Administration, Oral; Animals; Calcium Chloride; Cell Line, Tumor; Chemistry, Pharmaceutical; Colorectal Neoplasms; DNA; Drug Carriers; Drug Liberation; Genes, p53; Genetic Therapy; Microspheres; Pectins; Plasmids; Polymethacrylic Acids; Rats; Tablets, Enteric-Coated; Technology, Pharmaceutical; Transfection

The aim of this study was to compare the effects of cellulose and three soluble dietary fibers, pectin, konjac glucomannan (KGM), and inulin, on the cytotoxicity and DNA damage of fecal water-treated Caco-2 cells, a human colon adenocarcinoma cell line, and to investigate the fecal components that potentially modulate the fecal toxicity, that is, bacterial enzymes, bile acids, and short-chain fatty acids. Six-week-old BALB/cJ mice were randomly allocated to consume an AIN-93 diet that contained no dietary fiber (fiber-free) or 5% (w/w) cellulose, pectin, KGM, and inulin for 3 weeks. Feces were collected during days 18-21. Fecal waters were co-incubated with Caco-2 cells to determine the cytotoxicity and DNA damage. In addition, the fecal bacterial enzymes, bile acids, and short-chain fatty acids were determined. Results indicated that all fiber diets similarly increased the survival rate (%) of fecal water-treated Caco-2 cells as compared with the fiber-free diet. The inhibition of fecal water-induced DNA damage in Caco-2 cells was greater for the pectin and inulin diets than for the cellulose and KGM diets. In contrast, cellulose exerted the greatest inhibitory effect on the fecal β-glucuronidase activity. Cellulose and all soluble dietary fibers reduced the secondary bile acid concentrations in the fecal water, but only soluble fibers increased the fecal concentrations of short-chain fatty acids, as compared with no fiber. Therefore, this study suggests that all dietary fibers substantially reduced the fecal water toxicity, which is associated with decreased secondary bile acid levels by all fibers, reduced fecal β-glucuronidase activity by cellulose, and increased short-chain fatty acid levels by soluble dietary fibers.

Topics: Animals; Bile Acids and Salts; Caco-2 Cells; Cellulose; Colorectal Neoplasms; Cytotoxins; Dietary Fiber; Fatty Acids, Volatile; Feces; Fermentation; Humans; Inulin; Male; Mannans; Mice; Mice, Inbred BALB C; Pectins; Solubility

The purpose of the present study is to assess the biodistribution and pharmacokinetics of pectin/ethylcellulose film-coated and uncoated pellets containing 5-fluorouracil (5-FU) in rats. Both coated and uncoated pellets were orally administered to the rats at a dosage equivalent to 15mg/kg. 5-FU concentrations in different parts of the gastrointestinal (GI) tract and plasma were quantitatively analyzed using a high-performance liquid chromatography (HPLC) assay. 5-FU released from uncoated pellets mainly distributes in the upper GI tract, however, 5-FU released from coated pellets mainly distributes in the cecum and colon. In plasma, the observed mean C(max) from the coated pellets group (3.65+/-2.3microg/mL) was lower than that of the uncoated pellets group (23.54+/-2.9microg/mL). The AUC values obtained from the uncoated pellets and the coated pellets were 49.08+/-3.1 and 9.06+/-1.2microgh/mL, respectively. The relatively high local drug concentration with prolonged exposure time provides a potential to enhance anti-tumor efficacy with low systemic toxicity for the treatment of colon cancer.

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Area Under Curve; Biological Availability; Cecum; Cellulose; Colon; Colorectal Neoplasms; Delayed-Action Preparations; Drug Delivery Systems; Drug Implants; Fluorouracil; Gastric Mucosa; Hydrogen-Ion Concentration; Intestine, Small; Microscopy, Electron, Scanning; Pectins; Rats; Rats, Wistar; Surface Properties; Tissue Distribution

The number of colorectal tumors per mouse induced by 1,2-dimethylhydrazine in transgenic (Tg) mice carrying human c-Ha-ras genes was significantly reduced by ingestion of apple pectin (AP) or a culture condensate of Bifidobacterium longum(MB) compared with a control diet and non-Tg mice. However, there were no differences in the composition of fecal flora, water content, beta-glucuronidase and beta-glucosidase activities, and concentrations of organic acids and putrefactive products in the feces between the AP or MB diet and the control diet, or between the Tg mice and non-Tg mice. The concentration of secondary bile acids in the MB diet group was higher than that in the control group. These results suggested that there was no relationship between prevention of colorectal tumors in Tg mice and the AP or MB diet, or improvement of the intestinal environment due to these functional foods.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta-Glucosidase; Bifidobacterium; Colonic Neoplasms; Colorectal Neoplasms; Feces; Female; Fruit; Genes, ras; Glucuronidase; Humans; Male; Mice; Mice, Inbred Strains; Mice, Transgenic; Pectins; Rectal Neoplasms

The number and tumor score of colorectal tumors induced by 1,2-dymethylhydrazine in transgenic (Tg) mice carrying human c-Ha-ras genes were significantly reduced by ingestion of apple pectin (AP) or a culture condensate of Bifidobacterium longum (MB) when compared with a control diet. There was no statistical difference in the incidence of colorectal tumors in Tg mice between the AP or MB diet and the control diet. This study demonstrated that Tg mice are a useful tool for screening inhibition of colorectal tumors by functional foods.

Topics: 1,2-Dimethylhydrazine; Administration, Oral; Animals; Bifidobacterium; Colorectal Neoplasms; Culture Media; Female; Fruit; Genes, ras; Humans; Male; Mice; Mice, Transgenic; Pectins

The potential of the generic kaopectate (Upjohn) as a negative rectal contrast agent in MR imaging was investigated in the assessment of colorectal disease. 45 MR examinations in patients with colorectal disease (colorectal carcinoma 25 patients, inflammatory disease 12 patients, miscellaneous disorders of the colon 8 patients) were evaluated. All examinations were performed with T1 and T2 weighted SE sequences after rectal application of kaopectate. Gd-DTPA enhanced T1 SE sequences were obtained as well. Kaopectate revealed a signal void of the lumen of the large intestine in T1 and T2 weighted SE sequences. Intravenous administration of Gd-DTPA enabled good differentiation of contrast-enhanced malignant or inflammatory tissue and the low signal lumen of the bowels. No side effects were noted.

Topics: Adult; Aged; Aged, 80 and over; Bentonite; Colonic Diseases; Colorectal Neoplasms; Contrast Media; Drug Combinations; Drug Evaluation; Female; Gadolinium; Gadolinium DTPA; Humans; Kaolin; Magnetic Resonance Imaging; Male; Middle Aged; Models, Structural; Organometallic Compounds; Pectins; Pentetic Acid; Rectal Diseases; Rectum; Time Factors