betadex and Colorectal-Neoplasms

Curcumin (CUR), a curcuminoid originating from turmeric root, possesses diverse pharmacological applications, including potent anticancer properties. However, the use of this efficacious agent in cancer therapy has been limited due to low water solubility and poor bioavailability. To overcome these problems, a drug delivery system was established as an excipient allowing improved dispersion in aqueous media coupled with enhanced in vitro anticancer effects. Different analyses such as UV-vis spectroscopy, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), solubility and dissolution assays were determined to monitor the successful encapsulation of CUR within the inner cavity of a β-cyclodextrin (β-CD) complex. The results indicated that water solubility was improved by 205.75-fold compared to pure CUR. Based on cytotoxicity data obtained from MTT assays, the inclusion complex exhibited a greater decrease in cancer cell viability compared to pure CUR. Moreover, cancer cell migration rates were decreased by 75.5% and 38.92%, invasion rates were decreased by 37.7% and 35.7%, while apoptosis rates were increased by 26.3% and 14.2%, and both caused caspase 3 activation toward colorectal cancer cells (SW480 and HCT116 cells). This efficacious formulation that enables improved aqueous dispersion is potentially useful and can be extended for various chemotherapeutic applications. Preliminary toxicity evaluation also indicated that its composition can be safely used in humans for cancer therapy.

Topics: beta-Cyclodextrins; Calorimetry, Differential Scanning; Colorectal Neoplasms; Curcumin; Humans; Solubility; Spectroscopy, Fourier Transform Infrared; Water; X-Ray Diffraction

Using nanotechnology for improving the immunotherapy efficiency represents a major research interest in recent years. However, there are paradoxes and obstacles in using a single nanoparticle to fulfill all the requirements in the complicated immune activation processes. Herein, a supramolecular assembled programmable immune activation nanomedicine (PIAN) for sequentially finishing multiple steps after intravenous injection and eliciting robust antitumor immunity in situ is reported. The programmable nanomedicine is constructed by supramolecular assembly via host-guest interactions between poly-[(N-2-hydroxyethyl)-aspartamide]-Pt(IV)/β-cyclodextrin (PPCD), CpG/polyamidoamine-thioketal-adamantane (CpG/PAMAM-TK-Ad), and methoxy poly(ethylene glycol)-thioketal-adamantane (mPEG-TK-Ad). After intravenous injection and accumulation at the tumor site, the high level of reactive oxygen species in the tumor microenvironment promotes PIAN dissociation and the release of PPCD (mediating tumor cell killing and antigen release) and CpG/PAMAM (mediating antigen capturing and transferring to the tumor-draining lymph nodes). This results in antigen-presenting cell activation, antigen presentation, and robust antitumor immune responses. In combination with anti-PD-L1 antibody, the PIAN cures 40% of mice in a colorectal cancer model. This PIAN provides a new framework for designing programmable nanomedicine as in situ cancer vaccine for cancer immunotherapy.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antigen-Presenting Cells; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; beta-Cyclodextrins; Cancer Vaccines; Cell Line, Tumor; Colorectal Neoplasms; Dendrimers; Humans; Immunotherapy; Interleukin-6; Mice; Neoplasms, Experimental; Polyethylene Glycols; Tumor Microenvironment; Tumor Necrosis Factor-alpha

Chemotherapeutic drugs for colorectal cancer(CRC) which is currently the third most lethal cancer globally, are administered intravenously (iv) due to their low oral bioavailability resulting from their physicochemical properties. Non-selective biodistribution and difficulties of parenteral administration reduce treatment efficacy. The aim of this work is to develop cyclodextrin (CD) based cationic nanoparticles (NPs) for CRC treatment with model drug camptothecin (CPT) that can be administered orally, protecting CPT through gastrointestinal tract (GIT), accumulating at mucus layer and providing an effective local treatment for the tumor area. NPs using two different amphiphilic CDs were prepared and coated with polyethylenimine (PEI) or chitosan (CS) to obtain positively charged surface for all formulations. Pre-formulation studies resulted in optimal formulation, CPT loaded Poly-β-CD-C6 NPs, with 135 nm diameter and zeta potential of + 40 mV. In vitro release study was designed to represent gastrointestinal pH and transit time revealing 52% of encapsulated CPT successfully delivered all the way to simulated colon. CPT bound to Poly-β-CD-C6 NPs exhibited higher cytotoxicity on HT-29 cells compared to equivalent CPT in solution. Caco-2 cell permeability studies showed 276% increase in CPT permeability and significantly higher mucosal penetration in cationic CD nanoparticle form.

Topics: Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; beta-Cyclodextrins; Camptothecin; Cell Line; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Drug Carriers; Drug Compounding; Drug Liberation; Humans; Mice; Mucus; Nanoparticles

In our previous study, we demonstrated that folate-appended methyl‑β‑cyclodextrin (FA-M-β-CyD) was a promising antitumor agent for the treatment of folate receptor-α (FR-α)-expressing tumors. In the present study, to enhance the antitumor effect of FA-M-β-CyD against FR-α- and CD44-expressing colorectal cancer cells, we synthesized a dual targeting supramolecular complex composed of FA-M-β-CyD and adamantane-grafted hyaluronic acid (Ad-HA). The supramolecular complex of Ad-HA/FA-M-β-CyD showed higher cytotoxic activity in HCT116 cells (FR-α (+), CD44 (+)), a human colon cancer cell line, than FA-M-β-CyD alone. In addition, the cytotoxic activity of Ad-HA/FA-M-β-CyD was significantly impaired by the addition of FA and HA, as inhibitors of FR-α and CD44, respectively. Furthermore, tetramethylrhodamine isothiocyanate (TRITC)-labeled FA-M-β-CyD was efficiently internalized into HCT116 cells through supramolecular complexation with Ad-HA, compared to that of TRITC-FA-M-β-CyD alone. Additionally, Ad-HA/FA-M-β-CyD induced mitophagy in HCT116 cells. These results suggest that Ad-HA/FA-M-β-CyD targeted HCT116 cells, as well as induced mitophagy-mediated cell death. Notably, an intravenous injection of the Ad-HA/FA-M-β-CyD complex in a mouse model of colorectal cancer significantly ameliorated the growth of tumor polyps. Collectively, these results suggest that Ad-HA/FA-M-β-CyD has antiproliferation effects in tumors, based on the dual targeting activity.

Topics: Adamantane; Animals; Antineoplastic Agents; Autophagosomes; beta-Cyclodextrins; Biological Transport; Colorectal Neoplasms; Folic Acid; HCT116 Cells; Humans; Hyaluronic Acid; Male; Mice; Mitochondria; Molecular Targeted Therapy; Particle Size; Xenograft Model Antitumor Assays

Methyl-β-cyclodextrin (MβCD) is an effective agent for the removal of plasma membrane cholesterol. In this study, we investigated the modulating effects of MβCD on the antiproliferation induced by benzyl isothiocyanate (BITC), an ITC compound mainly derived from papaya seeds. We confirmed that MβCD dose-dependently increased the cholesterol level in the medium, possibly through its removal from the plasma membrane of human colorectal cancer cells. The pretreatment with a non-toxic concentration (2.5 mM) of MβCD significantly enhanced the BITC-induced cytotoxicity and apoptosis induction, which was counteracted by the cholesterol supplementation. Although BITC activated the phosphoinositide 3-kinase (PI3K)/Akt pathway, MβCD dose-dependently inhibited the phosphorylation level of Akt. On the contrary, the treatment of MβCD enhanced the phosphorylation of mitogen activated protein kinases, but did not potentiate their BITC-induced phosphorylation. These results suggested that MβCD might potentiate the BITC-induced anti-cancer by cholesterol depletion and thus inhibition of the PI3K/Akt-dependent survival pathway. Abbreviations: CDs: cyclodextrins; MβCD: methyl-β-cyclodextrin; ITCs: isothiocyanates; BITC: benzyl isothiocyanate; PI3K: phosphoinositide 3-kinase; PDK1: phosphoinositide-dependent kinase-1; MAPK: mitogen activated protein kinase; ERK1/2: extracellular signal-regulated kinase1/2; JNK: c-Jun N-terminal kinase; PI: propidium iodide; FBS: fatal bovine serum; TLC: thin-layer chromatography; PBS(-): phosphate-buffered saline without calcium and magnesium; MEK: MAPK/ERK kinase; PIP2: phosphatidylinositol-4,5-bisphosphate; PIP3: phosphatidylinositol-3,4,5-trisphosphate.

Topics: Antineoplastic Agents; Apoptosis; beta-Cyclodextrins; Cell Line, Tumor; Cell Proliferation; Cholesterol; Colorectal Neoplasms; Culture Media; Dose-Response Relationship, Drug; Drug Synergism; Humans; Isothiocyanates; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt

Albendazole (ABZ) is a microtubule depolymerizing agent with a remarkable activity against a variety of tumor cells in vitro and in vivo. However, the lack of water solubility limits its application. Therefore, the aim of this study was to formulate ABZ with acetic acid/2-hydroxypropyl-β-cyclodextrin (HPβCD) with the view of improving its aqueous solubility and therefore, its antitumor efficacy.. ABZ was dissolved in acetic acid and 25% HPβCD (w/v). Mice received a single dose of ABZ/HPβCD or a conventional suspension in hydroxypropyl methyl cellulose (HPMC) over 24 h and the concentration of ABZ and its metabolites in plasma were measured by HPLC. The antitumor efficacy of the two formulations were then evaluated and compared in nude mice bearing HCT-116 colorectal cancer xenografts.. Ionization with acetic acid together with complexation with hydroxylpropyl-β-cyclodextrin (HPβCD) dramatically improved the solubility of ABZ. The area under the curve (AUC) of ABZ and its active metabolite, ABZ sulfoxide (ABZSO) were approximately 2.3- and 7.3-folds higher in mice that received ABZ/HPβCD in comparison with animals that were treated with ABZ/HPMC. Additionally, the peak plasma concentration (C(max)) of ABZSO was nearly 18-times higher in mice that received ABZ/HPβCD. Furthermore, a significant delay in tumor growth that led to longer survival in mice was observed in the ABZ/HPβCD-treated group as compared to the ABZ/HPMC group.. These findings demonstrate that the combination of acetic acid and HPβCD significantly improves the solubility, pharmacokinetic profile and antitumor efficacy of ABZ. This newly-developed formulation of ABZ may be suitable for parenteral administration.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Acetic Acid; Albendazole; Animals; beta-Cyclodextrins; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Female; HCT116 Cells; Human Umbilical Vein Endothelial Cells; Humans; Hypromellose Derivatives; Injections, Intraperitoneal; Methylcellulose; Mice; Mice, Nude; Solutions; Suspensions; Tubulin Modulators; Xenograft Model Antitumor Assays

5-Fluorouracil (5-FU) in combination with its synergistic biomodulator folinic acid maintains a pivotal position in cancer chemotherapy. However, clinical limitations such as phlebitis and catheter blockages persist with the administration of these drugs in combination, and are associated with reduced efficacy and/or quality of life for patients. We have reported earlier on the novel, all-in-one, pH neutral, parenteral 5-FU and folinic acid formulations (termed Fluorodex) incorporating β-cyclodextrins. Fluorodex maintains potency while overcoming the accepted incompatibility of 5-FU and folinic acid. We carried out toxicological, pharmacokinetic and biodistribution, and efficacy evaluations of Fluorodex compared with 5-FU:folinic acid using several administration routes and schedules in two rodent models. These were compared with the dose-matched sequential administration of 5-FU:folinic acid. Fluorodex showed bioequivalence to 5-FU:folinic acid as assessed by the tissue distribution and pharmacokinetic studies of 5-FU, but was generally better tolerated as determined by weight loss, hematological, and other clinical parameters. Compared with 5-FU:folinic acid, Fluorodex was also associated with reduced phlebitis using a rabbit ear vein model. Furthermore, using human carcinoma tumor models in mice, Fluorodex resulted in equivalent or improved efficacy profiles compared with 5-FU:folinic acid. In conclusion, these novel, all-in-one formulations represent a superior injectable form of 5-FU that allows codelivery of folinic acid. This should translate into improved patient tolerability with potential for enhanced efficacy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; beta-Cyclodextrins; Breast Neoplasms; Cell Line, Tumor; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Combinations; Drug Screening Assays, Antitumor; Female; Fluorouracil; HCT116 Cells; HT29 Cells; Humans; Leucovorin; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Rabbits; Rats; Tissue Distribution; Xenograft Model Antitumor Assays

To evaluate the tumour growth delay of a peritoneal carcinomatosis (PC) of colorectal origin after intraperitoneal chemotherapy with paclitaxel/randomly-methylated-β-cyclodextrin (Pac/RAME-β-CD) versus Taxol® at normo- and hyperthermic conditions in rats.. Hyperthermic intraperitoneal chemotherapy (HIPEC) was performed 7 days post implantation of the tumour with both formulations at a Pac concentration of 0.24 mg/ml. Tumour evaluation was performed via positron emission tomography (PET) and magnetic resonance imaging (MRI) imaging, measuring tumour activity and tumour volume, respectively. Scans were taken at 2 and 7 days post treatment.. PET and MRI data showed a significant reduction in tumour activity and tumour volume for rats treated with Pac/RAME-β-CD (at normo- and hyperthermic conditions), compared to the control group. Treatment with Taxol® did not result in a significant reduction of tumour activity and tumour volume. No significant differences between the normo- and hyperthermic conditions were observed for both formulations, indicating that hyperthermia and paclitaxel were not synergistic despite the direct cytotoxic effect of hyperthermia.. Monitoring tumour growth via PET and MRI indicated that Pac/RAME-β-CD inclusion complexes had a significantly higher efficacy compared to Taxol® in a rat model for peritoneal carcinomatosis.

Topics: Animals; Antineoplastic Agents; beta-Cyclodextrins; Cell Line, Tumor; Colorectal Neoplasms; Combined Modality Therapy; Disease Models, Animal; Hyperthermia, Induced; Injections, Intraperitoneal; Magnetic Resonance Imaging; Paclitaxel; Peritoneal Neoplasms; Positron-Emission Tomography; Rats; Time Factors; Tumor Burden

The inhibitory effects of novel prodrugs, inclusion complexes of 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid (GOFA) and auraptene (AUR) with beta-cyclodextrin (CD), on colon carcinogenesis were investigated using an azoxymethane (AOM)/dextran sodium sulfate (DSS) model. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of AOM (10 mg/kg body weight) were promoted by the addition of 1.5% (w/v) DSS to their drinking water for 7 days. They were then given a basal diet containing 2 dose levels (100 and 500 ppm) of GOFA/beta-CD or AUR/beta-CD for 15 weeks. At Week 18, the development of colonic adenocarcinoma was significantly inhibited by feeding with GOFA/beta-CD at dose levels of 100 ppm (63% reduction in multiplicity, p < 0.05) and 500 ppm (83% reduction in the multiplicity, p < 0.001), when compared with the AOM/DSS group (multiplicity: 3.36 +/- 3.34). In addition, feeding with 100 and 500 ppm (p < 0.01) of AUR/beta-CD suppressed the development of colonic adenocarcinomas. The dietary administration with GOFA/beta-CD and AUR/beta-CD inhibited colonic inflammation and also modulated proliferation, apoptosis and the expression of several proinflammatory cytokines, such as nuclear factor-kappaB, tumor necrosis factor-alpha, Stat3, NF-E2-related factor 2, interleukin (IL)-6 and IL-1beta, which were induced in the adenocarcinomas. Our findings indicate that GOFA/beta-CD and AUR/beta-CD, especially GOFA/beta-CD, are therefore able to inhibit colitis-related colon carcinogenesis by modulating inflammation, proliferation and the expression of proinflammatory cytokines in mice.

Topics: Animals; beta-Cyclodextrins; Colonic Neoplasms; Colorectal Neoplasms; Coumarins; Diterpenes; Humans; Immunohistochemistry; Incidence; Inflammation; Inflammatory Bowel Diseases; Inhibitor of Apoptosis Proteins; Interleukin-1beta; Interleukin-6; Male; Mice; Mice, Inbred ICR; Microtubule-Associated Proteins; NF-kappa B; Proliferating Cell Nuclear Antigen; Propionates; Repressor Proteins; Survivin; Tumor Necrosis Factor-alpha