Co-Loaded Thermosensitive System of Irinotecan and Curcumin Nano-Vesicles for Colorectal Cancer

Abstract

Targeting the colorectal cancer (CRC) through rectal administration, by using the thermosensitive system of nanovesicles incorporating the irinotecan (IRT) and curcumin (CUR) is considered to be the preferable route to target the cancer and to prevent the enterohepatic circulation. Other routes have certain limitations. IV administration is one of non-invasive technique with severe cytotoxic effects and oral route has certain limitations including degradation by gastrointestinal enzymes and enterohepatic circulation. As reported in literature, combination therapy of IRT and CUR is effective against CRC. IRT has ability to interfere with the DNA synthesis, leading to cell death. CUR has capability of decreasing interleukins and proinflammatory mediators synthesis. Combination of these drugs helps to kills the cancer cell and also overcome the resistance developed by IRT. So, the aim of study is to develop the co-loaded thermosensitive system of co-loaded IRT and CUR nanotransferosomes (IRT-CUR-NTs) for targeting against CRC, and to overcome the barriers associated with the individual drugs for successful chemotherapy. For the preparation of IRT-CUR-NTs, thin film hydration method was used with some alteration in method defined in literature and for statistical optimization, Box Behnken Design was used. PL 90G, Tween®80 and drug concentration was chosen as independent variable to check their impact on dependent variables such as particle size (PS), polydispersity index (PDI), zeta potential (ZP) and entrapment efficiency (%EE) of drugs. For surface morphology and particle size confirmation, IRT-CUR-NTs were characterized in terms of Transmission Electron Microscopy (TEM), Differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). IRT CUR-NTs were loaded into thermosensitive system to form IRT-CUR-NTG, was characterized by physical appearance, pH, gelation time, gelation temperature, gel strength and mucoadhesive strength. The PS, PDI, ZP, %EE of IRT and %EE of CUR were found to be 136.15 ± 2.15, 0.143 ± 0.023, -15.5 ± 3.8, 95.05% ± 2.31 and 85.12 ± 1.42. TEM results showed that particles are spherical in shape. FTIR results showed that there was no interaction among the drugs and excipients and DSC results showed the incorporation of drugs into lipid structure. IRT-CUR-NTG characterization showed it to be clear, homogenous gel, with pH suitable for rectal administration. In vitro release analysis of IRT and CUR from IRT-CUR-NTs and IRT-CUR-NTG was DRSML QAU x performed. IRT-CUR-NTG showed prolonged release of IRT and CUR as compared to IRT-CUR-NTs and individual drugs. Pharmacokinetic study showed the improved bioavailability of drugs from IRT-CUR NTG in comparison to IRT-CUR-Gel, indicating the decrease in metabolism of CUR by gastrointestinal enzymes after incorporation into IRT-CUR-NTs and histopathological analysis showed IRT-CUR-NTG is safe in comparison to IRT-CUR Gel. In vitro antitumor analysis showed that IRT-CUR-NTs were found to be more effective against HT 29 cell lines in comparison to their solutions. The results obtained from stability study showed that IRT-CUR-NTs were stable at 4 ± 2 ℃ and should be stored in refrigerator. So, it has been deduced from present study that IRT-CUR-NTG is considered to be suitable for rectal administration with successful incorporation of IRT and CUR into IRT-CUR-NTs for colorectal cancer to overcome the problems linked to monotherapy.