Orally administered docetaxel-loaded chitosan-decorated cationic PLGA nanoparticles for intestinal tumors: formulation, comprehensive in vitro characterization, and release kinetics

Abstract

Intestinal cancers are the third most lethal cancers globally, beginning as polyps in the intestine and spreading with a severe metastatic tendency. Chemotherapeutic drugs used in the treatment of intestinal tumors are usually formulated for parenteral administration due to poor solubility and bioavailability problems. Pharmaceutically, clinical failure due to a drug’s wide biodistribution and non-selective toxicity is one of the major challenges of chemotherapy. In addition, parenteral drug administration in chronic diseases that require long-term drug use, such as intestinal tumors, is challenging in terms of patient compliance and poses a burden in terms of health economy. Especially in the field of chemotherapy research, oral chemotherapy is a subject that has been intensively researched in recent years, and developments in this field will provide serious breakthroughs both scientifically and socially. Development of orally applicable nanodrug formulations that can act against diseases seen in the distant region of the gastrointestinal tract (GIT), such as intestinal tumor, brings with it a series of difficulties depending on the drug and/or GIT physiology. The aim of this study is to develop an oral nanoparticle drug delivery system loaded with docetaxel (DCX) as an anticancer drug, using poly(lactic-co-glycolic acid) (PLGA) as nanoparticle material, and modified with chitosan (CS) to gain mucoadhesive properties. In this context, an innovative nanoparticle formulation that can protect orally administered DCX from GIT conditions and deliver the drug to the intestinal tumoral region by accumulating in mucus has been designed. For this purpose, DCX-PLGA nanoparticles (NPs) and CS/DCX-PLGA NPs were prepared, and their in vitro characteristics were elucidated. Nanoparticles around 250–300 nm were obtained. DCX-PLGA NPs had positive surface charge with CS coating. The formulations have the potential to deliver the encapsulated drug to the bowel according to the in vitro release studies in three different simulated GIT fluids for approximately 72 h. Mucin interaction and penetration into the artificial mucus layer were also investigated in detail, and the mucoadhesive and mucus-penetration characteristics of the formulations were examined. Furthermore, in vitro release kinetic studies of the NPs were elucidated. DCX-PLGA NPs were found to be compatible with the Weibull model, and CS/DCX-PLGA NPs were found to be compatible with the Peppas–Sahlin model. Within the scope of in vitro cytotoxicity studies, the drug-loaded NPs showed significantly higher cytotoxicity than a DCX solution on the HT-29 colon cell line, and CS/DCX-PLGA showed the highest cytotoxicity (p < 0.05). According to the permeability studies on the Caco-2 cell line, the CS/DCX-PLGA formulation increased permeability by 383% compared to free DCX (p < 0.05). In the light of all results, CS/DCX-PLGA NPs can offer a promising and innovative approach as an oral anticancer drug-loaded nanoformulation for intestinal tumors.

Ruxolitinib-loaded poly-ɛ-caprolactone (PCL) nanoparticles inhibit the JAK2/STAT5 signaling via downregulating Bcl-2 and Mcl-1 on BT474 breast cancer cells

“…Unal et al determined that in uncoated NPs, zeta potentials ranged from − 20.1 to -25.8, whereas in coated NPs, surface charges ranged from + 29.6 to + 57. [12]. They demonstrated that the zeta potential of NPs coated with chitosan and PCL used in the study changed from negative to positive [12].…”

“…Due to the biodegradable and biocompatible features of PCL, it is frequently used in drug development studies as it facilitates drug release and long-term degradation up to several months [8]. In literature, have been found studies related with Paclitaxel [12], Quercetin [18], Irinotecan [19], 5-Fluorouracil [20] and Atorvastatin calcium [21] loaded PCL nanoparticle. In the literature, there are just only two studies on the nanoform of ruxolitinib: gold-coated nanoparticles of Ruxolitinib [17] and a topical emulgel containing Ruxolitinib nanoliposome [22].…”

“…In contrast, smaller particles may have toxic effects because of their greater surface area [23]. Unal et al [12] showed that the average size of the Paclitaxel-loaded PCL nanoparticles they synthesized was between 199-383 nm and that the nanoparticle size may increase compared to blank nanoparticles due to Paclitaxel settling on the nanoparticle surface. Similarly, in this study, the average sizes of Ruxolitinib, PCL-NP, and Rux-PCL-NP were found to be 564.4641 ± 25.4505 nm, 159.4 ± 74.72 nm, 219 ± 88.66 nm, respectively (Table 1.).…”

“…Lyophilized Rux-PCL-NPs were coated with gold for 1 minute after being dropped onto the Stub with carbon tape attached. Then, they were placed in the SEM (ZEISS/ Supra 40 VP) sample apparatus, and their sizes and morphologies were determined [12].…”

“…In a UV spectrophotometer at 230 nm, samples were measured. The drug release amount was determined for each measurement hour by drawing a graph for each formulation with the measured absorbance values [12].…”