Bile Acid-Targeted Hyaluronic Acid Nanoparticles for Enhanced Oral Absorption of Deferoxamine.

Patients with ß-thalassemia and sickle cell disease often rely on blood transfusions which can lead to hemochromatosis and chronic oxidative stress in cells and tissues. Deferoxamine (DFO) is clinically approved to treat hemochromatosis but is suboptimal to patients due to its poor pharmacokinetics which requires long-term infusion regimens. Although the oral route is preferable, DFO has limited oral bioavailability. Studies have shown that hyaluronic acid (HA) and bile acid (BA) can enhance the oral absorption of poorly absorbed drugs. To improve upon the oral delivery of DFO, we report on the synthesis and characterization of HA (MW 15 kD) conjugated to two types of BA, deoxycholic acid (DOCA) and taurocholic acid (TCA), and DFO. The resulting seven polymeric conjugates all formed self-assembled nanoparticles. The degree of BA and DFO conjugation to the HA polymer was confirmed at each step through nuclear magnetic resonance, Fourier transform infrared spectroscopy, and UV-Vis spectroscopy. The best formulations for further in vitro testing were determined based on physicochemical characterizations and included HA-DFO, TCA9-HA-DFO, and DOCA9-HA-DFO. Results from in vitro assays revealed that TCA9-HA-DFO enhanced the permeation of DFO the most and was also less cytotoxic to cells compared to the free drug DFO. In addition, ferritin reduction studies indicated that the conjugation of DFO to TCA9-HA did not compromise its chelation efficiency at equivalent free DFO concentrations. This research provides supportive data for the idea that TCA conjugated to HA may enhance the oral absorption of DFO, improve its cytocompatibility, and maintain its iron chelation efficiency.

Oral Non-absorbable Polymer-Deferoxamine Conjugates for Reducing Dietary Iron Absorption.

Hereditary hemochromatosis (HH) is a non-transfusional genetic iron overload (IO) disease wherein patients are not able to regulate dietary iron absorption, which ultimately leads to excess cellular iron accumulation. Preventative measures for HH mainly include phlebotomy and asking patients to minimize dietary iron intake. To investigate alternative iron reduction strategies, we report on prophylactic non-absorbable polymer-deferoxamine (DFO) conjugates capable of chelating and reducing excessive gut uptake of dietary iron. Three different sizes of the conjugates (56 nm, 256 nm, and 7.4 µm) were prepared, and their physicochemical properties, transit times in the gut under fed/fasted conditions, acute safety, and efficacy at reducing iron absorption in a dietary iron-overload mouse model were investigated. The conjugates were synthesized through reverse phase water-in-oil (w/o) emulsions, followed by conjugation of DFO to the resulting polymer scaffolds. In vitro studies using Caco-2 transwell assays showed that the conjugates could not permeate across the monolayer, were poorly endocytosed, and did not induce cellular toxicity. In vivo mouse studies via oral gavage demonstrated that polymer-DFO conjugates remained in the gastrointestinal (GI) tract for up to 12 h and significantly prevented escalation of serum ferritin levels and excess liver iron accumulation. Ex vivo images of the duodenum suggest that nanometer-sized conjugates (56 and 246 nm) perform better at chelating dietary iron based on longer retention times (i.e., entrapment in the villi of the duodenum) and an overall slower transit from the GI tract compared to larger micron-sized (7.4 µm) conjugates. Overall, nanometer-sized polymer-DFO conjugates were orally non-absorbable, appeared safe, and were more efficacious at reducing dietary iron absorption when taken with non-heme containing food.

Comprehensive assessment on the applications of oncolytic viruses for cancer immunotherapy.

The worldwide burden of cancers is increasing at a very high rate, including the aggressive and resistant forms of cancers. Certain levels of breakthrough have been achieved with the conventional treatment methods being used to treat different forms of cancers, but with some limitations. These limitations include hazardous side effects, destruction of non-tumor healthy cells that are rapidly dividing and developing, tumor resistance to anti-cancer drugs, damage to tissues and organs, and so on. However, oncolytic viruses have emerged as a worthwhile immunotherapeutic option for the treatment of different types of cancers. In this treatment approach, oncolytic viruses are being modeled to target cancer cells with optimum cytotoxicity and spare normal cells with optimal safety, without the oncolytic viruses themselves being killed by the host immune defense system. Oncolytic viral infection of the cancer cells are also being genetically manipulated (either by removal or addition of certain genes into the oncolytic virus genome) to make the tumor more visible and available for attack by the host immune cells. Hence, different variants of these viruses are being developed to optimize their antitumor effects. In this review, we examined how grave the burden of cancer is on a global level, particularly in sub-Saharan Africa, major conventional therapeutic approaches to the treatment of cancer and their individual drawbacks. We discussed the mechanisms of action employed by these oncolytic viruses and different viruses that have found their relevance in the fight against various forms of cancers. Some pre-clinical and clinical trials that involve oncolytic viruses in cancer management were reported. This review also examined the toxicity and safety concerns surrounding the adoption of oncolytic viro-immunotherapy for the treatment of cancers and the likely future directions for researchers and general audience who wants updated information.