Cancer is a major health concern worldwide and is still in a continuous surge of seeking for effective treatments. Since the discovery of RNAi and their mechanism of action, it has shown promises in targeted therapy for various diseases including cancer. The ability of RNAi to selectively silence the carcinogenic gene makes them ideal as cancer therapeutics. Oral delivery is the ideal route of administration of drug administration because of its patients’ compliance and convenience. However, orally administered RNAi, for instance, siRNA, must cross various extracellular and intracellular biological barriers before it reaches the site of action. It is very challenging and important to keep the siRNA stable until they reach to the targeted site. Harsh pH, thick mucus layer, and nuclease enzyme prevent siRNA to diffuse through the intestinal wall and thereby induce a therapeutic effect. After entering the cell, siRNA is subjected to lysosomal degradation. Over the years, various approaches have been taken into consideration to overcome these challenges for oral RNAi delivery. Therefore, understanding the challenges and recent development is crucial to offer a novel and advanced approach for oral RNAi delivery. Herein, we have summarized the delivery strategies for oral delivery RNAi and recent advancement towards the preclinical stages.
Excessive body fat and high cholesterol are one of the leading reasons for triggering cardiovascular risk factors, obesity, and type 2 diabetes. Beta-glucan (BG)-based dietary fibers are found to be effective for lowering fat digestion in the gastrointestinal tract. However, the fat capturing mechanism of BG in aqueous medium is still elusive. In this report, we studied the dietary effect of barley-extracted BG on docosahexaenoic acid (DHA, a model fat molecule) uptake and the impact of the aqueous medium on their interactions using computational modeling and experimental parameters. The possible microscale and macroscale molecular interactions between BG and DHA in an aqueous medium were analyzed through density functional theory (DFT), Monte-Carlo (MC), and molecular dynamics (MD) simulations. DFT analysis revealed that the BG polymer extends hydrogen bonding and nonbonding interactions with DHA. Bulk simulation with multiple DHA molecules on a long-chain BG showed that a viscous colloidal system is formed upon increasing DHA loading. Experimental size and zeta potential measurements also confirmed the electrostatic interaction between BG−DHA systems. Furthermore, simulated and experimental diffusion and viscosity measurements showed excellent agreement. These simulated and experimental results revealed the mechanistic pathway of how BG fibers form colloidal systems with fat molecules, which is probably responsible for BG-induced delayed fat digestion and further halting of fatty molecule absorption in the GI tract.
Chemotherapy-induced cardiac toxicity is an undesirable
yet very
common effect that increases the risk of death and reduce the quality
of life of individuals undergoing chemotherapy. However, no feasible
methods and techniques are available to monitor and detect the degree
of cardiotoxicity at an early stage. Therefore, in this project, we
aim to develop a fluorescent nanoprobe to image the toxicity within
the cardiac tissue induced by an anticancer drug. We have observed
that vascular cell adhesion molecule 1 (VCAM1) protein alone with
collagen was overly expressed within the heart, when an animal was
treated with doxorubicin (DOX), because of inflammation in the epithelial
cells. We hypothesize that developing a VCAM1-targeted peptide-based
(VHPKQHRGGSKGC) fluorescent nanoprobe can detect and visualize the
affected heart. In this regard, we prepared a poly(lactic-co-glycolic
acid) (PLGA) nanoparticle linked with VCAM1 peptide and rhodamine
B (PLGA–VCAM1–RhB). Selective binding and higher accumulation
of the PLGA–VCAM1–RhB nanoprobes were detected in DOX-treated
human cardiomyocyte cells (HCMs) compared to the untreated cells.
For in vivo studies, DOX (5 mg/kg) was injected via the tail vein
once in two weeks for 6 weeks (3 injection total). PLGA–VCAM1–RhB
and PLGA–RhB were injected via the tail vein after 1 week of
the last dose of DOX, and images were taken 4 h after administration.
A higher fluorescent signal of PLGA–RhB–VCAM-1 (48.62%
± 12.79%) was observed in DOX-treated animals compared to the
untreated control PLGA–RhB (10.61% ± 4.90) within the
heart, indicating the specificity and targeting ability of PLGA–VCAM1–RhB
to the inflamed tissues. The quantified fluorescence intensity of
the homogenized cardiac tissue of PLGA–RhB–VCAM1 showed
156% higher intensity than the healthy control group. We conclude
that PLGA–VCAM1–RhB has the potential to bind inflamed
cardiac cells, thereby detecting DOX-induced cardiotoxicity and damaged
heart at an early stage.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.