Modeling the impact of fluid flow on resveratrol release from electrospun fibers.

Using electrospun fibers to deliver therapeutic agents has gained significant attention in various applications including cancer treatment and tissue regeneration. However, the effect of fluid flow and uptake by cells on the concentration profile is not well understood. In this study, we evaluated the release of lipophilic resveratrol from poly(ε-caprolactone) (PCL)-gelatin (GT) electrospun fibers experimentally and by using computational fluid dynamics (CFD). Resveratrol containing PCL-GT electrospun fibers were formed and used in a custom-built tubular bioreactor, to assess flow effect on concentration profile over 5 days. CFD model was developed to simulate release in both static cultures and under fluid flow conditions. Resveratrol stability in the culture medium and uptake by human umbilical vein endothelial cells and K562 cells over 3 days were used in the model. The concentration profile as a function of time was simulated and validated by experiments. The effects of inlet velocity, cellular uptake rate, bioreactor's length, and surrounding tissue porosity were assessed. The release profile was mainly affected by cellular uptake and the presence of porous media. The model suggests that the perfusion velocity might not have a significant effect relative to the cellular uptake rate and porosity of the surrounding tissue.

Recent advances in the combination delivery of drug for leukemia and other cancers.

Introduction: Combination therapy has been explored for its potential to reduce or eliminate multidrug resistance in treating different types of cancer including leukemia. Nutraceutical, small molecular drugs, and small interfering ribonucleic acid (siRNA) are some of the effective drugs. In order to avoid off-site targeting, reduce the dosage required, and increase the half-life of the drug in the circulation system, drug delivery vehicles, such as nanoparticles and microfibers have been explored.Areas covered: This review summarizes various therapies utilized in treating leukemia based on their effectiveness in inducing protein inhibition and/or apoptosis. In particular, treatment effectiveness using combination therapy using various devices is addressed. Recently explored drug delivery methods are reviewed, providing examples and their applications in cancer treatment. The drug listing, delivery systems classifications, along with the general modeling approach in this review, provide, to a full extent, a basis for cancer drug delivery future studies.Expert opinion: The reviewer's opinion tackles the potential of using a multi-delivery system to deliver multiple drugs, providing better control upon drug release and targeting. Both local and systemic delivery are considered and explored for their potential targets. Researchers are advised to pre-consider all aspects associated with their desired delivery method.

Targeted cancer treatment using a combination of siRNA-liposomes and resveratrol-electrospun fibers in co-cultures.

In this study, we evaluated a novel combination of drug delivery devices composed of holo-transferrin conjugated liposomes for siRNA (36 nM) delivery, and electrospun polycaprolactone (PCL)-gelatin (GT) microfibers for resveratrol (40 µM) release. Single- and co-cultures of cancerous K562 cells and human umbilical vein endothelial cells (HUVECs) were used to test the efficacy and targeting over eight days. BCR-ABL siRNA-encapsulated (36 nM) holo-transferrin-conjugated PEG-liposomes were characterized using dynamic light scattering, and transmission electron microscopy. RT-qPCR was performed to assess the silencing BCR-ABL gene. Two treatment protocols were explored: i) simultaneous administration ii) delayed liposomes addition by three days based on resveratrol release profile. Formed liposomes were 123 (±6.65) nm in diameter, holo-transferrin conjugation efficiency was 85.9 (±7.30)%, and siRNA loading efficiency was 92.3 (±2.57)%. Sphingosine-1-phosphate (S1P) content was analyzed by ELISA. Targeted siRNA release in combination with resveratrol release was more potent and has long-term effects compared to bolus doses. Delayed addition of liposomes increased non-viability of K562 cells to 92.7 (±2.00)% and 94.32 (±1.70)%, in the absence and presence of HUVECs, respectively. HUVECs non-viability level was significantly lower. Using two different delivery devices approach has a broader impact on cancer treatment.

Influence of controlled release of resveratrol from electrospun fibers in combination with siRNA on leukemia cells.

In this study, we evaluated the possibility of i) local release of resveratrol from poly(ε-caprolactone) (PCL) and gelatin (GT) electrospun fibers and ii) combining (i) with siRNA designed to downregulate BCR-ABL pathway on K562 cancer cells. Initially, K562 cell culture experiments were performed using various bolus doses of resveratrol in combination with siRNA for 3 days using a factorial design of experiments approach. Resveratrol content was analyzed using HPLC and cell viability was assessed using Annexin V (Non-viable), and Propidium Iodide (PI) (Necrotic) based flow cytometry. Coaxial electrospun fibers with resveratrol were made using 1:1 PCL-GT blends in different configurations: single fibers and coaxial fibers with same polymer blends, or with PCL inner core. Loading efficiency and release profile over five days were analyzed. Based on release profile, K562 cell viability with fibers was analyzed over eight days. Dose dependent cell death was observed with bolus resveratrol and siRNA in the culture. However, resveratrol content depleted significantly when added directly to solution. The combination therapy was additive in solution. SEM analysis showed no phase separation of components and resveratrol loading efficiency varied from 77% to 88% in different configurations; 95% of resveratrol was released by day five. Permeability of resveratrol showed no significant dependency on fiber configuration. After 8 days, non-viable cell percentages with controlled release were similar to that at three-day bolus dose of resveratrol. However, siRNA interacted with the fibers, resulting in reduced effect on cells. Loading resveratrol into electrospun fibers provides a localized delivery at therapeutic level, and increased resveratrol's apoptotic effect. Using single fibers is sufficient for controlled release.