Abstract
Magnetite nanoparticles (MNPs) have gained significant attention in several applications for drug delivery. However, there are some issues related to cell penetration, especially in the transport of cargoes that show limited membrane passing. A widely studied strategy to overcome this problem is the encapsulation of the MNPs into liposomes to form magnetoliposomes (MLPs), which are capable of fusing with membranes to achieve high delivery rates. This study presents a low-cost microfluidic approach for the synthesis and purification of MLPs and their biocompatibility and functional testing via hemolysis, platelet aggregation, cytocompatibility, internalization, and endosomal escape assays to determine their potential application in gastrointestinal delivery. The results show MLPs with average hydrodynamic diameters ranging from 137 ± 17 nm to 787 ± 45 nm with acceptable polydispersity index (PDI) values (below 0.5). In addition, we achieved encapsulation efficiencies between 20% and 90% by varying the total flow rates (TFRs), flow rate ratios (FRRs), and MNPs concentration. Moreover, remarkable biocompatibility was attained with the obtained MLPs in terms of hemocompatibility (hemolysis below 1%), platelet aggregation (less than 10% with respect to PBS 1×), and cytocompatibility (cell viability higher than 80% in AGS and Vero cells at concentrations below 0.1 mg/mL). Additionally, promising delivery results were obtained, as evidenced by high internalization, low endosomal entrapment (AGS cells: PCC of 0.28 and covered area of 60% at 0.5 h and PCC of 0.34 and covered area of 99% at 4 h), and negligible nuclear damage and DNA condensation. These results confirm that the developed microfluidic devices allow high-throughput production of MLPs for potential encapsulation and efficient delivery of nanostructured cell-penetrating agents. Nevertheless, further in vitro analysis must be carried out to evaluate the prevalent intracellular trafficking routes as well as to gain a detailed understanding of the existing interactions between nanovehicles and cells.
Highlights
No apparent differences in size were identified for the evaluated total flow rates (TFRs) and the concentration of the nanoconjugates used in the experiment for different flow rate ratios (FRRs)
There is a significant difference in size for the evaluated TFRs and the concentration of the nanoconjugates used in the experiment for different FRRs
The polydispersity index (PDI) values of the MLPs were below 0.5 in most cases, which for the 1:1 to the 2:1 FRR, where it is comparable with the results for the synthesis of liposomes for different FRRs [31,41]
Summary
Oral drug administration is one of the most convenient routes of drug delivery due to patient preference, shelf life, sustained delivery, cost-effectiveness, and ease of large-scale. Liposomes with encapsulated MNPs, called magnetoliposomes (MLPs), have been extensively used as carriers in the pharmaceutical industry due to their ability to release various active molecules at a given site without the need for molecularly targeted agents [17] This is in addition to the improvement in the biocompability, drug delivery rate for some compounds, and cellular uptake without a significant reduction in the activity of the functional compounds immobilized and delivered employing MNPs [18,19]. These novel drug delivery vehicles might offer potential improvements in targeting, stabilization of antimicrobial agents, and gastroretention This might help to reduce various possible side effects of oral administration, such as the uncontrolled destruction of both pathogenic and non-pathogenic microbiota, and, prevent the appearance of complications such as dysbiosis [20]. MLPs showed high biocompatibility, low endosomal entrapment, and high internalization rates, which are crucial factors in developing novel vehicles for delivering difficult-totransport drugs
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