Abstract
Delta inulin, also known as microparticulate inulin (MPI), was modified by covalently attaching doxorubicin to its nanostructured surface for use as a targeted drug delivery vehicle. MPI is readily endocytosed by monocytes, macrophages, and dendritic cells and in this study, we sought to utilize this property to develop a system to target anti-cancer drugs to lymphoid organs. We investigated, therefore, whether MPI could be used as a vehicle to deliver doxorubicin selectively, thereby reducing the toxicity of this antibiotic anthracycline drug. Doxorubicin was covalently attached to the surface of MPI using an acid–labile linkage to enable pH-controlled release. The MPI-doxorubicin conjugate was characterized using FTIR and SEM, confirming covalent attachment and indicating doxorubicin coupling had no obvious impact on the physical nanostructure, integrity, and cellular uptake of the MPI particles. To simulate the stability of the MPI-doxorubicin in vivo, it was stored in artificial lysosomal fluid (ALF, pH 4.5). Although the MPI-doxorubicin particles were still visible after 165 days in ALF, 53% of glycosidic bonds in the inulin particles were hydrolyzed within 12 days in ALF, reflected by the release of free glucose into solution. By contrast, the fructosidic bonds were much more stable. Drug release studies of the MPI-doxorubicin in vitro, demonstrated a successful pH-dependent controlled release effect. Confocal laser scanning microscopy studies and flow cytometric analysis confirmed that when incubated with live cells, MPI-doxorubicin was efficiently internalized by immune cells. An assay of cell metabolic activity demonstrated that the MPI carrier alone had no toxic effects on RAW 264.7 murine monocyte/macrophage-like cells, but exhibited anti-cancer effects against HCT116 human colon cancer cells. MPI-doxorubicin had a greater anti-cancer cell effect than free doxorubicin, particularly when at lower concentrations, suggesting a drug-sparing effect. This study establishes that MPI can be successfully modified with doxorubicin for chemotherapeutic drug delivery.
Highlights
Targeted drug release has received considerable interest to achieve the controlled release of therapeutic drug doses at target sites, thereby reducing peak systemic concentrations and the risks of dose-related side effects and toxicity [1,2]
The key advantages of using inulin particles in microparticulate inulin (MPI) rather than free soluble inulin, which was reported by Peppas and colleagues in 2013 [27], could further help drug conjugate effectiveness by preventing rapid renal excretion, increasing the biological half-life, and enabling uptake of the injected MPI particles by monocytes with subsequent selective tissue transport to lymphoid organs [28,29]
As the doxorubicin was released from MPI-doxorubicin, free doxorubicin was evaluated by HPLC using aliquots (200 μL) from the removed samples and following the validated method described below
Summary
Targeted drug release has received considerable interest to achieve the controlled release of therapeutic drug doses at target sites, thereby reducing peak systemic concentrations and the risks of dose-related side effects and toxicity [1,2]. Natural polysaccharides are often significantly cheaper to source and may be easier to manipulate than other carriers [12] Their many hydroxyl groups and other chemistries can act as a scaffold for chemical modification and drug attachment [13,14]. The key advantages of using inulin particles in MPI rather than free soluble inulin, which was reported by Peppas and colleagues in 2013 [27], could further help drug conjugate effectiveness by preventing rapid renal excretion, increasing the biological half-life, and enabling uptake of the injected MPI particles by monocytes with subsequent selective tissue transport to lymphoid organs [28,29]. We sought to design an acid–labile covalent linkage system to attach doxorubicin to the nanostructured MPI surface In this system, a covalent bond is formed, ameliorating the risk of a burst release mechanism, which is common for monocyte-targeted liposomal systems [30]. The reported results show the ability to use MPI-doxorubicin particles as a promising drug delivery system
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