Doxorubicin-Loaded Delta Inulin Conjugates for Controlled and Targeted Drug Delivery: Development, Characterization, and In Vitro Evaluation

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.

Apamin-Conjugated Alendronate Sodium Nanocomplex for Management of Pancreatic Cancer

“…In the case of preparation of APA-ALS-NC, incubation time is similar to reaction time offered for the attachment of ALS (drug) to APA. Increasing reaction time increases the conjugation process, i.e., the attachment of drug [ 36 ]. Thus, increasing incubation time increases the chance for attachment of more drug molecules and subsequent increase in particle size.…”

Polychemotherapy with Curcumin and Doxorubicin via Biological Nanoplatforms: Enhancing Antitumor Activity

“…It is worth mentioning that both DOX and curcumin suffer from poor bioavailability. In light of this, a wide variety of nanoplatforms have been developed for codelivery of curcumin and DOX [ 179 , 180 , 181 ]. In addition to promoting cellular internalization of DOX, nanocarriers can prevent development of chemoresistance, since a low amount of DOX is loaded on/in the encapsulants.…”

Potential applications of hydrophobically modified inulin as an active ingredient in functional foods and drugs - A review

“…It was observed that the administered delta inulin particles were transported to the liver as well as secondary lymphoid tissue after being primarily taken up by macrophages, hydrolyzed to be dispersed into the bloodstream and finally eliminated into the urine. Furthermore, delta inulin was modified by coating doxorubicin on its nanostructured surface for application in targeted drug delivery for anticancer therapy ( Wang et al, 2019 ). The authors used the property of delta inulin in which it is endocytosed by monocytes to design a platform to transport doxorubicin to lymphoid organs.…”

“…In addition, HMI such as amine derivatives have been grafted with biotin, retinoic acid, and vitamin E to produce mucoadhesive micelles, which exhibit transcorneal permeation properties, as well as long-circulating carriers for receptor-mediated targeted drug delivery ( Di Prima et al, 2017 ; Mandracchia et al, 2018 ). Studies have revealed that inulin serves as a promising transporter for colonic drug delivery because it is not digested in the stomach and small intestine ( Wang et al, 2019 ). SCFAs play an important physiological role in combating colon-related diseases and altering gut microbiota compositions.…”