Design and Characterization of Inulin Conjugate for Improved Intracellular and Targeted Delivery of Pyrazinoic Acid to Monocytes

Afinjuomo, Franklin; Barclay, Thomas G.; Parikh, Ankit; Song, Yunmei; Chung, Rosa; Wang, Lixin; Liu, Liang; Hayball, John D.; Petrovsky, Nikolai; Garg, Sanjay

doi:10.3390/pharmaceutics11050243

Cited by 10 publications

(19 citation statements)

References 67 publications

(75 reference statements)

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“…As expected, the INH thermogram is characterized by a single major thermal event (major decomposition) starting around 170 °C and finishing around 300 °C [77]. Inulin microparticles display typical three-step mass loss as reported in the literature [49,78]. The first stage weight loss of about 7% is attributed to the loss of water residue, followed by 51% major weight loss due to the inulin decomposition.…”

Section: Resultsmentioning

confidence: 61%

“…The inulin particles are made exclusively from very short polymer chains typically isolated at ~40 fructose units and up to 100 units by the annealing conditions [53]. The microparticles are normally between 1 and 2 μm diameter [49,51,54].…”

Section: Methodsmentioning

confidence: 99%

“…To expand the potential use of delta inulin as a drug delivery platform, we hypothesized that inulin microparticles may promote passive homing of drugs to the monocytes for targeted drug delivery in TB. This is based on well-documented use of microparticle conjugates for monocyte-mediated delivery [49,50]. Furthermore, previous work that shows delta inulin is efficiently internalized by monocytes [51] and suggests it could work as a conjugate to deliver isoniazid to Mtb infected cells.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Characterization of pH-Sensitive Inulin Conjugate of Isoniazid for Monocyte-Targeted Delivery

et al. 2019

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The use of particles for monocyte-mediated delivery could be a more efficient strategy and approach to achieve intracellular targeting and delivery of antitubercular drugs to host macrophages. In this study, the potential of inulin microparticles to serve as a drug vehicle in the treatment of chronic tuberculosis using a monocytes-mediated drug targeting approach was evaluated. Isoniazid (INH) was conjugated to inulin via hydrazone linkage in order to obtain a pH-sensitive inulin-INH conjugate. The conjugate was then characterized using proton nuclear magnetic resonance (1HNMR), Fourier transform infrared spectroscopy (FTIR) as well as in vitro, cellular uptake and intracellular Mycobacterium tuberculosis (Mtb) antibacterial efficacy. The acid-labile hydrazone linkage conferred pH sensitivity to the inulin-INH conjugate with ~95, 77 and 65% of the drug released after 5 h at pH 4.5, 5.2, and 6.0 respectively. Cellular uptake studies confirm that RAW 264.7 monocytic cells efficiently internalized the inulin conjugates into endocytic compartments through endocytosis. The intracellular efficacy studies demonstrate that the inulin conjugates possess a dose-dependent targeting effect against Mtb-infected monocytes. This was through efficient internalization and cleavage of the hydrazone bond by the acidic environment of the lysosome, which subsequently released the isoniazid intracellularly to the Mtb reservoir. These results clearly suggest that inulin conjugates can serve as a pH-sensitive intracellular drug delivery system for TB treatment.

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Section: Resultsmentioning

confidence: 61%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis and Characterization of pH-Sensitive Inulin Conjugate of Isoniazid for Monocyte-Targeted Delivery

et al. 2019

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“…Inulin propionate esters showed an appetite-suppressing effect by suppressing energy intake and stimulating the release of satiety hormones, thus preventing weight gain [33]. The conjugation of inulin with some antibiotic drugs proved to be favorable for the delivery of the drug in the treatment of tuberculosis [34]. Polyesters of inulin with various carboxylic acids, obtained by chemical synthesis, demonstrated excellent properties for paint compositions as a binder [35].…”

Section: Introductionmentioning

confidence: 99%

Chemoenzymatic Synthesis of New Aromatic Esters of Mono- and Oligosaccharides

et al. 2020

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An efficient and convenient chemoenzymatic route for the synthesis of novel phenolic mono-, di- and oligosaccharide esters is described. Acetal derivatives of glucose, sucrose, lactose and inulin were obtained by chemical synthesis. The fully characterized pure sugar acetals were subjected to enzymatic esterification with 3-(4-hydroxyphenyl) propionic acid (HPPA) in the presence of Novozyme 435 lipase as a biocatalyst. The aromatic esters of alkyl glycosides and glucose acetal were obtained with good esterification yields, characterized by mass spectrometry (MALDI-TOF MS), infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (1H NMR, 13C NMR). The synthesis of aromatic esters of disaccharide acetals was successful only for the enzymatic esterification of sucrose acetal. The new chemoenzymatic route allowed the synthesis of novel aromatic esters of inulin as the inulin monoacetal monoester and diester and the inulin diacetal monoester with a polymerization degree of two, as well as the inulin monoacetal monoester with a degree of polymerization of three, were obtained by enzymatic acylation of inulin acetals with HPPA. These compounds could represent a new class of sugar ester surfactants with enhanced bioactivity, antioxidative and antimicrobial properties and with potential application in drug delivery systems.

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“…A previous study showed that doxorubicin conjugated to soluble inulin using a carboxymethylation method enabled the cytotoxic response to be maintained or improved at lower doses as compared to free doxorubicin [27]. 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]. Consequently, we hypothesized that MPI might be a promising targeted drug delivery vehicle for immune cell cancers, such as myeloid leukemias.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Design and Characterization of Inulin Conjugate for Improved Intracellular and Targeted Delivery of Pyrazinoic Acid to Monocytes

Cited by 10 publications

References 67 publications

Synthesis and Characterization of pH-Sensitive Inulin Conjugate of Isoniazid for Monocyte-Targeted Delivery

Synthesis and Characterization of pH-Sensitive Inulin Conjugate of Isoniazid for Monocyte-Targeted Delivery

Chemoenzymatic Synthesis of New Aromatic Esters of Mono- and Oligosaccharides

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

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