Stimulation of Phagocytic Activity of Alveolar Macrophages Toward Artificial Microspheres by Infection with Mycobacteria

Hirota, Keiji; Tomoda, Keishiro; Inagawa, Hiroyuki; Kohchi, Chie; Soma, Gen‐Ichiro; Makino, Kimiko; Terada, Hiroshi

doi:10.1007/s11095-007-9525-8

Cited by 15 publications

(12 citation statements)

References 51 publications

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“…14,33,34 These intracellular reactive nitrogen intermediate are directly mycobactericidal. 14,35,36 NO in concentration of 4-5 mM is toxic to lung epithelial cells. 37 In the present investigation the maximum concentration of NO was found to be 0.0055 mM after 15 min of administration of INH-PM.…”

Section: In Vivo Study For Inh Im and Inh-pmmentioning

confidence: 99%

Inhaled microparticles of antitubercular antibiotic for in vitro and in vivo alveolar macrophage targeting and activation of phagocytosis

et al. 2014

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Tuberculosis (TB) is a chronic infectious disease with increasing incidence of drug resistance. Oral treatment for TB and multidrug resistance-TB can have serious side effects. The causative agent of TB, Mycobacterium tuberculosis, resides in alveolar macrophages (AMs). Pulmonary administration of antitubercular (anti-TB) antibiotic can help in delivery of high concentration to AM. The ability of AM to phagocytose can also be utilized to generate mycobactericidal nitric oxide (NO) to improve efficacy of anti-TB antibiotics. The objective in this investigation was made to prepare isoniazid microparticles (IM) and polymeric microparticles of isoniazid (INH-PM) using poly-ε-caprolactone as polymer and to evaluate in vitro through cell culture techniques and in vivo through pulmonary administration of IM and INH-PM for uptake of isoniazid by AM. The hepatotoxicity was determined through serum glutamate oxaloacetate transferase (SGOT) and serum glutamate pyruvate transferase (SGPT) levels and histological examination. The results depicted that the significantly higher (P<0.05) concentration of isoniazid was found in AM with INH-PM in vitro and in vivo. NO production was also significantly higher but less than toxic level. SGOT and SGPT levels, uptake of INH by liver and histological examination were indicative of no hepatotoxicity with INH-PM and IM. Phagocytosis of IM and INH-PM leads to significantly higher drug level in AM as well as production of significantly higher levels of NO without compromising the viability of cells. The administration of IM and INH-PM as dry powder inhalation formulation may reduce the treatment time of TB and chances of drug-resistant TB.

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Section: In Vivo Study For Inh Im and Inh-pmmentioning

confidence: 99%

Inhaled microparticles of antitubercular antibiotic for in vitro and in vivo alveolar macrophage targeting and activation of phagocytosis

et al. 2014

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“…Such activation leads to accumulation of reactive nitrogen intermediates (RNIs) in forming phagosome (Marcinkiewicz, 1997;Ricciardolo et al, 2004;Kolodziej & Kiderlen, 2007). These intracellular RNIs are directly mycobactericidal (Nathan & Hibbs, 1991, Ricciardolo et al, 2004Hirota et al, 2008).…”

Section: Phagocytosis Activity and Generation Of Nomentioning

confidence: 99%

Microparticles of rifampicin: comparison of pulmonary route with oral route for drug uptake by alveolar macrophages, phagocytosis activity and toxicity study in albino rats

Parikh¹,

Patel

Dalwadi³

2013

Drug Delivery

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Context: Tuberculosis (TB) is a chronic infectious disease with increasing incidence of drug resistance. Oral treatment for TB and multidrug resistance (MDR)-TB can have serious side effects. The causative agent of TB, Mycobacterium tuberculosis, resides in alveolar macrophages (AM). Pulmonary administration of anti-TB drugs can help in delivery of high concentration to AM. The ability of AM to phagocytose can also be utilized to generate mycobactericidal nitric oxide (NO) to improve efficacy of anti-TB drugs. Objective: To compare the uptake of rifampicin (RIF) by AM post oral and pulmonary administration of RIF microparticles (RM) and to compare hepatotoxicity and phagocytosis activity. Materials and Methods: RM were produced by spray drying process. RM were administered to rats through oral as well as intratracheal route. The uptake of RIF by AM and liver was measured. NO was measured in bronchoalveolar lavage (BAL) fluid. SGOT and SGPT levels were measured in serum. Results: Significantly higher (p50.05) concentration of RIF was found in AM post intratracheal administration. NO production was also significantly higher but less than toxic level. SGOT and SGPT levels as well as uptake of RIF by liver were indicative of no hepatotoxicity post intratracheal administration. Discussion: Phagocytosis of RM post intratracheal administration leads to significantly higher drug level in AM as well as production of significantly higher levels of NO. Conclusion: The administration of RM as dry powder inhalation (DPI) formulation may reduce treatment time of TB and chances of drug resistance TB.

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“…For micro particle formulations, 3-5 micron size range has been shown to be ideal for oral delivery [20]. The suitable size range for phagocytosis is 1-7µm [21][22]. Thus, the NF-κB antisense particle will be similarly functional in terms of size after gammairradiation.…”

Section: Resultsmentioning

confidence: 99%

Untitled

2017

MOJDDT

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Gamma irradiation is the most common sterilization process used in the pharmaceutical industry. Here, we have determined the stability and integrity of a NF-κB antisense after applying gamma radiation. A radiation of 25 kGy was applied to the microencapsulated antisense. The micro particle was characterized by SEM, Zeta potential, and HPLC before and after gamma-irradiation for evaluation. An in vitro study was conducted to determine the biological functionality. The size of the particle before and after radiation was similar. The zeta potential value was negative in both cases. The HPLC analysis showed that the antisense was intact after gamma irradiation. In vitro study showed the gamma radiated antisense blocks TNF-µ and IL-1b cytokines. The microsphere was unchanged during the gamma irradiation in terms of size, shape, surface morphology and surface charge. No degradation of the antisense drug during the radiation process was observed and is biologically active.Keywords: Gamma radiation; Microspheres; Albumin; NF-κB; Cytokine; after sterilization using gamma-irradiation. Encapsulation of drug molecules with polymers is an important aspect of drug delivery that facilitates effective therapy by targeting the drug entities as well as protecting the molecules from adverse conditions, such as harsh acidic environment or enzymatic degradation before reaching the target [12]. Antisense oligonucleotides are short single stranded DNA or RNA molecules (15-25 nucleotides) which are effective blocking agents for protein expression with high sequence specificity [13]. Antisense drugs are less stable in blood serum, when delivered orally, because they are prone to enzymatic degradation in the body. Hence, enhanced stability of the antisense drug after oral administration is desirable for its therapeutic use [14]. When antisense is microencapsulated with a biodegradable polymer, it has to be sterilized before administration. Gammairradiation is commonly used for antisense micro particle sterilization, but the radiation may have adverse effect on the particles. Gamma-irradiation can cause not only the degradation of the antisense, but also the polymer that encapsulates the antisense. Therefore, it is very crucial to determine the stability and integrity of the polymer/drug after gamma-irradiation. The goal of the present study is to determine the stability, integrity and biological activity of the microencapsulated antisense after radiation sterility. Materials and Methods Materials and chemicalsAntisense oligonucleotides specific to the rat and mouse mRNA sequence of the NF-κB p65 subunit were obtained from TriLink Bio Technologies (San Diego, CA). The sequence of the NF-κB p65 antisense oligonucleotides was provided by AVI Biopharma (Corvallis, Oregon) and was as follows: 5′-GGA AAC ACA TCCTCC ATG-3′. The oligonucleotides were purified using anion exchange HPLC and were packaged as a lyophilized solid. Bovine serum albumin (BSA; Fraction V, DNAase, RNAase, and protease-free) was obtained from Fisher Scientific (No...

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Stimulation of Phagocytic Activity of Alveolar Macrophages Toward Artificial Microspheres by Infection with Mycobacteria

Abstract: Mycobacterial infection stimulated the phagocytic uptake toward cPLGA MS. These results suggest that RFP-PLGA MS is favorable for overcoming tuberculosis.

Cited by 15 publications

References 51 publications

Inhaled microparticles of antitubercular antibiotic for in vitro and in vivo alveolar macrophage targeting and activation of phagocytosis

Inhaled microparticles of antitubercular antibiotic for in vitro and in vivo alveolar macrophage targeting and activation of phagocytosis

Microparticles of rifampicin: comparison of pulmonary route with oral route for drug uptake by alveolar macrophages, phagocytosis activity and toxicity study in albino rats

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