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Targeting Drug-Resistant Tuberculosis Using SMART Nanotechnology Approach

Al-Shammaa, Zaid
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439310613

Abstract Details

2015, MS, University of Cincinnati, Pharmacy: Pharmaceutical Sciences.
Stimulus-induced drug delivery systems and nanotechnology allow selective targeting of disease-affected tissues in order to improve pharmacokinetic properties of therapeutics while minimizing adverse events associated with systemic exposure. The objective of this research was to explore Eudragit L-100, a pH sensitive co-polymer comprised of methacrylic acid and methyl methacrylate, in the fabrication of nanoparticles (NPs) that efficiently accumulate in alveolar macrophages and preferentially release the payload in Mycobacteria tuberculosis (TB)-infected lysosomes. The lipophilic fluorescent dye Rhodamine123 (Rh123) was selected as a surrogate for the anti-TB agent rifampicin. Eudragit L-100 NPs were prepared using the nanoprecipitation technique, which afforded colloids with a hydrodynamic diameter between 238-270 nm and a zeta potential ranging from –21.8 to –33.1 mV. Subsequent in vitro release experiments performed in phosphate-buffered saline at pH 5.5, 6.2 and 7.4 demonstrated pH-dependent release kinetics of Rh123 from NPs. In comparison to pH 5.5, the cumulative amount of Rh123 released was approximately 3-fold greater at pH 6.2 and 6-fold increased at pH 7.4. Regression analyses using various mathematical models suggested predominant contribution of passive diffusion in Rh123 release at pH 5.5, with increasing assistance of carrier erosion at pH 6.2 and 7.4. Incubation of the mouse alveolar macrophage (MH-S) cell line with Rh123-containing NPs revealed a 50% decrease in cellular viability at NP concentrations of 2.8 mg/mL. Consequently, cellular uptake experiments were performed using a NP concentration of 1.62 mg/mL where viability > 99.9% was guaranteed. To simulate less acidic lysosomal pH conditions of TB-infected macrophages, MH-S cells were exposed to NH4Cl concentrations up to 100 mM. Only the highest NH4Cl concentration increased the lysosomal pH of MH-S cells from resting pH 5.5 to the desired pH 6.2. Cellular uptake of Rh123-containing Eudragit L-100 NPs was assessed spectrophotometrically using NH4Cl- and vehicle-treated control cells. Interestingly, intracellular Rh123 concentrations were significantly decreased in NH4Cl-treated cells. As confocal microscopy was unable to distinguish intracellular distribution pattern between NP-associated and dissolved Rh123, alternative methodologies must be explored to determine whether less acidic lysosomal pH alters the release of Eudragit L-100 NP payload in TB-infected macrophages.
Giovanni Pauletti, Ph.D. (Committee Chair)
Gary Thompson, Ph.D. (Committee Member)
Kevin Li, Ph.D. (Committee Member)
89 p.
Pharmaceuticals
EUDRAGIT L-100; NANOPARTICLES; TUBERCULOSIS; STIMULUS-INDUCED DRUG DELIVERY SYSTEM

Recommended Citations

Citations

  • Al-Shammaa, Z. (2015). Targeting Drug-Resistant Tuberculosis Using SMART Nanotechnology Approach [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439310613

    APA Style (7th edition)

  • Al-Shammaa, Zaid. Targeting Drug-Resistant Tuberculosis Using SMART Nanotechnology Approach. 2015. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439310613.

    MLA Style (8th edition)

  • Al-Shammaa, Zaid. "Targeting Drug-Resistant Tuberculosis Using SMART Nanotechnology Approach." Master's thesis, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439310613

    Chicago Manual of Style (17th edition)

ucin1439310613
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This open access ETD is published by University of Cincinnati and OhioLINK.