Date of Award
1-1-2021
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
Department
Pharmaceutics and Drug Delivery
First Advisor
Seongbong Jo
Second Advisor
Michael A. Repka
Third Advisor
S. Narasimha Murthy
Relational Format
dissertation/thesis
Abstract
Methylene blue (MB) with a 10-N-carbamoyl linkage was discovered and developed as a multifunctional far-red (660 nm) photocleavable ligand capable of rendering a series of MB conjugated compounds with off-to-on fluorescence switch properties through the controlled release of MB. The released MB was successfully demonstrated to be an effective photosensitizer, imaging probe, and therapeutic agent. The complete release of MB was achieved with a cumulative light dose of 15 J/cm2. The photosensitivity was demonstrated to be dependent on the type of chemical bond at 10-N of the phenothiazine ring which links MB to a side group. Specifically, the urea bond-based derivatives could undergo a complete photolysis, while those with carbamate bond showed negligible photolysis. The released MB was subsequently utilized as fluorescent imaging dye, and photosensitizer demonstrated through the significant reduction in cell viability compare to un-irradiated samples (16.1 ± 16.7 % and 72.8±0.33 %, respectively). The 10-N carbamoyl linkage MB was also reported to be a hydroxyl radical triggered cleavable ligand. Probed by this platform, hemoproteins were demonstrated to be a much more efficient Fenton’s catalyst than commonly used inorganic Fe(II) salts. The applicability of this ligand was demonstrated through the capability of being triggered by elevated reactive oxygen species levels at diseased tissue, with malaria-parasitized erythrocytes as an in vitro model. The conjugation between antimalarial agent primaquine (PQ), and MB moiety, was suggested to be preferentially activated by malaria parasite. Subsequently, the hybrid drug MB-PQ successfully demonstrated a relatively low IC50 (<30 >nM) towards malaria, and 2-5 times higher selectivity index compare to the parent compounds. The applicability of MB ligand was also utilized in the synthesis of liposome-forming material for drug delivery purposes. The MB conjugated phospholipid demonstrated the capability to form stimuli-responsive liposome. Specifically, upon irradiating with UV light or the treatment with ROS, the liposome structure was disrupted leading to the release of the payload.
Recommended Citation
Dao, Huy, "METHYLENE BLUE AS LIGHT AND REACTIVE OXYGEN SPECIES SENSITIVE LIGAND: APPICABILITY IN HYBRID DRUG AND MATERIAL SYNTHESIS" (2021). Electronic Theses and Dissertations. 1995.
https://egrove.olemiss.edu/etd/1995