Development of Closomer And MIBG based Nanoformulation: Application to HIV Prevention and Neuroblastoma Therapy
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Abstract
This dissertation is divided into two parts. Part #1 focuses on the development and characterization of closomer based nanoformulation for the prevention of HIV/AIDS sexual transmission. Part #2 focuses on the development and characterization of a meta-iodobenzylguadinine (MIBG) based nanoformulation of etoposide (VP-16) intended for the treatment of neuroblastoma. This work is presented in 6 chapters as described below, and partially in 3 peer-reviewed papers (see appendix). Part #1 and #2 are summarized in Chapters 4-5 and 6, respectively. In Chapters 1 and 2, an overview of the aims and scope of this study, and a literature review of the two parts of this dissertation is extensively discussed. In Chapter 3, it was hypothesized that fluorine 19 nuclear magnetic resonance (¹⁹F qNMR) can be used for real time quantification and in vitro release of maraviroc (MVC) – a first in its class FDA approved HIV entry inhibitor. The calibration assay produced a linearity curve in concentration range (0.42 mg/ml – 15 mg/ml), and the limits of detection and quantification values were 0.97 mg/ml and 2.93 mg/ml, respectively. The method was confirmed to be specific, accurate, precise, and robust (%RSE < 2%). The motivation for this study is that knowledge gained can be applied to subsequent work; quantifying, in real time fluorinated drug potency, purity, and stability, and in evaluating in vitro drug release kinetic from different formulations, in different biological medias. In chapter 4, it was hypothesized that phenyboronic acids (PBA) (gp-120 ligand) and MVC conjugated to closomer scaffold will be safer and more effective in HIV/AIDS prevention. The subsequent conjugation was completed via a one-pot microwave-assisted organic synthesis, and the reaction conditions were optimized using a screening method. Proton (¹H), carbon (¹³C), boron (¹¹B) NMR, and Fourier transform infrared (FTIR) spectroscopy were used to monitor the chemical reaction progress and elucidate the chemical structure and formula of the new compound. In Chapter 5, the novel Closogel is characterized, and its rheological properties thoroughly elucidated with hydroxy ethyl cellulose (HEC) used as a reference standard. The undiluted and 25 mg/ml (2.5% w/v) Closogels were more viscous than elastic (tan () > 1) in the linear viscoelastic range, while the 2.5 mg/ml (0.25% w/v) Closogel nearly exhibited a Newtonian behavior with a flow index of 0.93. The Herschel-Bulkley model showed a significant fitting to all experimental data (R² > 0.95). These data suggest that the Closomer-based gels have the desired rheological behavior, with lower complex modulus, and can be a promising platform used for delivery of topical antiviral or other bioactive agents. In Chapter 6, it was hypothesized that meta-iodobenzylguanidine (MIBG) complexation with VP-16 will improve drug solubility and specificity towards BE(2)C neuroblastoma (NB) cells, 90% of which are known to be MIBG avid. The resulting (1: 3 w/w) VP-16: MIBG complex had a mean diameter and zeta potential of 458.5 nm, and 0.951 mV, respectively, and the drug apparent water solubility was dramatically increased (~12-folds). MTS assay and exponential decay models (EDM) were used to assess the cell viability and decay rates, respectively. Multi-factorial ANOVA and an independent t-test were used to assess cell viability and solubility data, respectively. The EDM relating to percent cell viability to drug concentration yielded an excellent fit (r² > 0.95) and enabled to estimate the IC₅₀ values of both native drug and its complex: 6.2 µM and 5.23 µM, respectively (indicating a conservation of drug anticancer activity). Furthermore, the efficiency of the EDM for drug IC₅₀ estimation provides alternative mathematical method for such in vitro cytotoxicity studies. Overall, a novel PBA-closo gel of chemical formula closo-B₁₂O(C₇H₈BO₂)₁₂ was successfully synthesized. It has similar rheological properties as the commercially available HEC gel and could be used as a potential topical microbicide. Moreover, the VP-16-MIBG nanocrystalline complex, with conserved anticancer activity and enhanced solubility provides a new platform for NB theranostics.
Table of Contents
Introduction -- Literature review -- Fluorine (¹⁹F) nuclear magnetic resonance spectroscopy for real time maraviroc analysis from microparticulate systems -- Microwave assisted synthesis of 4-(bromomethyl) phenylboronic acid closomer nanoconjugate -- Rheological analysis of a novel phenylboronic acid-closomer gel -- Novel meta iodobenzylguanidine and etoposide complex: physicochemical characterization and mathematical modeling of anticancer activity -- Summary and future directions
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Ph.D. (Doctor of Philosophy)