Conjugated Polymer Nanoparticles for Biological Labeling and Delivery

Cancer remains one of the world’s most devastating diseases, with more than 10 million new cases every year. However, traditional treatments have proven insufficient for successful medical management of cancer due to the chemotherapeutics’ difficulty in achieving therapeutic concentrations at the target site, non-specific cytotoxicity to normal tissues, and limited systemic circulation lifetime. Although, a concerted effort has been placed in developing and successfully employing nanoparticle(NP)-based drug delivery vehicles successfully mitigate the physiochemical and pharmacological limitations of chemotherapeutics, work towards controlling the subcellular fate of the carrier, and ultimately its payload, has been limited. Because efficient therapeutic action requires drug delivery to specific organelles, the subcellular barrier remains critical obstacle to maximize the full potential of NP-based delivery vehicles. The aim of my dissertation work is to better understand how NP-delivery vehicles’ structural, chemical, and physical properties affect the internalization method and subcellular localization of the nanocarrier. In this work we explored how side-chain and backbone modifications affect the conjugated polymer nanoparticle (CPN) toxicity and subcellular localization. We discovered how subtle chemical modifications had profound consequences on the polymer’s accumulation inside the cell and cellular retention. We also examined how complexation of CPN with polysaccharides affects uptake efficiency and subcellular localization. This work also presents how changes to CPN backbone biodegradability can significantly affect the subcellular localization of the material. A series of triphenyl phosphonium-containing CPNs were synthesized and the effect of backbone modifications have on the cellular toxicity and intracellular fate of the material. A mitochondrial-specific polymer exhibiting time-dependent release is reported. Finally, we present a novel polymerization technique which allows for the controlled incorporation of electron-accepting benzothiadiazole units onto the polymer chain. This facilitates tuning CPN emission towards red emission. The work presented here, specifically, the effect that side-chain and structure, polysaccharide formulation and CPN degradability have on material’s uptake behavior, can help maximize the full potential of NP-based delivery vehicles for improved chemotherapeutic drug delivery.

Association between mean residual life (MRL) and failure rate functions for continuous and discrete lifetime distributions

The purpose of this study was to correct some mistakes in the literature and derive a necessary and sufficient condition for the MRL to follow the roller-coaster pattern of the corresponding failure rate function. It was also desired to find the conditions under which the discrete failure rate function has an upside-down bathtub shape if corresponding MRL function has a bathtub shape. The study showed that if discrete MRL has a bathtub shape, then under some conditions the corresponding failure rate function has an upside-down bathtub shape. Also the study corrected some mistakes in proofs of Tang, Lu and Chew (1999) and established a necessary and sufficient condition for the MRL to follow the roller-coaster pattern of the corresponding failure rate function. Similarly, some mistakes in Gupta and Gupta (2000) are corrected, with the ensuing results being expanded and proved thoroughly to establish the relationship between the crossing points of the failure rate and associated MRL functions. The new results derived in this study will be useful to model various lifetime data that occur in environmental studies, medical research, electronics engineering, and in many other areas of science and technology.

New Bivariate Lifetime Distributions Based on Bath-Tub Shaped Failure Rate

A class of lifetime distributions which has received considerable attention in modelling and analysis of lifetime data is the class of lifetime distributions with bath-tub shaped failure rate functions because of their extensive applications. The purpose of this thesis was to introduce a new class of bivariate lifetime distributions with bath-tub shaped failure rates (BTFRFs). In this research, first we reviewed univariate lifetime distributions with bath-tub shaped failure rates, and several multivariate extensions of a univariate failure rate function. Then we introduced a new class of bivariate distributions with bath-tub shaped failure rates (hazard gradients). Specifically, the new class of bivariate lifetime distributions were developed using the method of Morgenstern’s method of defining bivariate class of distributions with given marginals. The computer simulations and numerical computations were used to investigate the properties of these distributions.

Conjugated polymer nanoparticles for biological labeling and delivery

Cancer remains one of the world’s most devastating diseases, with more than 10 million new cases every year. However, traditional treatments have proven insufficient for successful medical management of cancer due to the chemotherapeutics’ difficulty in achieving therapeutic concentrations at the target site, non-specific cytotoxicity to normal tissues, and limited systemic circulation lifetime. Although, a concerted effort has been placed in developing and successfully employing nanoparticle(NP)-based drug delivery vehicles successfully mitigate the physiochemical and pharmacological limitations of chemotherapeutics, work towards controlling the subcellular fate of the carrier, and ultimately its payload, has been limited. Because efficient therapeutic action requires drug delivery to specific organelles, the subcellular barrier remains critical obstacle to maximize the full potential of NP-based delivery vehicles. The aim of my dissertation work is to better understand how NP-delivery vehicles’ structural, chemical, and physical properties affect the internalization method and subcellular localization of the nanocarrier. ^ In this work we explored how side-chain and backbone modifications affect the conjugated polymer nanoparticle (CPN) toxicity and subcellular localization. We discovered how subtle chemical modifications had profound consequences on the polymer’s accumulation inside the cell and cellular retention. We also examined how complexation of CPN with polysaccharides affects uptake efficiency and subcellular localization. ^ This work also presents how changes to CPN backbone biodegradability can significantly affect the subcellular localization of the material. A series of triphenyl phosphonium-containing CPNs were synthesized and the effect of backbone modifications have on the cellular toxicity and intracellular fate of the material. A mitochondrial-specific polymer exhibiting time-dependent release is reported. Finally, we present a novel polymerization technique which allows for the controlled incorporation of electron-accepting benzothiadiazole units onto the polymer chain. This facilitates tuning CPN emission towards red emission. ^ The work presented here, specifically, the effect that side-chain and structure, polysaccharide formulation and CPN degradability have on material’s uptake behavior, can help maximize the full potential of NP-based delivery vehicles for improved chemotherapeutic drug delivery.^