Design and biological evaluation of new NSAIDS based anticancer agents and their controlled release from an addressable hydrogel based delivery system.

摘要

In recent years scientific and technological advancements have been made in the research and development of controlled drug delivery systems and new chemopreventive agents. For many potential drug candidates a modified in vivo drug release is desired to improve efficacy, sustain drug effect or minimize drug toxicity. To tackle the problems associated with the delivery of drug, delivery systems (DDS) with multiple functionalities such as environment-sensitive drug release mechanisms have motivated the biomedical community as well as materials chemists for more than a decade. Polymeric drug delivery systems have been extensively studied in an attempt to achieve modified drug release. Here we report on a novel thermo-responsive based system to fabricate biocompatible polymeric hydrogels as drug delivery as well as the development of a new class of non-steroidal anti-inflammatory drugs as chemopreventive agents. Biocompatible Pluronic F127 (PF127), a triblock copolymer, was employed as matrix materials for polymeric-based DDS. This thermo-sensitivepolymeric system have been modified by acrylation and cross-linked to form a hydrogel based drug delivery system. The modified polymeric system contains a hydrophobic polypropylene oxide (PPO) and a hydrophilic polyethylene oxide (PEO) blocks which undergoes a "hydrophilic-hydrophobic" phase transition in aqueous media and around the human body temperature. In addition, poly lactic-co-glycolic acid (PLGA) nanoparticles were assembled by solvent extraction method and incorporated in the modified Pluronic F127 hydrogels as drug carrier units. These modifications of PF127 were monitored by 1H-NMR and rheological studies. The rheological study determined that the degree of cross-linking affect the release rate of the drug from the PF127/PLGA system. The control release rate of the chemopreventive compounds seems to be further enhanced due to the addition of the PLGA nanoparticles. The in vitro cellular uptake and the cytotoxicity studies of the PLGA nanoparticles have been considered to determine their enhancement of drug uptake and the lack of acute cytotoxicity. The sensitivity of the polymer to the temperature was shown to facilitate drug release upon administered temperature changes.This work also focuses on the development and analysis of non-steroidal anti-inflammatory drugs (NSAIDs) as chemopreventive agents. NSAIDs are a class of drugs that are commonly used as medications because of their pain- and fever reducing properties. Several chemopreventive studies have reported that NSAIDs and their derivatives have potential promise as anticancer agents. Based on pharmaco-kinetics, pharmaco-dynamic and structure activity relationship studies performed in this work, a new series of NSAID derivatives have been designed and synthesized. In vitro evaluation showed that these new generations of NSAIDs exhibit higher potency than that of traditional NSAIDs such as aspirin, especially against pancreatic and colon cancer.One of two NSAIDs hydrophobic model drugs, sulindac sulfide or Drug D was loaded in the modified Pluronic F127/PLGA drug delivery system. The NSAIDs have been shown to be successfully release from the modified PF217/PLGA drug delivery system applied both media and cell culture. This property can find application in externally stimulated drug release applications at the site of the disease.The studies performed in this dissertation to analysis, design and synthesize the old and new generations of NSAIDs was a collaborative effort of many persons. I performed the majority of the analysis and manuscript workings after the NSAIDs were synthesized and animals were treated and sacrifice by other collaborators. All studies in regards to the construct and design of the PF127/PLGA drug delivery system were done under the guidance or Prof. Miriam Rafailovich and Dr. Basil Rigas.