Optimization of reconstituted high density lipoprotein nanoparticles as a delivery system for neuroblastoma treatment

摘要

Despite many advances in cancer therapy over the last few decades, cancer remains one of the most common causes of death in not only the United States, but around the world. Two of the major problems cancer patients face today are the horrific side effects associated with chemotherapy, and the development of drug resistance. Both of these become even bigger problems when they are applied to children. Neuroblastoma is one of the most common forms of pediatric cancer. High risk Neuroblastoma patients are commonly faced with intensive multi-modal therapies in attempt to overcome a very aggressive disease. Due to the intensive therapy required, side effects can often linger even after remission is achieved in these patients, and multi-drug resistance is common due to the high levels of Doxorubicin administered. New solutions are needed in order to overcome both of these problems in Neuroblastoma as well as other types of cancer.;In this thesis, we studied the effects of different formulation and preparation techniques for the reconstituted high density lipoprotein nanoparticle model for anti-cancer agent delivery. During these studies we found that naturally derived mixes of phosphatidylcholine, and lower levels of apolipoprotein A-1 increase the encapsulation efficiency of the rHDL nanoparticles. We also determined that the addition of lyophilization during preparation before cholate dialysis, forms a more homogeneous preparation. After the optimization of the particle formulation and preparation, we tested the efficacy of two model anti-cancer agents in different cancer cells. First we showed the ability of the rHDL-siRNA nanoparticles to knockdown the SR-B1 protein is greater than the knockdown of a commercial transfection kit. Finally we prove that the rHDL also improves the cytotoxic efficacy of a novel treatment for Neuroblastoma involving Imatinib Mesylate and Saquinavir.;In conclusion, the results of this thesis show a more detailed knowledge of the rHDL nanoparticle formulation as well as how it can be applied as an effective delivery system for both siRNA and chemotherapeutic agents. This data should help push our formulations closer to clinical applications, and toward helping reduce the toxic side effects of many chemotherapeutic agents, as well as reducing the incidence of drug resistance.