| The overall purpose of this thesis is to develop methods for optimizing the administration of cisplatin and paclitaxel, both anticancer chemotherapeutic agents, and vancomycin, an antibiotic, using either hydrophobic ion-pairing (HIP) or a controlled release system for localized delivery, or a combination of the two. Besides generally introducing the needs for developing alternative methods for the formulation and delivery of chemotherapy other than the conventional methods, chapter I gives the rationales for using HIP and localized delivery via a controlled release system. There has been tremendous effort in developing new platinum (Pt)-based anticancer drugs with the purpose of developing less toxic and/or more effective Pt-based agents. Chapter II of this thesis demonstrates that, using HIP, it is possible to obtain a Pt-based complex with improved hydrophobicity, increased intracellular uptake, and enhanced in vitro potency. Chapter III evaluates the in vivo toxicity, pharmacokinetics, and efficacy of the HIP complex of cisplatin in a mouse mammary carcinoma model. This study indicates that the HIP complex of cisplatin is effective in preventing tumor from recurrence in the tested mouse model after surgery. Vancomycin is commonly used in treating deep bone infections in diabetic patients. However, its limited clinical efficacy in poorly vascularized body sites during parenteral use and the risks of toxicity associated with high serum concentrations warrant the search for new approaches to deliver this agent. In chapter IV, it is proposed to use HIP to form a hydrophobic complex of vancomycin and formulate this HIP complex into an aqueous poloxamer gel. A slow dissolution process of the HIP complex of vancomycin in physiochemical solution was observed. A prolonged release of the HIP complex from an aqueous poloxamer gel has been demonstrated, suggesting a potential clinical application. Paclitaxel is an important anticancer agent, but its delivery has been challenging. In this thesis, paclitaxel is formulated in two different types of polymeric systems and locally delivered by subcutaneous injection. One formulation uses the aqueous poloxamer 407 gel and the other one uses Atrigel®. In chapters V and VI, the pharmacokinetic profiles and toxicity are determined and the efficacy is evaluated in a mouse mammary carcinoma model in combination with surgery for the two formulations, respectively. It is demonstrated that no or low toxicity and improved therapeutic effects are associated with the localized delivery of paclitaxel via polymeric controlled release systems. |
