The overall objective of this research proposal is to determine mechanisms of drug release and mechanisms of drug action for a new thermal-sensitive liposomal delivery system that has already shown very positive local control in animal experiments. It is proposed to continue basic in vitro studies concerning temperature-triggered drug release from the new liposomes and the use of other lipids and surfactants to provide greater understanding and control over the process. These in vitro studies will be coupled with in vivo studies that will determine drug delivery, drug distributions, drug action and efficacy, all enhanced by the application of mild, clinically attainable hyperthermia. These goals will be accomplished by carrying out the following specific aims. SA1. To more fully characterize the mechanism of thermally-induced lipid membrane permeability to a range of solutes. SA2. To test other bilayer compatible compounds. SA3. To investigate mechanisms of tumor growth delay induced by the new doxorubicin formulation. SA4. To optimize liposomal doxorubicin delivery in solid tumors. SA5. To test preclinically the antitumor effect of two different liposomal drug formulations in tumor growth delay models. Methods in SAs 1, and 2 will include spectrophotometric and calorimetric analysis for drug release, electron microscopy for bilayer structure, and differential scanning calorimetry for characterizing the thermal properties of the liposomes. In the in vivo studies Homozygous NCr athymic nude mice (20 q 3g) will be used to grow four tumor lines: FaDu, a human squamous carcinoma, SKOV3, a human ovarian carcinoma, LNCaP, a human prostate carcinoma, and MCF7, a human mammary carcinoma. Experimental methods for SAs 3, 4 and 5, include, skin flap window chamber with fluorescence microscopy and subcutaneous tumors for drug deposition, distribution and tumor growth delay; tissue extraction and HPLC for drug analysis; and histological staining for apoptosis of endothelial cells. This new low temperature sensitive liposome provides an opportunity for a complete paradigm shift with regard to the use of hyperthermia clinically. It works effectively at less than or equal to 42 C, and so applications of this technology can now be considered for potentially curable deep-seated tumors, such as ovarian and prostate cancer. The studies are necessary in order to optimize the new system to achieve local control for a range of solid tumors in clinical trials of the new liposomal doxorubicin in a Program Project at Duke University. The results of the study will be critical to the burgeoning health-related field of drug delivery, and to cancer treatment in particular.
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