We have shown enhanced therapeutic efficacy of a novel doxorubicin-containing low temperature sensitive liposome (Dox-LTSL) which releases contents within seconds when heated (HT) above its transition temperature (40?C). We propose to expand this effort to better use Dox-LTSL and to test whether HT+ cisplatin-LTSL can effectively treat cisplatin-resistant xenografts and sensitize tumors to HT+cisplatin-LTSL+ radiotherapy (RT).
The specific aims are: (1) Using a novel MnSO4-Dox-LTSL, we show that drug can be """"""""painted"""""""" to tumor subregions (central, peripheral or uniform deposition) by manipulation HT protocol. The antitumor efficacy of these three drug deposition patterns will be compared. (2) We show that cisplatin-LTSL also shows rapid drug release. We will determine whether HT+cisplatin-LTSL can reverse cisplatin resistance and enhance local antitumor effects when combined with RT. (3) Dox-LTSL causes vascular shut down in preclinical models, probably by inducing endothelial cell necrosis. The pathophysiologic effects of HT+Dox-LTSL or HT+cisplatin-LTSL on tumors will be studied using functional imaging and pathological exam. 62-CuPTSM and 62-Cu-ATSM will be used before and after treatment to assess changes in perfusion and hypoxia, respectively. Apparent diffusion coefficient (ADC) will be used to determine changes in cell density. Parallel immunohistochemical analysis will provide mechanistic underpinning for imaging results. This project interfaces strongly with projects 1, 2 and 5. Spatial temperature control can control drug delivery features that maximize antitumor efficacy of the LTSL. Demonstration of enhanced activity of cisplatin-LTSL+HT will provide strong rationale for clinical development to treat drug resistant recurrent ovarian cancer and locally advanced tumors where combinations of chemotherapy and RT yield less than maximal effects. Functional imaging studies dovetail perfectly with parallel studies that are ongoing in the human liposome clinical trials and provide pathologic interpretation for these studies.
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