Beta-Lapachone Nanotherapeutics for Lung Cancer Therapy
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A rising trend in lung cancer chemotherapy involves the development of agents that exploit molecular targets overexpressed in tumors, with hopes of increasing specificity, and in turn, efficacy. apachone (᭬ap) is a novel anticancer drug whose mechanism of action relies on its bioactivation by the enzyme NAD(P)H:quinone oxidoreductase-1, NQO1, found overexpressed in NSCLC. While promising, its low water solubility limits its clinical translation. Moreovoer, a clinical formulation of the drug proves highly hemolytic and relatively ineffective. Our objective was to develop ᭬apachone polymer micelles for lung cancer treatment, in hopes of targeting tumors: 1) pharmacokinetically, through the use of a platform that will ensure drug stability, bioavailability, and targeted localized delivery; and 2) pharmacodynamically, through the use of an anticancer drug that is bioactivated by a tumor-specific enzyme. We hypothesize that ᭬apachone polymer micelles will result in a highly specific and effective nanotherapeutic platform for the treatment of lung cancer. Studies involving the clinical formulation of ᭬ap demonstrated that the vehicle, hydroxypropyl-᭣yclodextrin (HPᭃD), causes hemolysis. The rapid dissociation of ᭬ap with HPᭃD led to short blood circulation times and rapid distribution among all organs. By contrast, a micellar formulation of ᭬ap did not cause hemolysis, and displayed increased blood circulation times and relatively high and sustained accumulation in tumors. ap micelles were small in size (~30 nm), possessed core-shell morphology, and displayed favorable release kinetics. In vitro examination of ᭬ap micelle efficacy in cancer cell lines demonstrated an NQO1-dependent mechanism of cell death. Upon translation to in vivo models of lung cancer in mice, ᭬ap micelles hindered tumor growth in subcutaneous lung tumors. It is important to note at this time that the clinical formulation of ᭬ap displayed no antitumor effects when compared to control tumors. Upon examination in an orthotopic model of lung cancer in mice, ᭬ap micelles were shown to prolong animal survival. Results from this study point toward the therapeutic potential of ᭬ap micelles for lung cancer treatment. Future studies involve optimization of the basic platform, as well as adjuvant use with current therapeutic strategies, to help propel this technology to preclinical studies and eventual clinical use.