The MAPK signal transduction cascade is dysregulated in a majority of human tumors. Here we report that a nanoparticle-mediated targeting of this pathway can optimize cancer chemotherapy. We engineered nanoparticles from a unique hexadentate-polyD,Llactic acid-co-glycolic acid polymer chemically conjugated to PD98059, a selective MAPK inhibitor. The nanoparticles are taken up by cancer cells through endocytosis and demonstrate sustained release of the active agent, resulting in the inhibition of phosphorylation of downstream extracellular signal regulated kinase. We demonstrate that nanoparticle-mediated targeting of MAPK inhibits the proliferation of melanoma and lung carcinoma cells and induces apoptosis in vitro. Administration of the PD98059-nanoparticles in melanoma-bearing mice inhibits tumor growth and enhances the antitumor efficacy of cisplatin chemotherapy. Our study shows the nanoparticle-mediated delivery of signal transduction inhibitors can emerge as a unique paradigm in cancer chemotherapy.cancer ͉ signal transduction C ancer is the second leading cause of mortality in the United States, with an estimated 1,444,180 new cases and 565,650 deaths in 2008 (1). Standard chemotherapy nonspecifically targets all dividing cells, resulting in dose-limiting toxicities. Consequently, there is an urgent need to develop novel strategies that are more specifically targeted against the tumor. The MAPK pathway comprising of RAS, RAF, MEK, and ERK has been implicated in a majority of human tumors, often through gain of function mutations in the RAS and RAF families (2, 3). Indeed, RAS mutations occur in 30% of all cancer, and are particularly implicated in over 90% of pancreatic cancers (4) and 50% of colon cancers (5); RAF mutations are prevalent in over 60% of melanomas (6) and over 35% of ovarian cancers (7). As a result, the MAPK pathway has evolved as a focus of intense investigation for developing small molecule inhibitors as targeted therapeutics.Another emerging strategy for targeted chemotherapy is to harness nanovectors for preferential delivery of drugs into the tumor (8). A wide range of nanovectors, including liposomes, micelles, polymeric nanoparticles, silicon and gold nanoshells, polymeric dendrimers, and carbon-based nanostructures, have been used for drug delivery to the tumor (9). It is well established that nanoparticles preferentially localize at the tumors as a result of the enhanced permeation and retention effect (10, 11). Indeed, a nanoliposomal formulation of cisplatin was shown to attain 10-to 200-fold increased drug concentration in tumors during a Phase-I clinical trial (12). However, standard liposomal or protein carrier-based nanoplatforms have limited control over drug release. In contrast, controlled-release drug delivery systems have the potential to induce standardized and durable clinical responses.Interestingly, while extensive studies have been done on delivering cytotoxic agents to solid tumors using nanovectors, no report exists on combining targeted therapeutics with nanopa...

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BackgroundAnti-angiogenic therapy in certain cancers has been associated with improved control of tumor growth and metastasis. Development of anti-angiogenic agents has, however, been saddled with higher attrition rate due to suboptimal efficacy, narrow therapeutic windows, or development of organ-specific toxicities. The aim of this study was to evaluate the translational ability of the zebrafish efficacy–toxicity model to stratify anti-angiogenic agents based on efficacy, therapeutic windows, and off-target effects to streamline the compound selection process in anti-angiogenic discovery.MethodsThe embryonic model of zebrafish was employed for studying angiogenesis and toxicity. The zebrafish were treated with anti-angiogenic compounds to evaluate their effects on angiogenesis and zebrafish-toxicity parameters. Angiogenesis was measured by scoring the development of subintestinal vessels. Toxicity was evaluated by calculating the median lethal concentration, the lowest observed effect concentration, and gross morphological changes. Results of efficacy and toxicity were used to predict the therapeutic window.ResultsIn alignment with the clinical outcomes, the zebrafish assays demonstrated that vascular endothelial growth factor receptor (VEGFR) inhibitors are the most potent anti-angiogenic agents, followed by multikinase inhibitors and inhibitors of endothelial cell proliferation. The toxicity assays reported cardiac phenotype in zebrafish treated with VEGFR inhibitors and multikinase inhibitors with VEGFR activity suggestive of cardiotoxic potential of these compounds. Several other pathological features were reported for multikinase inhibitors suggestive of off-target effects. The predicted therapeutic window was translational with the clinical trial outcomes of the anti-angiogenic agents. The zebrafish efficacy–toxicity approach could stratify anti-angiogenic agents based on the mechanism of action and delineate chemical structure-driven biological activity of anti-angiogenic compounds.ConclusionThe zebrafish efficacy–toxicity approach can be used as a predictive model for translational anti-angiogenic drug discovery to streamline compound selection, resulting in safer and efficacious anti-angiogenic agents entering the clinics.