Abstract
Cancer is the second leading cause of death in the United States. Due to the increase in exposure to cancer-causing environmental factors, the presence of chronic conditions, and the increase in age-related mutations in normal tissue, cancer incidence is positively correlated with age. Because of the increase in life expectancy due to advances in medicine, the frequency of cancer incidence is expected to rise in the future. For these reasons, devising methods to efficiently diagnose and treat cancer is extremely important. Effective targeting of cancer cells within tumors would allow for improvement in the efficacy of treatment and the reduction of side effects. Tumor targeting falls into three broad categories: passive targeting, active targeting, and physical targeting. Passive targeting generally employs the enhanced permeability and retention effect, a phenomenon that leads to the localization of a certain range of sizes of macromolecules in tumor tissue due to the non-intact vasculature present in this tissue. Passive targeting can work well to deliver some therapeutic agents to solid tumors, but lacks targeting specificity and can therefore result in substantial targeting of healthy tissue, especially the liver, lymph nodes, and spleen. Active targeting relies on a much greater presence of certain characteristics, called biomarkers, on or in cancer cells than on/in normal cells. To exploit active targeting, therapeutic agents are conjugated to targeting moieties like antibodies, aptamers, or small molecules that have a high affinity to these biomarkers. Active targeting has some advantages over passive targeting, namely, higher targeting specificity. However, one significant disadvantage of active targeting is its reliance on the overexpression of biomarkers in cancer cells: tumor tissue is very heterogeneous, with varying levels of expression across the cancer cell population; additionally, these biomarkers are usually present in normal tissue, leading to the undesirable targeting of healthy tissue. Physical targeting relies on a difference in physical properties, such as temperature, oxygenation, or pH, between normal tissue and cancer tissue. These physical characteristics can be more universal to tumor tissue, regardless of the tissue vasculature or biomarker expression. Physical targeting offers specificity advantages over passive targeting, and offers advantages over active targeting based on the universality and specificity of the targeted physical traits, compared to the broader, varying levels of expression of active-targeted biomarkers. It has been known for over fifty years that tumor tissue undergoes acidification due to a switch in metabolic pathway resulting in the production of high levels of
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