Tripp Floyd, Heidi Keiler, Derek Van der Poll, Megan Fox, Steve Guillaudeu

Current methods of cancer chemotherapy suffer from several limitations. The drugs used typically have poor water solubility, which limits their administration to the patient. Once the drug is injected into the body, a large portion is filtered from the bloodstream by the kidneys, and so multiple doses are required to maintain an effective drug concentration. From the circulatory system, the drug can travel anywhere within the body, leading to side effects like fatigue, nausea, and hair loss. One possible way to address these limitations is to attach a drug to a suitable carrier, which would have the following properties: it would add water solubility and reduce the toxicity of the drug towards healthy tissue, cause the drug to accumulate only in the area surrounding the tumor, and then release the drug in its native form at the tumor site.

The Fréchet Group is investigating dendritic polymers as vehicles for anticancer drug delivery. It is known that in general large molecules (> 40 kDa) will accumulate selectively in tumor tissue due to the Enchanced Permeation and Retention (EPR) effect. Dendrimers, however, can carry multiple copies of a drug and thus increase the effective dose per carrier. We are also interested in exploiting the shape persistence of dendrimers to explore how polymers with different shapes and architectures will behave in vivo. Finally, the precision of dendrimer synthesis allows us to expand our system beyond simple carriers to multifaceted vehicles that include MRI contrast agents, targeting ligands, and even different types of drug, all in well-defined ratios.

The workhorses of this project are polyester dendrimers derived from bis-2,2-(hydroxymethyl)propionic acid, a non-toxic scaffold that can be synthesized on multigram scale using simple purification procedures. Poly(ethylene oxide) are then added to enhance water solubility and decrease immune response in vivo . From these two basic components and others have emerged a variety of polymer architectures: star polymers, “ball and chain” copolymers, dendronized linear polymers, and asymmetric dendrimers. We are interested in how these different polymer architectures behave within the body.

We have also addressed the method by which a drug is released from its carrier. Our group has focused primarily on drug release initiated by changes in pH, since after a large molecule enters a cell via endocytosis it is trafficked to the mildly acidic lysosome. The decrease in pH causes release of the free drug, which can then diffuse through the lysosomal membrane into the cytoplasm. We have used hydrazones and acetals for this task because they show first-order pH dependence and their variability in degradation rate is well documented. The method by which the drug is loaded and released varies. For example, in some cases we have used acetals as direct drug linkages, and in others we have used them as solubility switches to disrupt a micelle and release an encapsulated payload.

More recently, we have explored the use of external agents to initiate drug release. In this strategy, a dormant drug carrier is allowed to circulate throughout the entire body, but a directed beam of light causes release of the drug at a specific location. Thus the rest of the body is spared from the harmful effects of the drug. Work in our group has explored the use of near IR light for this purpose because of its ability to penetrate skin tissue. In a recent study, 2-diazo-1,2-naphthoquinone (DNQ) was found to act as a photoreactive solubility switch that destroyed a micelle containing a model drug. Currently, we are exploring polymer micelle systems that incorporate DNQ for the same purpose.

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