Targeting To Cancer

Nanoparticles may be targeted to the growing vasculature serving the growing cancer or to the cancer cells themselves. Targeted delivery utilizes unique phenotypic features of diseased tissues and cells in order to concentrate the drug at the location where it is needed. Targeted delivery can be divided into passive and active targeting. Passive targeting tries to minimize nonspecific interactions between the drug carrier and nontarget sites in the body by detailing the physiochem-ical properties of the aberrant tissue such as size, morphology, hydrophilicity, and surface charge.3 When targeting tumor tissue, the enhanced permeability and retention effect (EPR) is an example of passive targeting approach; it allows passage of drug carriers ranging in size from 10 to 500 nm through the highly permeable blood vessels that supply growing tumors and leads to entrapment of large molecules as a result of deficient lymphatic drainage.3-5 In fact, it has been reported that the intra-cellular openings in vascular endothelium of tumor blood vessels can be up to 2 mm in diameter and that the vessel leakiness in tumor vasculature can be up to an order of magnitude higher than that of normal blood vessels.5 Active targeting utilizes biologically specific interactions including antigen-antibody and ligand-receptor binding and may seek drug uptake by receptor-mediated endocytosis through association of the drug or drug carrier with such antigen or ligand.3 Receptor-mediated endocytosis commonly occurs through clathrin-coated vesicles and is carried out in mammalian cells continuously for the uptake of nutrients and for modulation of signal transduction through the up- or down-regulation of signaling receptors.6 Targeted delivery avoids the need for high systemic drug levels for the drug to be effective and consequently offers a more economic alternative for treatment. Not only is it useful for therapeutic purposes; it is also beneficial in diagnosis. Recent research has pointed to its ability to concentrate imaging or contrast agents for the detection of malignancies and for monitoring the effects of therapeutic agents.7,8 To date, most systems for targeted delivery have utilized drug conjugates, liposomes or micelles.9-11 Targeting of particulate systems has focused more often on passive targeting based on size than on active targeting. But systems that combine both methods, starting with passive targeting through EPR and enhancing the targeting through specific interactions are beginning to show great promise.

While it is challenging to deliver a drug or imaging agent-containing nanoparticle directly and selectively to a cancerous cell or tissue, the additional challenges of then having that particle and/or its contents being transported into the targeted cell have often been overlooked. Couvreur presented some of these challenges at the 11th International Symposium on Recent Advances in Drug Delivery Systems and also summarized that presentation in a recent publication.12 The tumor resistance can be due to the deliverance of nanoparticles to the tumor as well as to resistance to the active agent being delivered. In this article, many different pathways are described and the enhancement of drug delivery due to the presence of nanoparticles, especially polycyanoacrylate nanoparticles, is evaluated and summarized. The enhancement of drug permeability into cells due to interactions with biodegradation byproducts as well as the effect of nanoparticle surface charge is discussed.

In this chapter, we will first review recent work on targeting to the two most promising targets for cancer: Angiogenesis and folate receptors. We will then describe other potential targets for cancer imaging and therapy with nanoparticles, including antibodies strategies using biotin.

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