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Advances in nanotechnology—the discovery of materials with new compositions and performance properties—as well as advances in manufacturing processes and scale are having a revolutionary impact on the diagnosis, treatment, monitoring, and prevention of disease. One area where nanotechnology may have particular significance is in the treatment of cancer, especially in the safety and efficacy profile of chemotherapies.

In the United States, a total of 1.6 million new cancer cases and 571,950 deaths from cancer are projected to occur in 2011. Between 1990 and 2007, the most recent year for which data is available, overall death rates decreased by about 22% in men and 14% in women.1

Cancer is especially difficult to treat because the disease arises from an individual’s own cells and tissues and has a genetic profile as unique as the individual. Still, multiple mutations have been discovered including several oncogenes that are common in many tumor types. To treat cancer safely and more effectively, new targets and mutations that are unique to cancer are being actively sought.

Nanotechnology-enabled drug delivery may prove to be an important avenue for improving the delivery of chemotherapeutic drugs that are the current standard of care for many cancers. For a chemotherapeutic drug to be effective it must reach its target with sufficient concentration and for sufficient duration. This has proved to be an enormous challenge as the convoluted vasculature of tumors and the erratic blood flow associated with several tumor types complicates the selective delivery of drugs. An important byproduct of the flow patterns of blood in tumors is their contribution to the EPR or enhanced permeation and retention effect. In essence, these patterns make it more difficult for the drug to get into the tumor cells, but when it does, it also has trouble leaving. This increases the drug’s chances of adversely impacting the disease. This effect is linked to molecular weight and is the basis for accumulation within a tumor mass of encapsulated, liposomal, PEGylated—or otherwise polymer conjugated—drugs and prodrugs.2

The ability to accumulate within a tumor mass however, may be of lesser benefit if a drug target is intracellular. This is particularly true where the delivery technology may inhibit cellular uptake or limit diffusion throughout a tumor mass, where distance of blood vessels from tumor cells is associated with metabolic gradients, and even changes in cellular phenotype and protein expression.

Targeted delivery
Various prodrug strategies designed to release drugs from polymers have been explored, allowing "released drug" to diffuse and enter tumor cells. With this approach, the nature of the prodrug linkage chemistry becomes extremely important; finding the balance between stability in storage or in plasma as well as establishing drug release rate in tumors requires extensive testing.

Much research conducted on polymer conjugation—particularly with polyethylene glycol and related polymers—has been successful with proteins and some small-molecule drugs.3 There are also many encapsulation technologies, including using phospholipids, pegylated phospholipids, gold, or other nanoparticles often associated with surface linked antibodies or other ligands. Cornerstone Pharmaceuticals has been developing nanoparticles that can be manipulated in size and composition,4 as opposed to promoting only accumulation in the tumor mass. This approach would theoretically create a higher concentration and duration of exposure of drug to the drug target within the cancer cell, providing an advantage over simple diffusion. Achieving selective and targeted cellular delivery of small-molecule drugs with specificity similar to existing monoclonal antibodies could allow for safer and more effective dosing regimens. This selectivity should improve the concentration of drug at the target site, lowering the dosage required to achieve benefit and decreasing the risk of concentration-linked side effects.

Many challenges arise in drug and formulation stability as well as manufacturing, including the need to modify the structure of an active pharmaceutical ingredient (API). Chemical modification may alter pharmacokinetics and pharmacodynamics and can introduce changes in biodistribution that lead to exacerbation or the emergence of new unwanted side effects. One solution is to prepare an API without chemical modification as a nanoemulsion. This can be delivered in such a manner as to promote uptake into diverse tumor cell types without loss of the activity associated with the API, and without introducting undesirable changes in biodistribution and side effects.

One approach is to leverage the cancer cell’s metabolic requirements by creating a nanoemulsion that fits that specific metabolic need. It has been known since the 1980s that cancer patients have an altered metabolism that requires an increase in the cellular uptake of specific lipids and fatty acids.5 While common across diverse tumor types, the precise mechanisms by which this uptake occurs, along with the disruption of uptake regulation by receptors and signal transduction pathways are largely unknown. Aside from receptors and fatty acid uptake proteins, lipid rafts may also be involved in the enhanced uptake of lipids into cancer cells.

Nanotechnology has improved the possibilities for creating more specific drug delivery. While many advances have been made, with some in various stages of research and others in commercial products, there remains a significant opportunity to improve on the potential of non-specific chemotherapeutics by adding characteristics that confer specificity beyond the acknowledged benefits of increased particle size. One such approach is to leverage the metabolic needs of tumor cells to facilitate active uptake of nanoemulsion encapsulated drug.6

About the Author
Robert Shorr oversees the development of novel drugs and delivery technology for cancer disease management. He is focused on the research and discovery of the biochemical basis of neurotransmitter and hormone receptors; their link to metabolic events; their role in pathology; and the design and discovery of therapeutic agents.

References
1. Cancer Facts & Figures 2011. American Cancer Society. Available at http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2011. Accessed on November 22, 2011.
2. Devy L, et al. PEGylated DX-1000: Pharmacokinetics and antineoplastic activity of a specific plasmin inhibitor. Neoplasia. 2007;9(11):927–937.
3. Harris JM, et al. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov. 2003; 2(3):214-21.
4. Lee KC, et al. Formation and anti-tumor activity of uncommon in vitro and in vivo metabolites of CPI-613, a novel anti-tumor compound that selectively alters tumor energy metabolism. Drug Metab Lett. 2011;5(3):163.
5. Gal D, et al. Cholesterol metabolism in cancer cells in monolayer culture. III. Low-density lipoprotein metabolism. Int J Cancer. 1981;28(3):315.
6. Constantinides PP, Chaubal MV, Shorr R. Advances in lipid nanodispersions for parenteral drug delivery and targeting. Adv Drug Deliv Rev. 2008;60(6):757.

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