Foreword

We are at the threshold of a new era in cancer treatment and diagnosis, brought about by the convergence of two disciplines—materials engineering and life sciences—that 30 years ago might have been difficult to envision. The product of this curious marriage, nanobiotechnology, is yielding many surprises and fostering many hopes in the drug-development space. Nanoparticles, engineered to exquisite precision using polymers, metals, lipids, and carbon, have been combined with molecular targeting, molecular imaging, and therapeutic techniques to create a powerful set of tools in the fight against cancer. The unique properties of nanomaterials enable selective drug delivery to tumors, novel treatment methods, intraoperative imaging guides to surgery, highly sensitive imaging agents for early tumor detection, and real-time monitoring of response to treatment.

Using nanotechnology, it may be possible to leap over many of the hurdles of cancer drug delivery that have confounded conventional drugs. These hurdles include hindered access to the central nervous system through the blood-brain barrier, sequestration by the reticulo-endothelial system, inability to penetrate the interior of solid tumors, and overcoming multi-drug resistance mechanisms. These obstacles can be mitigated by manipulating the size, surface charge, hydrophilicity, and attached targeting ligands of a therapeutic nanoparticle.

The novelty of using nanotechnology for medical applications presents its own challenges, similar in many ways to the challenges faced by the introduction of the first synthetic protein-based drugs. In the early 1980s, protein-based drugs offered an entirely new approach to targeting and treating disease. They could be "engineered" to be highly specific and even offered the capability of separating the targeting and therapeutic functions of a drug, such as when monoclonal antibodies are conjugated to cytotoxic agents. But monoclonal antibodies and recombinant protein-based drugs necessitated a different approach to lead optimization, metabolism, and toxicity screening from that of small-molecule drugs. Factors such as stability, immunogenicity, and species specificity had to be considered and tested in ways that were not familiar to the developers of traditional drugs.

Nanotechnology-based drugs will catalyze a reevaluation of optimization, metabolism, and toxicity-screening protocols. Interactions between novel materials and biological pathways are largely unknown but are widely suspected to depend heavily on physical and chemical characteristics such as particle size, particle size distribution, surface area, surface chemistry (including charge and hydrophobicity), shape, and aggregation state—features not usually scrutinized for traditional drugs. Standard criteria for physicochemical characterization will have to be established before safety testing can yield interpretable and reproducible results.

Would nanotechnology-based drugs be successful? All drugs have to run an obstacle course through physiological and biochemical barriers. For monoclonal antibody drugs, only a minute portion of an intravenously administered drug reaches its target. However, drugs based on nanomaterials, including nanoparticles, have unique properties that enable them to specifically bind to and penetrate solid tumors. Size and surface chemistries can be manipulated to facilitate extravasation through tumor vasculature, or the therapeutic agent can be encapsulated in polymer micelles or liposomes to prevent degradation and increase circulation half-life to improve the odds of it reaching the target.

This level of functional engineering has not been available to either small-molecule or protein-based drugs. For these drugs, modification of one characteristic, such as solubility or charge, can have dramatic effects on other essential characteristics, such as potency or target specificity. Nanoparticles, however, introduce a much higher degree of modularity and offer at least four advantages over the antibody conjugates: (1) the delivery of a larger therapeutic payload per target recognition event, enhancing potency; (2) the ability to carry multiple targeting agents, enhancing selectivity; (3) the ability to carry multiple therapeutic agents, enabling targeted combination therapies; and (4) the ability to bypass physiological and biological barriers.

We would all like to hasten the day when chemotherapy—the administration of non-specific, toxic anti-cancer agents—is relegated to medical history. Improvements in diagnostic screening and the development of drugs that target specific biological pathways have begun to turn the tide and contribute to a slow, yet consistent decline in death rates. While confirming that early diagnosis and targeted therapies are pointing us in the right direction, the progress is still incremental. Nanotechnology may be our best hope for overcoming many of the barriers faced by today's drugs in the battle against cancer. The combined creative forces of engineering, chemistry, physics, and biology will beget new and hopefully transformative options to old, intractable problems.

Piotr Grodzinski, Ph.D.

National Cancer Institute

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