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Modern Advances of Chemotherapeutic Drug Delievery

By Edited Nov 13, 2013 0 0

        Many drugs have been developed for use as anti-cancer therapies, yet these “chemotherapies” continue to be systemically harmful even below their maximum tolerated doses.  For this reason, modern research is not only searching for a cure-all molecule, but is also looking to discover methods of increasing efficacy and efficiency of current and past drugs.

        Of many, two methods currently being researched are polymer-delivery systems and monoclonal antibody to drug conjugates.  Monoclonal antibody conjugates have the promise of increasing pharmokinetic half-lives and greatly increasing specificity of anti-cancer drugs; while polymer delivery systems focus on improving drug solubility, specificity, and active-half-life within tumor cells.

        It is necessary that chemotherapeutic drugs stay in the bloodstream long enough to destroy tumors; but also important that they eventually are removed from the body. Due to the toxicity of most chemotherapeutic drugs, large amounts cannot be administered. Therefore, a small dosage must be able to stay in your bloodstream long enough to have an effect on killing the tumor. One solution is attaching small polymers to these drugs to act as a carrier. These polymers have two roles: to transport the drug in the bloodstream to targeted cells and to reduce the systemic toxicity of the drug. Also important is the elimination of used polymers from the body.

        Molecular weight, size, shape and flexibility all have a role in the movement of the drug in the bloodstream and the polymer being removed from the body. If the polymer has a small molecular weight there will be little to no tumor uptake; though the kidneys will be able to eliminate it efficiently. If a polymer has a molecular weight greater than 215 kDa, it decreases tumor accumulation because the polymer is too big and becomes inhibited by the interstitial space in the tumor cell. If the polymer has no flexibility, it becomes harder for it to pass through the glomerulus in the kidney. Polymers can have “arms” which branch out.  The more arms a polymer contains, the more efficient it is in circulating in the bloodstream. Elimination of the branched polymer, however, becomes difficult. The arms have to pass the filters before the body can pass through and it becomes difficult for the polymer due to its many arms.

        If a polymer is constructed to prolong its stay in the bloodstream, it has a difficult time being eliminated. Ideally, the polymer must be less than 40 kDa and small in shape to be efficient in the bloodstream and also be eliminated from the body.

        These issues with elimination and specificity are the major factors in determining whether a drug can be used as effective treatment at levels lower than or equal to the maximum tolerated dose.  Another, relatively new, method of drug delivery has been touted as possibly being able to conquer many of the problems encountered with the traditional chemotherapies.

        By attaching small-molecule chemotherapeutic agents to monoclonal antibodies it has proven possible to confer cancer cell specificity to many anti-cancer medicines.  This has the promise of bringing back drugs which acted too broadly and were therefore deemed harmful; as well as having the ability to correct the ratio of medicine that destroys cancer-cells vs. non-cancer cells.

         Chari’s article­­­1 explains the evolution of research in conferring specificity via monoclonal antibodies.  He presents evidence from other studies as well as research from his own lab regarding what has failed to work and what is promising about current research.  For the theory of antibody-drug conjugates to be successful, several chemical mechanisms must be adjusted and refined.  The antibody should be monoclonal, preferably specific only for the targeted cancer cell type(s).  Also, the small-molecule drug must be able to bind to the antibody. Chari claims the drugs attach via lysine residues on antibodies, and though there are seventy-plus Lys residues, on average only four molecules typically bond to each antibody.   The antibody-drug conjugate must be internalized by the cancer cells by receptor-mediated endocytosis and, lastly, cleaved from the carrier antibody into its active form.

        The linkage between the monoclonal antibody and the anti-cancer drug seems to be of utmost important and is currently under investigation.  Also important is replacing the currently used murine antibodies with “nonimmunogenic ‘humanized’ forms” (Chari p.101).  The importance of this research, however, has become quite clear as second-generation conjugates have proven to be effective at both increasing the specificity of a drug and greatly increasing its pharmokinetic half-life.

Works Cited
[1]          Chari, Ravi V J. "Targeted Cancer Therapy: Conferring Specificity to Cytotoxic              Drugs." Acc. Chem. Res. 41, no. 1 (2007): 98-107.

[2]          Fox, Megan E, Francis C Szoka, and Jean M J Frchet. "Soluble Polymer Carriers          for the Treatment of Cancer: The Importance of Molecular Architecture."                              Acc. Chem. Res. 42.8 (2009): 1141-51.



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