Delivery Systems @ MMI
Dendrimers as a scaffold for cancer therapy
IN A NUTSHELL: Because of their globular shapes, nanoscopic sizes, encapsulation ability and exceptionally high degree of functionality at higher generations, dendrimers represent ideal container molecules for delivery of therapeutic drugs in various fields of modern medicine, including internal and cardiovascular medicine, immunology, oncology, gene therapy, etc. Among dendrimers, polyamidoamine (PAMAM) dendrimers are particularly well suited for such applications because of their protein-like chemical composition that does not cause immunological responses and high water solubility that are required for in vivo applications in the human body. As a consequence, they represent ideal carriers for complex drug delivery systems aimed at targeted chemo and radiation therapies. It is possible that in using such systems these therapies can be advanced from being generally applicable for a variety of different cancers to being highly specific and even personalized for treatment of a specific cancer in a particular patient.
THE PROBLEM: Targeted chemotherapy is the treatment of cancer with drugs that can selectively find malignant cells and attack them without interfering with the surrounding normal ones. At present, this concept is still at the research level and clinical oncology procedures still use traditional intravenous or oral drug administration. Chemotherapy utilizes the ability of certain drugs to kill cells that divide rapidly (which is one of the main characteristics of malignant cells), but it also affects normal cells that divide rapidly, including those in the bone marrow, digestive tract, blood and hair. As a consequence, traditional chemotherapy often results in more or less serious but always unpleasant side effects and it is the matter of appropriate dosing to balance the desired therapeutic performance with the maximum comfort of the patient. Similar is the situation with radiation therapy which is often used alone or in combination with other approaches, including chemotherapy. It works by damaging the DNA, including those in the cancer cells, and causing them to die or reproduce more slowly. Just like traditional chemotherapy, it is also not selective and although various techniques have been developed in attempts to spare as much as possible the healthy tissue that surrounds malignant regions, some degree of damage is unavoidable particularly when internal organs are treated. At present, targeted radiation therapy is even further away from clinical practice than chemotherapy.
THE STATE OF TECHNOLOGY: To achieve selective drug targeting and eliminate malignant tumors without destroying healthy tissue, various approaches based on differences in the physiology of normal and cancerous cells have been explored. Some of the most prominent of these include: (a) the use of high molecular weight polymer-drug conjugates which, because of their size, preferentially penetrate the porous cancerous tissue rather than the healthy, normal one, (b) the use of drug-carrier systems in which the drug-carrier bonds break under the pH or thermal conditions found in the cancerous environment to release the drug molecules, and (c) the use of systems in which the carrier contains targeting functional groups that can selectively bind to the overexpressed receptors or antigens on the surface of cancer cells allowing the system to deliver its drug content into the tumor only. An ideal drug delivery system should perform a combination of the features listed above, so as to maximize the curing function while minimizing the systemic toxicity of the cancer therapeutics to the healthy parts of the body, and it must remain water soluble (i.e., compatible with bodily fluids) in spite of the highly hydrophobic nature of the delivering drug molecule.
Polyamidoamine (PAMAM) dendrimers have attracted exceptional research attention for the development of such systems because they have an ideal combination of chemical, physical and physiological properties to satisfy this purpose. Among others, these unique properties include: (1) a branched polypeptide composition which is highly hydrophilic and compatible with physiological media and processes in the human body, (2) globular molecular shapes and nanoscopic sizes which do not trigger an immunological reaction and make them easily excretable through the kidneys, (3) some of the highest density of exo-presented molecular functionality known to chemistry (particularly at higher dendrimer generations) that enables covalent attachment of a large number and variety of different functional groups to the molecular carrier skeleton, including targeting groups, drug molecules, surface modifiers, etc., (4) availability in a number of end-group modifications that exhibit no, or very little toxicity and do not cause irritation, (5) high level of synthetic control that enables the preparation of very high quality products required for in vivo biomedical applications, and (6) convenient availability in a variety of grades, types, generations and commercial quantities from Dendritech, Inc.
OUR NOVELTY: Recently, Dendritech and MMI scientists developed a completely new process for the preparation of biomedical grade amine-functionalized PAMAM dendrimers which represent the architecturally purest form of these materials available. This new process complements traditional processes for the preparation of technical and diagnostic grades of these dendrimers, and is applicable to the production of samples in several kilogram quantities. These products when functionalized with folate targeting groups have been successfully used as carrier vehicles for methotrexate for chemotherapy and are available for in vitro as well as in vivo applications.
We have also advanced the concept of targeted radiation therapy from inside the tumors which is based on the selective delivery of radioactive lanthanides encapsulated in the dendrimers having site-specific targeting groups and an appropriately functionalized dendrimer surface. Such particles can be designed to show exceptional affinity toward specific tumors and to provide predefined doses of short-living radioactivity limited to acting within the tumor boundaries and not damaging the surrounding healthy tissue.