Imagine that one of your close relatives contracts a fatal disease. What medical resources would be available to that person? Imagine if that person could go to the hospital, receive a simple injection, and be cured within a few hours. Imagine receiving the results of critical medical tests within a few seconds. Could your imagination become reality? Nanomedicine might be the answer. Nanomedicine is the study of the utilization of "artificial constructions from semiconductors, plastics, or glass,"1 and other substances on an atomic scale, for medicinal purposes. Nanomedicine is one of the exciting new fields of the future, of which drug delivery is an important subset. Advances in drug delivery and targeting methodologies could help cure diseases in a fraction of the time, and deliver medications to precise targeted areas of the body, without causing unnecessary damage to any healthy tissues.
Presently, drug delivery is rather limited. The delivery of medication is very unspecific to areas affected by disease, particularly cancer. For example, chemotherapy irradiates large areas of tissue and so does not discriminate between affected cells and unaffected cells. Other procedures used are the manual intake of pills (i.e. Advil and Tylenol), injection with hypodermic needles, transdermal transfer through patches (i.e. nicotine patches or motion sickness patches), or inhalation (i.e. asthma medication). The majority of these methods have limited efficiency and precision, as they often have to traverse throughout a person's entire body before they reach their intended destination. However, nanomedicine promises much more accurate methods of drug delivery. The three main molecules involved in this field are known collectively as dendrimers, nanotubes and nanoshells.
Dendrimers are polymer-like materials that have a strong potential for use in the field of drug delivery. Ordinary polymers are unsuitable for use in this field. Dendrimers, unlike polymers, have very "precisely defined chemical structures,"2 in which the position of any particular atom can be determined. The dendrimer is uniform throughout, and this predictability greatly aids their manufacture and study by the scientists who work with them. They are also about the size and weight of proteins, facilitating their movements throughout the human body.
Dendrimers are comprised of a "series of chemical shells built on a small core molecule."3 The core molecule is usually an amine or a sugar, with several identical bonding sites for shell molecules available on the surface. The shells usually alternate between an acid and an amine. Each combined acid and amine layer is called a generation. Thus, the surface of a half-generation is an acid, while the surface of a full generation is an amine. The structure of a dendrimer can easily be described in terms of generation; for example, one can identify generation 2.5 or 4.0. Dendrimers are also "branching molecules"4 with "branch points [at] about every half a dozen atoms." This means that after about every half-dozen atoms, the chain of atoms separates into two chains, forming the branch. (See Fig. 1) These branches would be useful for encapsulating medicines, therapeutic agents, or disease recognition technology for delivery to infected cells. The dendrimers would release medication when triggered by a stimulus, such as a diseased cell.
Dendrimers are manufactured by interacting a chosen core molecule with an excess of the molecule that will make up the second layer. This forces each molecule in the second layer to bond only once to the core molecule. The second layer molecules are then mixed with an excess of the molecules that would make up the third layer. This process is continued until the desired number of generations has been reached. (See Fig. 2) "By G5 [generation five] they have a consistent and specific three dimensional structure."5
The dendrimers being created now are mainly components of what are futuristically termed "tecto-dendrimers."6 These will be composites of several different dendrimers, which will be linked, but not bonded together. One dendrimer will carry a therapeutic agent, while another carries a mechanism to recognize diseased cells. One more images the diseased cell, another carries a mechanism to alert other tecto-dendrimers of the diseased cells, and yet another targets the actual diseased cell. (See Figs. 3 and 4) Thus, the dendrimers being manufactured now are only parts for a "smart therapeutic."7 In the future, the hope is to incorporate all the different functions associated with drug delivery, mentioned above, into the functions of one mechanism. This would undoubtedly make drug delivery infinitely more precise, efficient, cost effective, and successful.
Another area of nanomedicine emphasizes the use of nanoshells: a new class of nanoparticles made of extremely small gold-plated glass beads, approximately 100 nanometers in diameter. They were first invented by Naomi Halas, a professor of electrical and computer engineering and chemistry at Rice University. (See Fig.5) Nanoshells are able to absorb light at almost all wavelengths, especially in the near-infrared region. Infrared radiation can also pass through human tissue. By varying the thickness of the constituent metal layers on the surface of the nanoparticles, the color and light- absorbing properties of nanoshells can be accurately controlled. Making use of their light absorbing properties, nanoshells have been tested in three medical applications: cancer therapy, drug delivery for chemotherapy and pain management within the body, and medical testing.
In current technology for cancer therapy, patients have to go through chemotherapy, which damages healthy tissue while destroying diseased cells. However, laboratory experiments have demonstrated that nanoshells can target specific diseased cells, while leaving healthy tissues unimpaired. This can be done by injecting nanoshells into the body that will absorb the heat from an outside infrared source, because infrared is able to reach more than a few centimeters below human skin. The heat absorbed by the nanoshells is localized and can be used to destroy the targeted cells.
Another application making use of nanoshells is to deliver drugs within the body. This can be done by attaching nanoshells to temperature-sensitive polymers that change shape when they are heated. In Photothermally Modulated Drug Delivery, temperature-sensitive hydrogels (a type of polymer) made of N-isopropylacrylamine (NIPPAm) and acryamine (AAm) are used. They have a critical solution temperature (LCST) that is slightly higher than body temperature. When a strong outside infrared source is applied, the nanoshells are able to absorb the heat and pass the heat to the hydrogels. Once the temperature exceeds LCST, the hydrogel will liquefy and the medication within it will be released.
The third application of nanoshells is blood testing. Before targeting and drug delivery mechanisms can be employed, a quick and accurate diagnosis must be reached. Nanoshells can greatly speed up diagnoses. The current medical test uses a procedure called immunoassay, which uses antibodies that have fluorescent tags on them. In order to make a sample optically clear, the whole thing must be purified. It takes a few days for the purification to be completed and to obtain the result of the test. In critical medical situations, the amount of time this takes could be the difference between life and death. Nanoshell based tests can be performed in seconds because they can have spectral emissions in the infrared region, rendering the purification step unnecessary. 8
Another method of drug delivery is polymer nanotubes - cylindrical tubes that are 50,000 times narrower than the diameter of human hair. Polymers' chemical inertness, incredible strength, and range of electrical and thermal conductivity possibilities make them ideal for medicinal purposes. Polymers are "good choice[s] for a drug-delivery material, because researchers can work with it more easily - and less expensively - than silicon." Moreover, polymers may be molded into shapes to better access different parts of the body. "To work inside the body, the capsules wouldn't have to be round.
'On the contrary, capsules with more complex and angular shapes may adhere to targets better'."9 In general, nanotubes are made up of "buckyball" molecule C60 or buckminsterfullerene. The first nanotubes - carbon nanotubes - were introduced when Japanese electron microbiologist Sumio Iijima performed the standard arc-evaporation method. Iijima vaporized carbon through the conduction of electrical sparks between two closely spaced graphite rods and allowed the carbon to condense and curl. A completely unexpected product lay before him. Tiny, hollow, multi-layered tubes of carbon had formed as C60 shaped themselves into tubes10. Later, in 1996, the synthesis of single-layer nanotubes - laser- vaporization of graphite discovered by Richard Smalley, a professor at Rice University - allowed for the emergence of nanotubes for drug delivery11. The basic idea is that molecular drugs are deposited within these thin, single- walled tubes and released within the body when triggered by the presence of certain stimuli12.
How would the mechanism for responding to signals work? Researchers suggest that the nanotubes are to be coated on the surface with active sites or inserted into the wall. Acting as electrochemical sensors, these nanotubes could detect electron transfer in chemical reactions by the flow of current through its tube or detect the presence of elements (i.e. calcium) in cell fluid13. Applying knowledge from molecular biology, nanotubes could also possibly be covered with lipid membranes, transforming them into an artificial cell. Moreover, the optimized natural proteins for specific biological tasks within the body can be genetically engineered to help develop this response mechanism14. This type of future drug delivery depends on the understanding of biology - the study of molecular interactions of surface attached proteins - to obtain a controlled release of drugs. Indeed, at present, a biopharmaceutical company, Flamel Technologies, S.A., is focusing on the development of two unique polymer-based delivery technologies for medical applications. A nano-encapsulation technology Medusa(R) is seeking a method to deliver therapeutic proteins while controlled release and taste-masking technology Micropump(R) is trying to master the oral administration of small molecule drugs15.
However, the potential for nanotubes does not end here. For instance, M. Reza Ghadiri, Ph.D., Professor of Chemistry at TSRI, and his fellow colleagues formed a class of biological polymers, cyclic peptide nanotubes. These nanotubes are built by "putting alternating right and left-handed amino acids (L-a-form) together into short 6 and 8 amino acid chains, and then joining the two ends of the chain together."16 The cyclic peptide nanotubes stack inside the cell membranes of bacteria, and poke holes in their membranes, killing the cells. (See Fig. 6) These cyclic peptides can spontaneously self-assemble into nanotubes within the walls of a bacterium. By forming nanotubes, effectively poking holes in the cell walls, and disrupting the normal electric potential and ion gradients that bacteria use "to maintain homeostasis, generate energy, and carry out important chemical reactions," cyclic peptides disrupt these survival gradients and kill the targeted cells. Hopefully, in the future, these cyclic peptide nanotubes or a different class of biological polymers can be designed to eliminate cancerous cells from a patient's body and alleviate the damage that is done to normal tissue cells.
The main objectives of nano-drug delivery are the targeting of diseased cells and the release of drugs into specific portions of the body. By making use of the special properties of dendrimers, nanoshells, and nanotubes, we can destroy diseased cells without severe side effects and without causing harm to healthy cells within the body. Dendrimers could be used to encapsulate medications. Nanoshells' light absorbing properties could be used for the destruction of diseased cells through heat. Nanotubes could be used to eradicate diseased cells by puncturing their cell walls. With these emerging technologies, we may well be able to achieve what seem today to be medicinal miracles.
1 A. Paul Alivisatos, "Less is More in Medicine," Scientific American, September 2001, 67-73.