It can be argued that nanotechnology has already affected drug delivery. Submicron particles of poorly soluble drugs are currently
being used to "solubilize" drugs to enhance oral bioavailability. Three products using such technology are on the market with
sales of over $1 billion: Tricor (fenofibrate) tablets, Rapamune (sirolimus) tablets, and Emend (aprepitant) capsules. The
approach will likely be used for injectable suspensions as well.
NONVIRAL GENE DELIVERY
The number of gene-therapy clinical trials that have been conducted is now over 1,000.27 However, success to date is fairly limited. Significant challenges exist for gene delivery systems, including avoiding the
immune system and efficiently transferring the gene to the nucleus of the target cell. If an efficient delivery system for
gene delivery can be developed, it has the potential to revolutionize treatment paradigms, particularly for inherited, malignant,
and infectious diseases.
VACCINE ADJUVANT/DELIVERY SYSTEMS
The visibility of vaccines has significantly increased due to efforts to combat bioterrorism, drug-resistant bacteria, cancer,
and viral diseases. Advances in today's vaccines include the use of recombinant proteins, DNA, and genetically-modified toxins.While
aluminum hydroxide remains one of the most-used adjuvants for injectable vaccines, new adjuvant systems such as the saponin
QS-21, and MF-59, a squalene-based emulsion, are now available.
Better adjuvants coupled with efficient delivery systems have the potential to enhance the effectiveness of vaccines.28–30 This is particularly critical in the case of cancer vaccines. Not only are patients often immunocompromised, but tumor antigens
are often poorly immunogenic, and tumor escape mechanisms exist (e.g., secretion of suppressive cytokines).31,32 Thus, adjuvants for cancer vaccines may need to be more toxic than prophylactic adjuvants. The ideal vaccine delivery system
would not only intensify the immune response, but would also provide an optimized exposure profile (e.g., prolonged or pulsatile
Kola and Landis reviewed success rates over the last decade for various classes of compounds gaining approval after having
reached initial clinical trials.33 Drugs for oncology and central nervous system (CNS) diseases have two of the lower success rates (less than 10%, as shown
in Figure 4). [Editors note: Figures for this article are not available online. To obtain a complete copy of the article with
figures, please send your mailing address to firstname.lastname@example.org
]. While there are a number of factors involved, the failures in drug delivery to tumors and the CNS can be attributed at
least partly to the drugs not reaching the target efficiently.
Treating cancer has long been aimed at selectively targeting the tumor while sparing normal tissue. Two approaches to cancer
targeting are physical methods and specific binding. Enhanced permeability and retention is an example of physical targeting.
Tumor vasculature is generally leakier than normal vasculature, allowing particles such as liposomes and macromolecules to
extravasate and reach the tumor in higher concentrations than in normal tissue.34,35 Accumulation at the desired site is further enhanced because lymphatic vessels do not form in tumors, so that the extracellular
material is not drained as in normal tissue.
Antibody-based therapeutics, such as Herceptin and antibody-conjugated delivery systems, are examples of specific binding
targeting. Recent advances in humanized antibodies have facilitated advances in this area.36 The use of specific antibodies to treat patient subpopulations is a key area in personalized medicine.37 By attaching nanoparticles or liposomes to antibodies, it is possible to specifically target the dose to the appropriate
site of action.38, 39
DELIVERY ACROSS THE BLOOD BRAIN BARRIER
It seems appropriate to end by discussing drug delivery to that most complex of organs, the brain. As noted above, success
rates for CNS drugs have been low. In contrast to tumor vasculature, the capillaries of the the blood-brain barrier (BBB)
are characterized by tightly packed endothelial cells held firm by tight junctions.40 In general, this limits passive diffusion to small, highly lipophilic molecules. Even if a drug can permeate the membrane,
the BBB has effective efflux mechanisms. Due to these restrictions, nearly 100% of large-molecule and greater than 98% of
small-molecule drugs do not cross the BBB.41