Technology > PLATFORM TECHNOLOGY

  The traditional drug delivery technology has been successful in developing controlled-release devices such as polymer-based caplets and mini-pumps, and developing alternative administrative routes such as pulmonary (inhalation), oral, and transdermal (patches) formulations to a substantial commercial success; annual sales of such drug delivery systems in the U.S. was estimated to be more than $20 billion in 2000. (Science, 2001, 293, July 6 issue, p58)

  Substantial scientific and technical challenges and tremendous commercial potentials remain in the drug delivery technology aimed at overcoming various biomembrane barriers and targeting for specific organs and tissues. Even many of small molecule drugs are not utilized to their full therapeutic potential because of either the poor water solubility and/or inadequate ADME properties. Anti-cancer agents such as vinblastine, doxorubucin, taxol, antibiotics such as vancomycin, and anti-viral agents such as nucleoside reverse transcriptase inhibitors (zidovudine, lamivudine, stavudine) may be cited as good examples, as well as many potential protein/peptide drugs, and nucleotide drugs (siRNA) and genes (DNA). They cannot be adequately delivered to the desired sites because of poor uptake by the cells or nuclei. Cellular and nuclear (or organellar) membranes do not allow crossing to a drug molecule searching for its therapeutic target, when a drug does not show an optimum balance of lipophilicity and hydrophilicity combined with an optimum molecular size. Although the cell membrane is constructed through an association of proteins and lipids, and the membrane lipid bilayer is only 7-10 nanometers thick, it tightly controls the cross-membrane traffic of molecules. Many of the membrane bound molecular transporters thus identified are unique to particular organs and selective to specific molecules to be ferried. The ideal solution to the membrane permeation problem might be based on harnessing cell’s active transport processes of various kinds, but unfortunately our understanding of the cross-membrane transport machinery and mechanism is grossly incomplete.

  For the foreseeable future, the drug delivery technology development is expected to take advantage of passive absorption mechanisms available in the cells, organelles and tissues. Typically, a drug molecule has to be water-soluble in order to travel through an aqueous environment to reach its target cells. However, crossing of the plasma membrane by the drug molecule requires a certain degree of lipophilicty. Only a very small subset of molecules possesses the required solubility-lipophilicity profile. Thus a large proportion of drug candidates fall victim to this hydrophilicity-lipophilicity paradox and fail to proceed to further developmental stages. A number of approaches have been examined to overcome this difficulty. A typical solution known as “pro-drug technology” involves conjugation through an easily hydrolyzable linkage of the drug molecule to a carrier vector that can provide the needed hydrophility or lipophilicity. For example, a carbohydrate or a lipid can serve as the carrier molecules conferring the hydrophilicity or lipophilicity to a drug candidate, respectively. In the cases of protein drugs and DNA, polyethyleneimine, polylysine, polyamidoamine dendrimers and cationic liposomes, andβ-cyclodextrin-based polymers have been extensively investigated as potential molecular carrier vehicle.

  Sometime ago a seminal discovery was made that the HIV-1 Tat protein, a viral transcription factor could cross cell membranes in a receptor independent manner, and a relatively short domain of the peptide sequence, Tat (49-57) was determined to be responsible for the transmembrane localization. Similar discoveries have subsequently been made with a number of proteins and peptides. The most striking structural feature of these peptides is that they are generally rich in basic or cationic amino acids such as lysine and arginine. Futaki, Wender, and their coworkers have studied various arginine-rich natural and synthetic peptides by means of fluorescence probe attached to the peptides and confocal microscopy with various cell lines, and found that they all have translocating activity similar to Tat (49-57). These peptides have no specific primary or secondary structural motif in common, except that they all have several arginine residues in the sequence. It has been subsequently observed that in order to be effective translocators, these peptides need to have an optimum number of arginine residues and some conformational flexibility, but no requirement for the absolute stereochemistry of the peptide backbone has been noted.

  A number of practical problems have been identified to be associated with the Tat (49-57) and related peptides as potential carrier vector. They include 1) a high ratio of entrance over exit rate in the cells with resultant poor in vivo tissue distribution, 2) instability due to endogenous proteases, 3) potential cytotoxicity and/or immunogenicity liabilities, 4) intellectual property rights issue, and 5) processing cost and associated economic issues among others. Several lines of R/D efforts have been continuing in order to overcome or circumvent these technical and economic issues, and they include developing artificial carrier vectors such as peptides based on D-amino acids, β-peptides, peptoids, oligocarbamates, peptides nucleic acids, and de novo carrier vector designs.

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