|
Most drugs work by binding to intracellular targets such as enzymes, receptors, and DNA in the appropriate organs and tissues. Thus, the drug must somehow get to the right place of the intracellular target at the right time at the right dosage level in order to have the maximum desired therapeutic effect. In reality, many drug candidates with promising in vitro activity fail to proceed to the developmental stage
|
|
|
because of poor absorption, distribution, metabolism or excretion (ADME) profiles, and many drugs also have limited administrative routes, e.g. injection, limited bioavailability, and limited efficacy, thus limited commercial success. Available data suggests that about 1 in 10 candidates entering clinical development survive and more than 30% of failures in early clinical phase are attributable to inadequate ADME profiles. Ideally, a drug molecule must be soluble in aqueous medium and translocate itself into cells (and organelles) in the target tissues. Only a small fraction of chemical substances readily cross various biomembranes. It was estimated that pharmaceuticals with high aqueous solubility and permeability accounted for mere 9% of all NDA substances. In terms of the brain delivery, the BBB excludes more than 98% of all potential neurotherapeutics. In addition, an increasing number of proteins are getting developed as therapeutic agents and DNAs and siRNAs are increasingly used in the gene therapy and stem cell reprogramming, but at present they cannot be properly delivered to the desired sites because of their instability toward endogenous hydrolytic enzymes and poor uptake by the cells, organelles and tissues. In particular, for the mitochondrial diseases including highly degenerative Huntington's, Lou Gehrig's (ALS) and even Alzheimer's disease, there is no available means to selectively deliver either diagnostic or therapeutic agent to the diseased mitochondrial site.
|
