Drug targeting and tumor heterogeneity.

“Missile drug,” “Magic bullet” or similar words found in newspaper articles or public magazines have often fascinated general readers and scientists for the reason that these words in some way implicate ‘remote,’ ‘seeking’ and ‘selective destruction.’ “Drug targeting” was initially used to describe the possible in vivo action of an anticancer drug conjugated to amonoclonal antibody (mAb) which is specific to a surface antigen on target cancer cells. Since then, a range of targeting systems were devised and appeared in scientific papers. These targeting systems exploit over-expressed receptors of nutrients or specific chemistry on cancer cells. The ‘targeting’ has also given an impression that such conjugates find target cells similar to a smart missile, which may actively chase its target from miles away. This is certainly not the case. It is seemingly not possible that any water-soluble or nano-sized construct, designed as a drug carrier and introduced into the blood stream, will actively seek target cells that are remotely sitting in solid tumors. It is likely that the drug carriers stumble on floating cells such as leukemic cells in the blood compartment by a probability of collision. To reach its target solid tumor site, a drug conjugate or drug carrier must find the fenestraes (openings) on the tumor blood vessels by chance through convectional flow and random diffusional process. This process, which is linked to probability issues, is called ‘passive targeting’ coupled with ‘enhanced permeability (EP)’ [1]. The EP effect on carrier accumulation at tumor sites may be compromised by an opposite force; hydrostatic pressure, which is slightly higher in tumor extracellular space than in normal tissues/organs. Traditionally, tumor targeting approaches are classified into ‘passive targeting’ and ‘active targeting’; however, the active targeting process cannot be separated from the passive because it occurs only after passive accumulation in tumors. Long-circulating property has always been valuable. A longer circulation time definitely improves the probability for a carrier to find large openings on the blood vessels. During circulation in the blood stream, the incorporated drug should remain in the carrier to give high enough concentrations at the target sites. If premature release of drug occurs before the carrier reaches therapeutic sites, it may not help in drug accumulation at the tumor sites.