Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect

For over half a century extensive research has been undertaken for the control of cancer. However, success has been limited to certain malignancies, and surgical intervention is potentially curative for early stage patients. For the majority of patients with advanced stage of cancer, the treatment is limited to chemotherapy or radiation. Chemotherapy in particular has limitations due to the lack of selectivity with severe toxicity. Under these circumstances tumor-targeted delivery of anticancer drugs is perhaps one of the most important steps for cancer chemotherapy. We reported such a drug for the first time, styrene-maleic acid copolymer-conjugated neocarzinostatin (SMANCS) in 1979, and it eventually led to formulate the concept of the enhanced permeability and retention (EPR) effect of solid tumors in 1986. Monoclonal antibody conjugates are another direction, of which interest is increasing recently though with limited success. The EPR-effect appears as a universal phenomenon in solid tumors which warrants the development of other polymeric drugs or nanomedicine.EPR-effect is applicable for any biocompatible macromolecular compounds above 40 kDa, even larger than 800 kDa, or of the size of bacteria; thus complexed molecules like micelles and liposomes containing anticancer drugs are hallmark examples. The drug concentration in tumor compared to that of the blood (T/B ratio) can be usually as high as 10-30 times. In case of SMANCS/Lipiodol given via tumor feeding artery, the T/B ratio can be as high as 2000, a real pin-point targeting. EPR-effect is not just passive targeting for momentary tumor delivery, but it means prolonged drug retention for more than several weeks or longer.This review describes the pathophysiological mechanisms of the EPR-effect, architectural difference of tumor blood vessel, various factors involved and artificial augmentation of EPR-effect with respect to tumor-selective delivery, and then advantages and problems of macromolecular drugs.