Tumor targeting with polymeric molecules having extended conformation

Abstract

Enhanced drug delivery to tumor tissue is obtained by attaching drug molecules to elongated polypeptide carrier molecules several orders of magnitude longer than wide. These are chosen to have a high net negative charge. The carrier molecules are created by unfolding long polypeptides by a large degree of substitution with steric hindrance molecules, such as diethylene triamine pentaacetic acid (DTPA) with at least 90% substitution. This causes the conformation to be worm-like as evidenced by a measure of persistence length, with a diameter small enough squeeze through the pore structures of tumor tissue but not so small as to pass through pores of vessels in normal tissue. The length is determined by optimizing two processes, blood circulation lifetime, and tumor uptake. The elongated conformation may cause the complex to become entwined with stroma in tumor interstitium and become trapped. The complex molecules provides increased therapeutic benefit in effecting tumor tissue destruction, or may be used in enhancing imaging contrast depending upon the active agent attached to the carrier molecules. The enhanced concentration and retention of the complex molecules within the tumor reduces side effects of the active agent in other tissues.