The success of cancer chemotherapy is limited by the concentration of chemotherapeutic agents that can be accumulated in the tumor without exceeding limits imposed by systemic toxicity. Thus, means of altering the biodistribution have to be devised. In our approach we utilize the finding that the vasculature at tumor sites is hyperpermeble so that macromolecules such as polymer-drug conjugates can only extravasate at the tumor site. We have developed a family of water-soluble polymers containing acid-labile acetal linkages in the polymer backbone, modified with amine functionalities that serve as attachment points for chemotherapeutic agents. The polyacetal is stable in plasma but unstable in the low pH environment of endosomes and lysosomes. Because the polymer is biodegradable, high molecular weight materials can be safely injected without the need to stay below the renal threshold. Such materials can circulate for prolonged periods of time thus maximizing accumulation in tumors. The polymer is prepared by acondensation reaction between divinyl ether and two diols, one bearing an Fmoc-blocked amine. The polymer and its hydrolysis products are non-toxic as determined by cell lysis studies. Tissue distribution studies have shown that there is no acccumulation in any specific organ, including the liver. Pharmacokinetic studies using iodine labelled polymer has shown plasma levels that are significantly (p<0.05) higher relative to those of PK1 after 5, 48 and 72 hours. Doxorubicin levels in B16F10 murine melanoma following intravenous injection of equivalent amounts of PK1 and the polyacetat cojugate showed significantly (p<0.05) higher levels for the polyacetat-DOX conjugate after 48 and 72 hours. Tumor AU1-72h for the polyacetal conjugate and PKt were 384.1 and 280.7% respectively. In the preliminary study, doxorubicin has been attached to the polyacetal via an amide linkage which is nondegradable. In the proposed Phase I study, we will use paclitaxel as the chemotherapeutic agent. Paclitaxel will be attached to the polyacetat via an ester bond, so that ultimate hydrolysis will yield native paclitaxel.
Thesaurus Terms: chemical conjugate, drug delivery system, drug design /synthesis /production, ketal, pharmacokinetics, polymer chemical reaction, ester, hydrolysis, paclitaxel, water solubility chemical synthesis
