Abstract 2645: Customized PEG linkers improve the pharmaceutical properties of cytotoxic small molecules

Introduction: PEGylation is an established delivery technology for proteins with benefits such as decreased immunogenicity and prolonged circulating half-life. The application of PEGylation to small molecules may improve the poor pharmaceutical properties including poor solubility, suboptimal pharmacokinetic (PK) profiles, and unwanted toxicities. Here we utilized Customized PEG Linkers to enhance the therapeutic index of several cytotoxic agents including doxorubicin, ara-C, gemcitabine, and SN38. Experimental procedures: drug molecules were either reacted with proper linker moieties first before PEGylation, or conjugated directly with PEG linkers. For those compounds thathave more than two reactive functional groups, the unwanted reactive sites were first protected before conjugation with PEG linkers. The PEG conjugates were incubated in PBS and plasma to study their stability, followed by in vivo PK studies in mice. Additionally, in vitro anti-proliferation assays with different human cancer cell lines were conducted to evaluate the PEG conjugates with different half-lives. Furthermore, the PEG conjugates were evaluated in vivo in multiple human cancer models in mice for their anticancer activities. Summary of data: a series of novel PEG conjugates were synthesized with different Customized PEG Linkers. In general, while these PEG conjugates were stable in PBS buffer, they demonstrated a broad range of half-lives in rat and human plasma, varying from minutes to days. PEG conjugates with longer half-lives have shown prolonged circulation time and increased AUC compared to native drugs in the PK studies in mice. In addition, PEGylation also greatly increased the water solubility for those insoluble molecules, for instance by about 1000-fold for SN38. In the cellular based studies, PEG conjugates showed different degrees of anticancer activities against a panel of human cancer cells. Remarkably, enhanced anticancer activities compared to the non-pegylated agent have been observed for many of the conjugates in a variety of cancer models, including both solid tumors and hematological malignancies. Conclusions: Customized PEG Linkers have greatly improved the solubility of certain small molecule drugs and enabled the systemic administration of these drugs. It allowed us to generate a variety of PEG-drug conjugates with broad half-life ranges in plasma which are clinically relevant. The combined effect of increased solubility, optimized PK profile, and passive accumulation of macromolecular PEG conjugates in tumors due to the enhanced permeation and retention effect may all contributed to the greatly enhanced anticancer efficacy of these PEG conjugates in animal models. In summary, customized PEG Linkers represent a promising technology to improve current cytotoxic agents. One agent, PEG-SN38 is undergoing Phase II evaluation in cancer patients with metastatic colorectal and breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2645.