Abstract NG06: The Trojan Horse Strategy: Packaging chemotherapeutics can help alleviate toxicity

Most cancer drugs have a narrow therapeutic window where dose is dictated by toxicity and, in turn, causes decreased efficacy. Adverse side effects are the primary cause of early cessation of chemotherapy as well as high failure rates of new entities during clinical trials. This has led to intense research into various tumor-selective delivery modalities. We present here two novel strategies by which we reformulate promising cancer drug candidates and dramatically lower their toxic side effects. The first strategy involved development of a generalizable method for efficiently loading poorly soluble, non-ionizible organic molecules into stealth liposomes using a pH gradient. Using this new methodology we successfully encapsulated the PLK-1 inhibitor, BI-2536 and the MEK-1 inhibitor, PD-0325901, both of which had failed Phase II despite exceptional promise in preclinical and Phase I stages. In the second case we successfully packaged the potent anti-glycolytic alkylating agent, 3-bromopyruvate, previously used only under loco-regional therapy settings, for systemic therapy and demonstrated its exceptional promise in an orthotopic xenograft model of pancreatic cancer. Together, our data presented below demonstrate innovative strategies for opening up the therapeutic window of toxic cancer drugs. Our first approach uses drug-packaged stealth However, liposomal formulations have not gained widespread use because many drugs are highly hydrophobic and non-ionizable, and as such, cannot be efficiently loaded into liposomes through established passive or active techniques. To overcome these issues we designed a generalized strategy that have three important features: 1) pH gradient across liposome bilayer for directional loading of drugs, 2) use of β-cyclodextrins to create solubilize hydrophobic drugs regardless of the physico-chemical properties of the agents themselves, 3) synthetic analogs of β-cyclodextrins containing multiple weakly basic or weakly acidic functional groups on their solvent exposed surfaces to trap the cyclodextrin-drug complexes in liposomes, exploiting the ionizable groups on the cyclodextrins, rather than on the drugs themselves. First, we established that cyclodextrins labelled with a fluorescent moiety, but without a drug payload, accumulated in liposomes containing acidic citrate buffer with >90% loading efficiency compared to minimal accumulation in neutral liposomes at pH 7.4 without the pH gradient. These data suggests that the cyclod