Retargeting FDA Approved Anticancer Liposomal Drugs to Cancer Stem Cells

DESCRIPTION provided by applicant The goal of this research is to develop a ligand product and facile method to use it to target FDA approved liposomal anticancer drugs to cancer stem cells that overexpress CD We have devised a highly efficient chemo enzymatic synthesis of a hyaluronan lipid HA lipid ligand and have teamed with ZoneOne Pharma to develop a simple and robust micelle transfer method to insert the HA lipid into the FDA approved liposome cytotoxic drugs Doxil R LipoDox R and Daunoxome R This will target the approved liposomal drugs to CD a cell surface marker that is over expressed on many human cancers such as breast prostate colon glioblastoma head neck ovarian and pancreatic cancers Recently CD was found to be expressed at high levels on cancer stem cells which are considered essential for rapid tumor proliferation and tumor metastases CD is a cell surface receptor that is part of a complex biochemical physiological system involved in the synthesis degradation and signaling of hyaluronan The principle ligand for CD is hyaluronan itself a high molecular weight carbohydrate polymer that consists of a two sugar repeat We will pursue three aims Aim At UCSF we will synthesize and characterize large quantities of the lipid modified HA ligand of a low molecular weight and narrow polydispersity and a fluorescent modified HA ligand Aim Scientists at ZoneOne Pharma Inc will devise and validate a micelle transfer method to introduce the ligand into commercial available FDA approved Doxil R LipoDox R and Daunoxome R with retention of the drug content and particle size of the starting liposomes They will verify the ligand density required to effectivel target the liposomes to CD expressing cells in culture Aim At the UC cancer center the therapeutic activity of Doxil R will be compared to HA modified Doxil R in the primary tumor and tumor metastases in the orthotopic T breast tumor model The company will prepare the HA targeted Doxil R and transfer it to the UCSF cancer center to determine the antitumor activity of the HA modified liposomes in the T tumor in BALB c mice Completion of the first two aims will enable a test of the hypothesis that the insertion of a HA lipid ligand into approved
liposomal anticancer drugs can target the liposomal drug to CD over expressing cancer cells Completion of aim will provide a test of the hypothesis that administration of the HA lipid modified Doxil R to CD results in a better antitumor effect in the T breast cancer in BALB c mice both in the primary tumor and in metastatic lesions than does administration of the non targeted Doxil R Successful completion of the research plan would validate the potential of targeting FDA approved liposomes to treat human cancers that express CD We think the evaluation of a targeting lipid HA ligand added in the pharmacy to available liposomal drugs would experience a rapid entry into clinical trials This is because the comparator population would be patients who receive the unmodified liposomal drug and in the targeted arm of the study there could be a lesser risk of treatment failures hence patients would be less likely to be
placed at risk than if a completely new drug was being evaluated Finally the path to commercialization could be shortened since ZoneOne Pharma would manufacture the ligand product not the entire formulation and provide a robust validated protocol for inserting the lipid
HA into the currently approved liquid FDA liposome formulations

PUBLIC HEALTH RELEVANCE A critical barrier to developing new cancer treatments is the time it takes for a new treatment to prove it is efficacious in clinical trials We propose to re target currently approved liposomal anticancer drugs such as Doxil LipoDox and Daunoxome by adding to the liposome at the bedside a ligand that binds to the cancer stem cell marker CD CD is over expressed in cancer stem cells and also in breast prostate colon glioblastoma head neck ovarian and pancreatic tumors Successful completion of the plan could lead a vial of lyophilized sterile lipid carbohydrate ligand to which the approved liposomes can be added This would enable the rapid introduction into clinical trials novel targeted liposomal drugs that could dramatically slow the progression of aggressive CD expressing human cancers