title: Multistep, effective drug distribution within solid tumors.
abstract: The distribution of drugs within solid tumors presents a long-standing barrier for efficient cancer therapies. Tumors are highly resistant to diffusion, and the lack of blood and lymphatic flows suppresses convection. Prolonged, continuous intratumoral drug delivery from a miniature drug source offers an alternative to both systemic delivery and intratumoral injection. Presented here is a model of drug distribution from such a source, in a multistep process. At delivery onset the drug mainly affects the closest surroundings. Such 'priming' enables drug penetration to successive cell layers. Tumor 'void volume' (volume not occupied by cells) increases, facilitating lymphatic perfusion. The drug is then transported by hydraulic convection downstream along interstitial fluid pressure (IFP) gradients, away from the tumor core. After a week tumor cell death occurs throughout the entire tumor and IFP gradients are flattened. Then, the drug is transported mainly by 'mixing', powered by physiological bulk body movements. Steady state is achieved and the drug covers the entire tumor over several months. Supporting measurements are provided from the LODER system, releasing siRNA against mutated KRAS over months in pancreatic cancer in-vivo models. LODER was also successfully employed in a recent Phase 1/2 clinical trial with pancreatic cancer patients.
authors.affiliation: Silenseed Ltd., Jerusalem, Israel.
authors.forename: Amotz
authors.initials: A
authors.lastname: Shemi
authors.affiliation: Silenseed Ltd., Jerusalem, Israel.
authors.forename: Elina Zorde
authors.initials: EZ
authors.lastname: Khvalevsky
authors.affiliation: Silenseed Ltd., Jerusalem, Israel.
authors.forename: Rachel Malka
authors.initials: RM
authors.lastname: Gabai
authors.affiliation: Faculty of Medicine - School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Abraham
authors.initials: A
authors.lastname: Domb
authors.affiliation: Membrane and Liposome Research Lab, Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yechezkel
authors.initials: Y
authors.lastname: Barenholz
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport; D002986:Clinical Trials as Topic; D018481:Convection; D004058:Diffusion; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D015552:Injections, Intralesional; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000493:pharmacokinetics; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering
keywords: KRAS; RNAi; drug delivery; solid tumor; tumor microenvironment