Oncotarget

Research Papers:

Multistep, effective drug distribution within solid tumors

Amotz Shemi _, Elina Zorde Khvalevsky, Rachel Malka Gabai, Abraham Domb, Yechezkel Barenholz

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Oncotarget. 2015; 6:39564-39577. https://doi.org/10.18632/oncotarget.5051

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Abstract

Amotz Shemi1, Elina Zorde Khvalevsky1, Rachel Malka Gabai1, Abraham Domb2, Yechezkel Barenholz3

1Silenseed Ltd., Jerusalem, Israel

2Faculty of Medicine - School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel

3Membrane and Liposome Research Lab, Hebrew University Hadassah Medical School, Jerusalem, Israel

Correspondence to:

Amotz Shemi, e-mail: amotz@silenseed.com

Keywords: drug delivery, RNAi, tumor microenvironment, KRAS, solid tumor

Received: June 02, 2015     Accepted: September 10, 2015     Published: September 22, 2015

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.

Author Information

Amotz Shemi
Primary Contact  _

Elina Zorde Khvalevsky

Rachel Malka Gabai

Abraham Domb

Yechezkel Barenholz


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