TY - JOUR
T1 - Multistep, effective drug distribution within solid tumors
AU - Shemi, Amotz
AU - Khvalevsky, Elina Zorde
AU - Gabai, Rachel Malka
AU - Domb, Abraham
AU - Barenholz, Yechezkel
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Drug delivery
KW - KRAS
KW - RNAi
KW - Solid tumor
KW - Tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=84950124883&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.5051
DO - 10.18632/oncotarget.5051
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 26416413
AN - SCOPUS:84950124883
SN - 1949-2553
VL - 6
SP - 39564
EP - 39577
JO - Oncotarget
JF - Oncotarget
IS - 37
ER -