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Multistep, effective drug distribution within solid tumors
#MMPMID26416413
Shemi A
; Khvalevsky EZ
; Gabai RM
; Domb A
; Barenholz Y
Oncotarget
2015[Nov]; 6
(37
): 39564-77
PMID26416413
show ga
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.
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