Multistep, effective drug distribution within solid tumors

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

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish
Pages (from-to)39564-39577
Number of pages14
JournalOncotarget
Volume6
Issue number37
DOIs
StatePublished - 24 Nov 2015
Externally publishedYes

Keywords

  • Drug delivery
  • KRAS
  • RNAi
  • Solid tumor
  • Tumor microenvironment

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