Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging

ACS Nano. 2016 Apr 26;10(4):4209-18. doi: 10.1021/acsnano.5b07573. Epub 2016 Mar 16.

Abstract

The blood-brain barrier (BBB) is partially disrupted in brain tumors. Despite the gaps in the BBB, there is an inadequate amount of pharmacological agents delivered into the brain. Thus, the low delivery efficiency renders many of these agents ineffective in treating brain cancer. In this report, we proposed an "autocatalytic" approach for increasing the transport of nanoparticles into the brain. In this strategy, a small number of nanoparticles enter into the brain via transcytosis or through the BBB gaps. After penetrating the BBB, the nanoparticles release BBB modulators, which enables more nanoparticles to be transported, creating a positive feedback loop for increased delivery. Specifically, we demonstrated that these autocatalytic brain tumor-targeting poly(amine-co-ester) terpolymer nanoparticles (ABTT NPs) can readily cross the BBB and preferentially accumulate in brain tumors at a concentration of 4.3- and 94.0-fold greater than that in the liver and in brain regions without tumors, respectively. We further demonstrated that ABTT NPs were capable of mediating brain cancer gene therapy and chemotherapy. Our results suggest ABTT NPs can prime the brain to increase the systemic delivery of therapeutics for treating brain malignancies.

Keywords: autocatalytic delivery; blood−brain barrier; brain cancer; nanoparticles.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Biological Transport
  • Blood-Brain Barrier / metabolism*
  • Brain Neoplasms / diagnostic imaging*
  • Brain Neoplasms / therapy*
  • Cell Line, Tumor
  • Decanoic Acids / chemistry
  • Drug Delivery Systems
  • Ethanolamines / chemistry
  • Female
  • Genetic Therapy
  • Heterografts
  • Humans
  • Matrix Metalloproteinase 2 / chemistry
  • Mice
  • Mice, Inbred C57BL
  • Nanoparticles / chemistry*
  • Optical Imaging
  • Paclitaxel / administration & dosage
  • Permeability
  • Polymers / chemistry
  • Purines / chemistry
  • Pyrazoles / chemistry
  • Scorpion Venoms / chemistry
  • Transcytosis
  • Tumor Microenvironment

Substances

  • Antineoplastic Agents
  • Decanoic Acids
  • Ethanolamines
  • Polymers
  • Purines
  • Pyrazoles
  • Scorpion Venoms
  • Chlorotoxin
  • regadenoson
  • N-methyldiethanolamine
  • Matrix Metalloproteinase 2
  • ethyl sebacate
  • Paclitaxel