PH-Sensitive Multiligand Gold Nanoplatform Targeting Carbonic Anhydrase IX Enhances the Delivery of Doxorubicin to Hypoxic Tumor Spheroids and Overcomes the Hypoxia-Induced Chemoresistance

Ahmed M. Shabana, Utpal K. Mondal, Md Raqibul Alam, Taylor Spoon, Codee Alicia Ross, Muniswamy Madesh, Claudiu T. Supuran, Marc A. Ilies

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Hypoxia is a common feature of solid tumors contributing to resistance to chemotherapy. Selective delivery of chemotherapeutic drugs to hypoxic tumor niche remains an unsolved issue. For this purpose, we constructed a gold nanoplatform targeting carbonic anhydrase IX (CA IX) epitope, which is overexpressed in hypoxic tumor cells versus in normal tissues. We designed compatible low-molecular weight carbonic anhydrase inhibitor (CAI) ligands and doxorubicin (Dox) ligands and optimized protocols for efficient decoration of gold nanoparticles (Au NPs) to achieve both good targeting ligand density and optimum drug loading, while preserving colloidal stability. The optimized Dox-HZN-DTDP@Au NPs-LA-PEG2000-CAI (THZN) nanoplatform was proved to be very efficient toward killing HT-29 tumor cells, especially under hypoxic conditions, as compared with the nontargeting nanoplatform. This also mediated the effective release of doxorubicin in the lysosomes following internalization, as revealed by confocal microscopy. Furthermore, using tumor spheroids as a representative model for hypoxic solid tumors, our THZN nanoplatform enhanced the selective delivery of doxorubicin up to 2.5 times and minimized chemoresistance, showing better tumor drug penetration as compared to that in free drug treatment. Our technology is the first CA IX-targeting gold nanoplatform for efficient delivery of doxorubicin to hypoxic tumors in a controlled fashion, with the perspective to improve the therapy of solid tumors and minimize chemoresistance.

Original languageEnglish (US)
Pages (from-to)17792-17808
Number of pages17
JournalACS Applied Materials and Interfaces
Volume10
Issue number21
DOIs
StatePublished - May 30 2018

Keywords

  • carbonic anhydrase IX
  • chemoresistance
  • doxorubicin delivery
  • gold nanoparticles
  • hypoxia
  • inhibitor
  • tumor spheroids

ASJC Scopus subject areas

  • Materials Science(all)

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