Liposomal bortezomib nanoparticles via boronic ester prodrug formulation for improved therapeutic efficacy in vivo

J Med Chem. 2014 Jun 26;57(12):5282-92. doi: 10.1021/jm500352v. Epub 2014 Jun 13.


In this study, we describe the development of liposomal bortezomib nanoparticles, which was accomplished by synthesizing bortezomib prodrugs with reversible boronic ester bonds and then incorporating the resulting prodrugs into the nanoparticles via surface conjugation. Initially, several prodrug candidates were screened based upon boronic ester stability using isobutylboronic acid as a model boronic acid compound. The two most stable candidates were then selected to create surface conjugated bortezomib prodrugs on the liposomes. Our strategy yielded stable liposomal bortezomib nanoparticles with a narrow size range of 100 nm and with high reproducibility. These liposomal bortezomib nanoparticles demonstrated significant proteasome inhibition and cytotoxicity against multiple myeloma cell lines in vitro and remarkable tumor growth inhibition with reduced systemic toxicity compared to free bortezomib in vivo. Taken together, this study demonstrates the incorporation of bortezomib into liposomal nanoparticles via reversible boronic ester bond formation to enhance the therapeutic index for improved patient outcome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Apoptosis
  • Boronic Acids / administration & dosage*
  • Boronic Acids / chemical synthesis
  • Boronic Acids / chemistry
  • Bortezomib
  • Cell Line, Tumor
  • Esters
  • Humans
  • Liposomes
  • Mice, SCID
  • Multiple Myeloma / drug therapy
  • Nanoparticles
  • Neoplasm Transplantation
  • Prodrugs / administration & dosage*
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Proteasome Endopeptidase Complex / metabolism
  • Pyrazines / administration & dosage*
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry


  • Antineoplastic Agents
  • Boronic Acids
  • Esters
  • Liposomes
  • Prodrugs
  • Pyrazines
  • Bortezomib
  • Proteasome Endopeptidase Complex