Liposomal Bortezomib Nanoparticles via Boronic Ester Prodrug Formulation for Improved Therapeutic Efficacy in Vivo
journal contributionposted on 26.06.2014, 00:00 by Jonathan D. Ashley, Jared F. Stefanick, Valerie A. Schroeder, Mark A. Suckow, Tanyel Kiziltepe, Basar Bilgicer
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.
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Liposomal Bortezomib Nanoparticlesisobutylboronic acidsynthesizing bortezomib prodrugsliposomal nanoparticlesTherapeutic Efficacysize rangebortezomib prodrugsprodrug candidatesmodel boronic acid compoundboronic ester stabilityproteasome inhibitionpatient outcometumor growth inhibitionliposomal bortezomib nanoparticles100 nmmyeloma cell linesboronic ester bond formationsurface conjugationBoronic Ester Prodrug Formulationboronic ester bonds