Use of nanoscale delivery systems to maintain synergistic drug ratios in vivo.

IMPORTANCE OF THE FIELD: Drug combinations have been the standard of care in the treatment of cancer for > 50 years. Typically, combination chemotherapy uses agents with non-overlapping toxicities which are escalated to their maximum tolerated dose. However, emerging evidence indicates that this approach may not be providing optimal efficacy depending on the drug ratios to which the tumor is exposed. Combined drugs can be synergistic whereas other ratios of the same agents may be antagonistic or additive. AREAS COVERED IN THIS REVIEW: In this review, we examine the importance of drug ratios in cancer therapy. We describe how manipulation of the lipid membrane and internal buffer composition maintains synergistic ratios of irinotecan and floxuridine (CPX-1), daunorubicin and cytarabine (CPX-351) or cisplatin and irinotecan (CPX-571). For polymer-based nanoparticles, prodrug hydrophobicity was exploited to coordinate the release of gemcitabine and the more hydrophobic paclitaxel. We present preclinical data for liposomal drug combinations which demonstrate that the most efficacious formulation is not always the highest dose of both agents. WHAT THE READER WILL GAIN: An insight into the use of liposomes and polymer-based nanoparticles to deliver synergistic drug combinations to the tumor site and avoid antagonistic drug-drug interactions. TAKE HOME MESSAGE: The ability to control and maintain drug ratios in vivo through the use of nanoscale delivery vehicles results in a significant improvement in therapeutic activity.