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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Celator Pharmaceuticals Corp., 1779 West 75th Ave, Vancouver, BC V6P 6P2, Canada.
Awa
A
Dicko
Lawrence D
LD
Mayer
Paul G
PG
Tardi
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004357:Drug Synergism; D006801:Humans; D008081:Liposomes; D053758:Nanoparticles; D009369:Neoplasms / Q000188:drug therapy
D008081:Liposomes