Improving the systemic drug delivery efficacy of nanoparticles using a transferrin variant for targeting.

Abstract

Targeted therapy for the treatment of cancers using nanoparticles (NPs) decorated with transferrin (Tf) has been relatively successful, as several such nanocarriers are currently undergoing clinical trials. However, since native Tf has a low probability of delivering its payload due to its short residence time in the cell, or low cellular association, there is room to significantly improve the potency of current systems. We pioneered the redesign of this targeting ligand by altering the ligand-metal interaction, as suggested by our mathematical model, and here we present the first study to investigate the enhanced therapeutic efficacy of NPs conjugated to our engineered oxalate Tf. Our mathematical model was first used to predict that NPs conjugated to oxalate Tf will exhibit a higher degree of cellular association compared to native Tf-conjugated NPs. Our in vitro trafficking experiments validated the model prediction, and subsequent in vitro and in vivo efficacy studies demonstrated that this increase in cellular association further translates into an enhanced ability to deliver chemotherapeutics. Our findings signify the importance of the cellular trafficking properties of targeting ligands, as they may significantly influence therapeutic potency when such ligands are conjugated to NPs. Given the early success of a number of native Tf-conjugated NPs in clinical trials, there is potential for using Tf-variant based therapeutics in systemic drug delivery applications for cancer treatment.

• Authors: Ricky Y T Chiu, Takuma Tsuji, Stephanie J Wang, Juntian Wang, Christina T Liu, Daniel T Kamei
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 180 Pg. 33-41 (Apr 28 2014) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 24524898 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Drug Carriers
• Transferrin
• Oxalic Acid
• Iron

Topics

• Animals
• Cell Line, Tumor
• Drug Carriers (chemistry, metabolism)
• Drug Delivery Systems (methods)
• Humans
• Iron (metabolism)
• Male
• Mice
• Models, Biological
• Nanoparticles (chemistry, metabolism)
• Neoplasms (drug therapy, metabolism)
• Oxalic Acid (chemistry, metabolism)
• Transferrin (chemistry, metabolism)