title: 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: Department of Bioengineering, University of California, Los Angeles 90095, USA.
authors: Ricky Y T
authors: RY
authors: Chiu
authors: Department of Materials, Physics, and Engineering, Nagoya University, Nagoya, Japan.
authors: Takuma
authors: T
authors: Tsuji
authors: Department of Bioengineering, University of California, Los Angeles 90095, USA.
authors: Stephanie J
authors: SJ
authors: Wang
authors: Department of Bioengineering, University of California, Los Angeles 90095, USA.
authors: Juntian
authors: J
authors: Wang
authors: Department of Bioengineering, University of California, Los Angeles 90095, USA.
authors: Christina T
authors: CT
authors: Liu
authors: Department of Bioengineering, University of California, Los Angeles 90095, USA. Electronic address: kamei@seas.ucla.edu.
authors: Daniel T
authors: DT
authors: Kamei
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D007501:Iron / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D019815:Oxalic Acid / Q000737:chemistry / Q000378:metabolism; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004337:Drug Carriers; D014168:Transferrin; D019815:Oxalic Acid; D007501:Iron
keywords: Cellular association; Intracellular trafficking; Mathematical modeling; Targeted drug delivery; Transferrin