title: Effect of drug release kinetics on nanoparticle therapeutic efficacy and toxicity.
abstract: The effects of nanoparticle (NP) properties, such as size, shape and surface charge, on their efficacy and toxicity have been studied extensively. However, the effect of controlled drug release on NP efficacy and toxicity has not been thoroughly evaluated in vivo. Our study aims to fill this knowledge gap. A key challenge in characterizing the relationship between drug release and therapeutic ratio is to fabricate NPs that differ only in their drug release profile but are otherwise identical. To overcome this challenge, we developed crosslinkable lipid shell (CLS) NPs, where the drug release kinetics can be modulated without changing any other NP property. Using CLS NPs with wortmannin and docetaxel as model drugs, we determined the relationship between the release kinetics and therapeutic efficacy and toxicity of the drugs. We have determined that drug release kinetics can affect the therapeutic efficacy of NP docetaxel and NP wortmannin in vitro and in vivo. Our study also demonstrates that a decrease in drug release kinetics can result in a decrease in the hepatotoxicity of CLS NP wortmannin. Using two model drugs, the current findings provide the first direct evidence that NP drug release profile is a critical factor in determining the NP therapeutics' efficacy and toxicity in vivo.
authors.affiliation: Carolina Center for Cancer Nanotechnology Excellence, Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, NC 27599, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Sethi
authors.affiliation: Carolina Center for Cancer Nanotechnology Excellence, Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, NC 27599, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Sukumar
authors.affiliation: Carolina Center for Cancer Nanotechnology Excellence, Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, NC 27599, USA.
authors.forename: Shrirang
authors.initials: S
authors.lastname: Karve
authors.affiliation: Carolina Center for Cancer Nanotechnology Excellence, Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, NC 27599, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Werner
authors.affiliation: Carolina Center for Cancer Nanotechnology Excellence, Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, NC 27599, USA.
authors.forename: Edina C
authors.initials: EC
authors.lastname: Wang
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Dominic T
authors.initials: DT
authors.lastname: Moore
authors.affiliation: Carolina Center for Cancer Nanotechnology Excellence, Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, NC 27599, USA.
authors.forename: Sonya R
authors.initials: SR
authors.lastname: Kowalczyk
authors.affiliation: Department of Nanoengineering, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Liangfang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Carolina Center for Cancer Nanotechnology Excellence, Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, NC 27599, USA.
authors.forename: Andrew Z
authors.initials: AZ
authors.lastname: Wang
mesh_terms: D000730:Androstadienes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000077143:Docetaxel; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D043823:Taxoids; D000077143:Docetaxel; D000077191:Wortmannin