title: Tumor-targeted drug delivery using MR-contrasted docetaxel - carboxymethylcellulose nanoparticles.
abstract: A carboxymethylcellulose-based polymer conjugate with nanoparticle forming properties (Cellax) has been shown to enhance the pharmacokinetics, specificity of biodistribution, anti-tumor efficacy and safety of docetaxel (DTX) in comparison to the Taxotere™ formulation. We examined Cellax and Taxotere efficacy in four tumor models (EMT-6, B16F10, PC3, and MDA-MB-231), and observed variances in efficacy. To explore whether differences in tumor uptake of Cellax were responsible for these effects, we incorporated superparamagnetic iron oxide nanoparticles (SPIONs) into Cellax particles to enable magnetic resonance (MR) imaging (Cellax-MR). In the EMT-6 tumor model, Cellax-MR nanoparticles exhibited peak tumor accumulation 3-24 h post intravenous injection, and 3 days post-treatment, significant MR contrast was still detected. The amount of Cellax-MR deposited in the EMT-6 tumors was quantifiable as a hypointense volume fraction, a value positively correlated with drug content as determined by LC/MS analysis (R(2) = 0.97). In the four tumor models, Cellax-MR uptake was linearly associated with anti-tumor efficacy (R(2) > 0.9), and was correlated with blood vessel density (R(2) > 0.9). We have affirmed that nanoparticle uptake is variable in tumor physiology, and that this efficacy-predictive parameter can be non-invasively estimated in real-time using a theranostic variant of Cellax.
authors.affiliation: Drug Delivery and Formulation Group, Medicinal Chemistry Platform, Ontario Institute for Cancer Research, MaRS Centre South Tower, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ernsting
authors.forename: Warren D
authors.initials: WD
authors.lastname: Foltz
authors.forename: Elijus
authors.initials: E
authors.lastname: Undzys
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Tagami
authors.forename: Shyh-Dar
authors.initials: SD
authors.lastname: Li
mesh_terms: D000818:Animals; D002266:Carboxymethylcellulose Sodium / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry*; D004195:Disease Models, Animal; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009369:Neoplasms / Q000097:blood / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D013194:Staining and Labeling; D040521:Subcutaneous Tissue / Q000187:drug effects / Q000473:pathology; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use*; D014018:Tissue Distribution / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D003287:Contrast Media; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D043823:Taxoids; D000077143:Docetaxel; D002266:Carboxymethylcellulose Sodium