Preclinical pharmacokinetic, biodistribution, and anti-cancer efficacy studies of a docetaxel-carboxymethylcellulose nanoparticle in mouse models

• Published in: Biomaterials 2012-02, Vol.33 (5), p.1445-1454
• Main Authors: Ernsting, Mark J, Tang, Wei-Lun, MacCallum, Noah W, Li, Shyh-Dar
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biodistribution; Carboxymethylcellulose; Carboxymethylcellulose Sodium - chemistry; Conjugated polymers; Dentistry; Disease Models, Animal; Docetaxel; Drug Screening Assays, Antitumor; Intracellular Space - drug effects; Intracellular Space - metabolism; Mice; Mice, Inbred BALB C; Nanoparticles - chemistry; Neoplasm Metastasis; Neoplasms - drug therapy; Neoplasms - pathology; Pharmacokinetics; Polyethylene Glycols - chemistry; Polymers - chemical synthesis; Polymers - chemistry; Taxoids - blood; Taxoids - pharmacokinetics; Taxoids - therapeutic use; Tissue Distribution - drug effects; Treatment Outcome
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2011.10.061

Abstract We have developed a polymer conjugate (Cellax) composed of acetylated carboxymethylcellulose (CMC), docetaxel (DTX), and PEG, designed to enhance the pharmacokinetics (PK) and antitumor efficacy of DTX. Our design placed an emphasis on nanoparticle self-assembly to protect DTX during blood transport, stability of the nanoparticle, and PEGylation to enhance PK. Compared to Taxotere, Cellax exhibited a 38.6 times greater area under the curve (AUC), and significantly lower clearance (2.5%) in PK. Less than 10% of DTX was released from Cellax in the blood circulation, indicating that Cellax were stable during blood transport. Cellax reduced non-specific distribution of DTX to the heart, lung and kidney by 48, 90, and 90%, respectively, at 3 h, compared to Taxotere. The uptake of Cellax at 3 h in the liver and spleen was high (15–45 μg DTX/g) but declined rapidly to