Biodistribution and bioimaging studies of hybrid paclitaxel nanocrystals: lessons learned of the EPR effect and image-guided drug delivery.
Paclitaxel (PTX) nanocrystals (200 nm) were produced by crystallization from a solution. Antitumor efficacy and toxicity were examined through a survival study in a human HT-29 colon cancer xenograft murine model. The antitumor activity of the nanocrystal treatments was comparable with that by the conventional solubilization formulation (Taxol®), but yielded less toxicity as indicated by the result of a survival study. Tritium-labeled PTX nanocrystals were further produced with a near infrared (NIR) fluorescent dye physically integrated in the crystal lattice. Biodistribution and tumor accumulation of the tritium-labeled PTX nanocrystals were determined immediately after intravenous administration and up to 48 h by scintillation counting. Whole-body optical imaging of animals was concurrently carried out; fluorescent intensities were also measured from excised tumors and major organs of euthanized animals. It was found that drug accumulation in the tumor was less than 1% of 20mg/kg intravenous dose. Qualitatively correlation was identified between the biodistribution determined by using tritium-labeled particles and that using optical imaging, but quantitative divergence existed. The divergent results suggest possible ways to improve the design of hybrid nanocrystals for cancer therapy and diagnosis. The study also raises questions of the general role of the enhanced permeability and retention (EPR) effect in tumor targeting and the effectiveness of bioimaging, specifically for theranostics, in tracking drug distribution and pharmacokinetics.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington 40536, USA.
Christin P
CP
Hollis
Biostatistics, Division of Cancer Biostatistics, Markey Cancer Center, University of Kentucky, Lexington 40506, USA.
Heidi L
HL
Weiss
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington 40536, USA.
Markos
M
Leggas
Department of Surgery, Markey Cancer Center, University of Kentucky, Lexington 40506, USA.
B Mark
BM
Evers
Departments of Biopharmaceutical Sciences, Bioengineering, and Ophthalmology and Visual Sciences, University of Illinois, Chicago 60612, USA.
Richard A
RA
Gemeinhart
Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette 47907, USA. Electronic address: tonglei@purdue.edu.
Tonglei
T
Li
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000032:analysis* / Q000648:ultrastructure; D061848:Optical Imaging; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D010539:Permeability; D014018:Tissue Distribution
D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel
Biodistribution; Chemotherapy; EPR; Nanocrystals; Paclitaxel; Theranostics