Folate-targeted polymeric nanoparticle formulation of docetaxel is an effective molecularly targeted radiosensitizer with efficacy dependent on the timing of radiotherapy.
Nanoparticle (NP) chemotherapeutics hold great potential as radiosensitizers. Their unique properties, such as preferential accumulation in tumors and their ability to target tumors through molecular targeting ligands, are ideally suited for radiosensitization. We aimed to develop a molecularly targeted nanoparticle formulation of docetaxel (Dtxl) and evaluate its property as a radiosensitizer. Using a biodegradable and biocompatible lipid-polymer NP platform and folate as a molecular targeting ligand, we engineered a folate-targeted nanoparticle (FT-NP) formulation of Dtxl. These NPs have sizes of 72 ± 4 nm and surface charges of -42 ± 8 mV. Using folate receptor overexpressing KB cells and folate receptor low HTB-43 cells, we showed folate-mediated intracellular uptake of NPs. In vitro radiosensitization studies initially showed FT-NP is less effective than Dtxl as a radiosensitizer. However, the radiosensitization efficacy is dependent on the timing of radiotherapy. In vitro radiosensitization conducted with irradiation given at the optimal time (24 h) showed FT-NP Dtxl is as effective as Dtxl. When FT-NP Dtxl is compared to Dtxl and nontargeted nanoparticle (NT-NP) Dtxl in vivo, FT-NP was found to be significantly more effective than Dtxl or NT-NP Dtxl as a radiosensitizer. We also confirmed that radiosensitization is dependent on timing of irradiation in vivo. In summary, FT-NP Dtxl is an effective radiosensitizer in folate-receptor overexpressing tumor cells. Time of irradiation is critical in achieving maximal efficacy with this nanoparticle platform. To the best of our knowledge, our report is the first to demonstrate the potential of molecularly targeted NPs as a promising new class of radiosensitizers.
Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
Michael E
ME
Werner
Jonathan A
JA
Copp
Shrirang
S
Karve
Natalie D
ND
Cummings
Rohit
R
Sukumar
Chenxi
C
Li
Mary E
ME
Napier
Ronald C
RC
Chen
Adrienne D
AD
Cox
Andrew Z
AZ
Wang
D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002626:Chemistry, Pharmaceutical; D000077143:Docetaxel; D005492:Folic Acid / Q000378:metabolism*; D058972:Folic Acid Transporters / Q000172:deficiency / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D007624:KB Cells; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D011838:Radiation-Sensitizing Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D043823:Taxoids / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D058972:Folic Acid Transporters; D011108:Polymers; D011838:Radiation-Sensitizing Agents; D043823:Taxoids; D000077143:Docetaxel; D005492:Folic Acid