Folate-Targeted Polymeric Nanoparticle Formulation of Docetaxel Is an Effective Molecularly Targeted Radiosensitizer with Efficacy Dependent on the Timing of Radiotherapy

Abstract

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 over-expressing 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 hours) showed FT-NP Dtxl is as effective as Dtxl. When FT-NP Dtxl is compared to Dtxl and non-targeted 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 over-expressing 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.

Polysilsesquioxane nanoparticles for triggered release of cisplatin and effective cancer chemoradiotherapy

“…Indeed, preclinical studies have suggested that NP therapeutics are more effective than small molecule chemotherapeutics in chemoradiotherapy. 8, 11–13 …”

Improving Cancer Chemoradiotherapy Treatment by Dual Controlled Release of Wortmannin and Docetaxel in Polymeric Nanoparticles

“…19,20,23–25,28,36,48,49 The degree of DNA damage caused by chemotherapy and/or CRT can be quantified by γ -H2AX immunohistochemistry stain, a biomarker for DNA double-strand breaks. As shown in Figure 10, the administration of Wtmn NPs did not trigger any significant DNA damage compared with the control group.…”

Experimental Therapies in Breast Cancer

“…The surge of interest in dendrimers was marked by Tomalia's finding in the mid-1980s (Werner et al 2011). Since then, the use and complexity of dendrimers has evolved at an impressive rate (Tomalia et al 1985;Malik et al 1999Malik et al , 2000.…”