Folate-Targeted Polymeric Nanoparticle Formulation of Docetaxel Is an Effective Molecularly Targeted Radiosensitizer with Efficacy Dependent on the Timing of Radiotherapy
- 19 October 2011
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Nano
- Vol. 5 (11), 8990-8998
- https://doi.org/10.1021/nn203165z
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 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.Keywords
This publication has 34 references indexed in Scilit:
- Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapyProceedings of the National Academy of Sciences, 2010
- Trastuzumab-functionalized nanoparticles of biodegradable copolymers for targeted delivery of docetaxelNanomedicine, 2009
- Preclinical and clinical studies of anticancer agent‐incorporating polymer micellesCancer Science, 2009
- Self-Assembled Lipid−Polymer Hybrid Nanoparticles: A Robust Drug Delivery PlatformACS Nano, 2008
- 130-nm Albumin–Bound Paclitaxel Enhances Tumor Radiocurability and Therapeutic GainClinical Cancer Research, 2007
- The chemoradiation paradigm in head and neck cancerNature Clinical Practice Oncology, 2007
- Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assayAnalytical Biochemistry, 2005
- Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced MalignanciesClinical Cancer Research, 2004
- Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a reviewJournal of Controlled Release, 2000
- Repopulation of γ-irradiated Lewis lung carcinoma by malignant cells and host macrophage progenitorsBritish Journal of Cancer, 1978