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

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.
ACS Nano (Impact Factor: 12.88). 11/2011; 5(11):8990-8. DOI: 10.1021/nn203165z
Source: PubMed

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.

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    • "On one hand, HP was covalently grafted inside the silica shell [20e22] to serve as both photosensitizer and radiosensitizer for synergetic radio-/photodynamic therapy. On the other hand, Dtxl was encapsulated into the inner cavity to be applied as both chemodrug and radiosensitizer for synergetic chemo-/radiotherapy [16] [17]. In summary, we aim to achieve the following goals by fabricating the novel rattle-structured Gd-UCNPs core/mesoporous silica shell nanotheranostics (UCMSNs): (1) UCMSNs can be used for positioning tumors by serving as contrasting agents in MR/UCL bimodal imaging; (2) By the co-delivery of HP and Dtxl, UCMSNs- HP-Dtxl can achieve synergetic chemo-/radio-/photodynamic trimodal therapy upon NIR excitation and X-ray irradiation, which may lead to the satisfactory treatment efficiency for tumor eradication ; (3) UCMSNs may cast lights on the multimodal imagingguided therapeutic alliance with significant synergetic therapeutic effects in the future. "
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    ABSTRACT: To achieve the accurate diagnosis and efficient in situ therapy of malignant tumors is encouraging but still remains a big challenge. The integration of upconversion nanoparticles and mesoporous silica that can combine the diagnostic/therapeutic functions within a single platform, may provide a more advanced way for the efficient theranostics of cancer. In this study, sub-80 nm rattle-structured multifunctional Gd-UCNPs core/mesoporous silica shell nanotheranostics (UCMSNs) were successfully constructed for the co-delivery of a radio-/photo-sensitizer hematoporphyrin (HP) and a radiosensitizer/chemodrug docetaxel (Dtxl). Upon NIR excitation and X-ray irradiation, the complete tumor elimination has been achieved by the synergetic chemo-/radio-/photodynamic tri-modal therapy under the assistance of simultaneous magnetic/upconversion luminescent (MR/UCL) bimodal imaging. To the best of our knowledge, this study is the first example of achieving tri-modal synergetic therapy in one single nanotheranostic system, and we anticipate that it may serve as a particularly useful platform for the clinical diagnosis and efficient treatment of cancer from bench to beside.
    Biomaterials 08/2014; 35(32). DOI:10.1016/j.biomaterials.2014.07.024 · 8.56 Impact Factor
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    • "However, there is a notable limitation in the use of hydrophobic bile acids such as deoxycholic acid as absorption enhancers, because the conjugated hydrophobic bile acid is located within the core of micelles formed in water [22]. Docetaxel (DTX) is widely used in treating a broad range of human cancers, including refractory ovarian and breast cancer, non-small-cell lung carcinoma, head and neck carcinoma and leukemia [23] [24] [25] [26]. However , docetaxel shows very low rates of oral absorption and bioavailability (less than 3%) due to both its low aqueous solubility and pre-systemic intestinal metabolism [27]. "
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    ABSTRACT: We have synthesized taurocholic acid (TCA) linked heparin-docetaxel (DTX) conjugates for oral delivery of anticancer drug. The ternary biomolecular conjugates formed self-assembly nanoparticles where docetaxel was located inside the core and taurocholic acid was located on the surface of the nanoparticles. The coupled taurocholic acid in the nanoparticles had enhanced oral absorption, presumably through the stimulation of a bile acid transporter of the small intestine. The oral absorption profile demonstrated that the concentration of the conjugates in plasma is about 6 fold higher than heparin alone. An anti-tumor study in MDA-MB231 and KB tumor bearing mice showed significant tumor growth inhibition activity by the ternary biomolecular conjugates. Ki-67 histology study also showed evidence of anticancer activity of the nanoparticles. Finally, noninvasive imaging using a Kodak Molecular Imaging System demonstrated that the nanoparticles were accumulated efficiently in tumors. Thus, this approach for oral delivery using taurocholic acid in the ternary biomolecular conjugates is promising for treatment of various types of cancer.
    Journal of Controlled Release 05/2013; 170(1). DOI:10.1016/j.jconrel.2013.04.024 · 7.71 Impact Factor
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    ABSTRACT: The in vivo behaviors of doxorubicin (DOX)-loaded dextran-poly(3-acrylamidophenylboronic acid) (Dextran-PAPBA) nanoparticles (NPs) were studied. The DOX-loaded NPs had a narrowly distributed diameter of ca. 74 nm and mainly accumulated in liver of tumor-bearing mice after intravenous injection as demonstrated by in vivo real-time near infrared fluorescent imaging. The DOX contents in various tissues were quantified and consisted well with the results of fluorescent imaging. The biodistribution pattern of DOX-loaded NPs encourages us to investigate their liver tumor treatment by using an orthotopically implanted liver tumor model, revealing that the DOX-loaded NPs formulation had better antitumor effect than free DOX.
    Chinese Journal of Polymer Science 05/2013; 31(5). DOI:10.1007/s10118-013-1267-y · 1.84 Impact Factor
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