Folate Receptor Targeted Nanophosphors for Enhanced Tumor Radiotherapy


Sun, C. G., Ravilisetty, P., Carpenter, C., Pratx, G., & Xing, L. (2010). Folate Receptor Targeted Nanophosphors for Enhanced Tumor Radiotherapy. International Journal of Radiation Oncology, Biology, Physics, 78(3), S653.



The balance between patient safety and complete eradication of tumor cells generally limits the effectiveness of many cancer therapies. Recently, significant efforts have focused on exploiting nanotechnology for unique solutions in clinical oncology. In particular, the development of tumor specific in vivo imaging nanoparticles and therapeutic drug carriers are actively being investigated. Here we present a folic acid (FA) conjugated nanophosphor (NP) intended to enhance the therapeutic effect of radiotherapy by augmenting the production of reactive oxygen species with simultaneous photodynamic therapy (PDT). In this approach, x-ray luminescent NPs serve as a targeted carrier and activator of conjugated photosensitizers. By targeting the folate receptor (FR), which is overexpressed on many human cancer cells (e.g. ovarian, lung, breast, endometrial, renal, and colon), these NPs can be internalized via receptor-mediated endocytosis.


Lanthanide-based NPs, including gadolinium oxysulfide and lanthanum oxysulfide, were synthesized and doped with Tb3+ to impart x-ray luminescence. FA and protoporphyrin IX (PpIX) were covalently linked via carboxyl groups to the NPs through a bifunctional poly(ethylene glycol) (PEG) linker. PEG also increases NP biocompatibility and reduces agglomeration. NP-PEG-PpIX/FA conjugates were characterized by transmission electron microscopy (TEM) and UV spectroscopy. In vitro experiments were performed using FR expressing HeLa and FR-negative MCF-7 cells over a range of concentrations and incubation times. Uptake of NPs by target cells was determined by fluorescence microscopy and inductively coupled plasma (ICP) atomic emission spectrometry.


NPs were synthesized, coated with PEG and conjugated with both FA and PpIX. TEM analysis showed particles 107±29 nm in diameter, while UV confirmed the presence of both functional ligands. Intracellular uptake of the NPs was observed by fluorescence microcopy using a FITC filter set. ICP quantification of lanthanum or gadolinium showed preferential binding of NP-PEG-PpIX/FA conjugates to FR-positive HeLa, as compared to FR-negative MCF-7 cells. Significant uptake was also observed for HeLa cells cultured with NP-PEG-PpIX/FA conjugates compared to those incubated with non-specific control NPs.


Using this novel treatment approach, we seek to employ the depth penetration of x-rays and NP luminescence to enable radiotherapy enhanced by PDT. Here, we have demonstrated the synthesis, chemical conjugation and specific targeting of NP-PEG-PpIX/FA to FR-positive cancer cells. The successful development of this technique would provide an innovative tool with a synergistic cytotoxic effect and potential to lower therapeutic radiation doses.

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