PEG-PLA-Coated and Uncoated Radio-Luminescent CaWO4 Micro- and Nanoparticles for Concomitant Radiation and UV-A/Radio-Enhancement Cancer Treatments.

Currently, there is great interest in the development of ways to achieve the benefits of radiation treatments with reduced negative effects. The present study demonstrates the utilization of radio-luminescent particles (RLPs) as a means to achieve radio-sensitization and enhancement and their ability to affect head- and neck-cancer-cell cultures (in vitro) and xenografts (in vivo). Our approach utilizes a naturally abundant radio-luminescent mineral, calcium tungstate (CaWO4), in its micro or nanoparticulate form for generating secondary UV-A light by γ ray or X-ray photons. In vitro tests demonstrate that unoptimized RLP materials (uncoated CaWO4 (CWO) microparticles (MPs) and PEG-PLA-coated CWO nanoparticles (NPs)) induce a significant enhancement of the tumor-suppressive effect of X-rays and γ rays in both radio-sensitive- and radio-resistant-cancer models; uncoated CWO MPs and PEG-PLA-coated CWO NPs demonstrate comparable radio-sensitization efficacies in vitro. Mechanistic studies reveal that concomitant CaWO4 causes increased mitotic death in radio-resistant cells treated with radiation, whereas CaWO4 sensitizes radio-sensitive cells to X-ray-induced apoptosis and necrosis. The radio-sensitization efficacy of intratumorally injected CaWO4 particles (uncoated CWO MPs and PEG-PLA-coated CWO NPs) is also evaluated in vivo in mouse head- and neck-cancer xenografts. Uncoated CWO MPs suppress tumor growth more effectively than PEG-PLA-coated CWO NPs. On the basis of theoretical considerations, an argument is proposed that uncoated CWO MPs release subtoxic levels of tungstate ions, which cause increased photoelectric-electron-emission effects. The effect of folic acid functionalization on the in vitro radio-sensitization behavior produced by PEG-PLA-coated CWO NPs is studied. Surface folic acid results in a significant improvement in the radio-sensitization efficiency of CaWO4.

Technical Note: A simulation study on the feasibility of radiotherapy dose enhancement with calcium tungstate and hafnium oxide nano- and microparticles.

PURPOSE: To assess the radiotherapy dose enhancement (RDE) potential of calcium tungstate (CaWO4 ) and hafnium oxide (HfO2 ) nano- and microparticles (NPs). A Monte Carlo simulation study was conducted to gauge their respective RDE potentials relative to that of the broadly studied gold (Au) NP. The study was warranted due to the promising clinical and preclinical studies involving both CaWO4 and HfO2 NPs as RDE agents in the treatment of various types of cancers. The study provides a baseline RDE to which future experimental RDE trends can be compared to. METHODS: All three materials were investigated in silico with the software Penetration and Energy Loss of Positrons and Electrons (PENELOPE 2014) developed by Francesc Salvat and distributed in the United States by the Radiation Safety Information Computational Center (RSICC) at Oak Ridge National Laboratory. The work utilizes the extensively studied Au NP as the "gold standard" for a baseline. The key metric used in the evaluation of the materials was the local dose enhancement factor (DEFloc ). An additional metric used, termed the relative enhancement ratio (RER), evaluates material performance at the same mass concentrations. RESULTS: The results of the study indicate that Au has the strongest RDE potential using the DEFloc metric. HfO2 and CaWO4 both underperformed relative to Au with lower DEFloc of 2-3 × and 4-100 ×, respectively. CONCLUSIONS: The computational investigation predicts the RDE performance ranking to be: Au > HfO2 > CaWO4 .

Elucidating a Unified Mechanistic Scheme for the DBU-Catalyzed Ring-Opening Polymerization of Lactide to Poly(lactic acid).

The synthesis of poly(lactic acid), PLA, is facile in the presence of the cyclic, organic amidine catalyst 1,8-diazabicyclo[5.4.0]undec-7-ene, DBU. Since DBU's catalytic capability was first reported by Lohmeijer and colleagues in 2006 for ring-opening polymerizations (ROP), there have been numerous studies conducted by a variety of groups on the catalytic functioning of DBU in the ROPs of cyclic esters resulting in a large body of un-unified material from a mechanistic standpoint. This lack of clarity will hamper engineering polymers with desired characteristics from cyclic ester and lactone monomers. The work outlined in this paper seeks to propose a unified picture of the mechanisms in the DBU catalyzed ROP of lactide. In providing this unified picture of the ROP our work encompassed: (i) proposing a detailed reaction network scheme, (ii) conducting syntheses of lactide and DBU over a range of initial concentrations, and (iii) kinetic modeling to further support the proposed reaction network. As a result, our work has produced: (i) kinetic data, (ii) a consistent, viable reaction scheme verified through kinetic modeling, (iii) deduced and quantified the interplay between polymerization routes facilitated by the presence of DBU, thus demonstrating the need for detailed kinetic studies to deconstruct complex reaction networks, (iv) the first experimental evidence in support of the combination of ketene aminal-ended chains with alcohol-ended chains, and (v) analyzed the robustness of the catalyst to acid contamination.