Dual-Responsive and ROS-Augmented Nanoplatform for Chemo/Photodynamic/Chemodynamic Combination Therapy of Triple Negative Breast Cancer.

Integrating chemodynamic therapy (CDT) and photodynamic therapy (PDT) into one nanoplatform can produce much more reactive oxygen species (ROS) for tumor therapy. Nevertheless, it is still a great challenge to selectively generate sufficient ROS in tumor regions. Meanwhile, CDT and PDT are restricted by insufficient H2O2 content in the tumor as well as by the limited tumor tissue penetration of the light source. In this study, a smart pH/ROS-responsive nanoplatform, Fe2+@UCM-BBD, is rationally designed for tumor combination therapy. The acidic microenvironment can induce the pH-responsive release of doxorubicin (DOX), which can induce tumor apoptosis through DNA damage. Beyond that, DOX can promote the production of H2O2, providing sufficient materials for CDT. Of note, upconversion nanoparticles at the core can convert the 980 nm light to red and green light, which are used to activate Ce6 to produce singlet oxygen (1O2) and achieve upconversion luminescence imaging, respectively. Then, the ROS-responsive linker bis-(alkylthio)alkene is cleaved by 1O2, resulting in the release of Fenton reagent (Fe2+) to realize CDT. Taken together, Fe2+@UCM-BBD exhibits on-demand therapeutic reagent release capability, excellent biocompatibility, and remarkable tumor inhibition ability via synergistic chemo/photodynamic/chemodynamic combination therapy.

Yb3+, Er3+ Codoped Cerium Oxide Upconversion Nanoparticles Enhanced the Enzymelike Catalytic Activity and Antioxidative Activity for Parkinson's Disease Treatment.

Oxidative stress plays an important role in Parkinson's disease (PD) and is considered a therapeutic target for PD. However, most therapeutic antioxidants show limitations due to their low reactive oxygen species (ROS) catalytic properties and low crossing of blood-brain barrier. Herein, the antioxidative activity of Yb3+ and Er3+ double-doped CeO2-x (Yb/Er/CeO2-x) upconversion nanoparticles (UCNPs) is obtained for PD treatment. Doping of Yb3+ and Er3+ ions increases oxygen vacancies, which leads to higher enzymelike catalytic activities compared to CeO2-x nanoparticles alone. Tyrosine hydroxylase protein and glial fibrillary acidic protein expression in substantia nigra and striatum as well as the open-field activity test indicates that Yb/Er/CeO2-x is effective for treatment of PD. The activities of glutathione peroxidase and total antioxidant capacity increase and the production of ROS decreases with Yb/Er/CeO2-x UCNP treatment compared with MPTP-induced injury. This indicates that the mechanism of PD treatment is to catalyze ROS products. There have been no reports to date on the usage of Yb/Er/CeO2-x as an antioxidant for PD treatment. Yb/Er/CeO2-x UCNPs cross the blood-brain barrier and exhibit biocompatibility and antioxidant catalytic properties, which decrease the ROS and effectively help in treating PD.

A Janus upconverting nanoplatform with biodegradability for glutathione depletion, near-infrared light induced photodynamic therapy and accelerated excretion.

The major limitations of photodynamic therapy (PDT) are the poor tissue penetration of excitation light and the neutralization of reactive oxygen species (ROS) generated by overexpressed glutathione (GSH) in cancer cells. Despite tremendous efforts to design nanoplatforms, PDT still suffers from unsatisfactory effects. Furthermore, the residual of nanomaterials in the body has restricted their clinical application. To address these issues, Janus nanocomposites containing an Yb/Er codoped NaYF4 upconverting nanocrystal head and a disulfide-bridged mesoporous organosilicon body (UCN/MON) with loaded chlorin e6 (Ce6) were designed. On one hand, the upconverting nanocrystal head can convert near-infrared (NIR) light into visible light to activate Ce6 to release ROS. On the other hand, the silica body can be degraded though a redox reaction with GSH, to not only improve the tumor selectivity of the photosensitizer by redox- and pH-triggered Ce6 release, but also diminish the concentration of GSH in cancer cells to reduce the depletion of ROS. Thereby, an enhanced PDT triggered by NIR irradiation was achieved. Furthermore, UCN/MONs showed a higher clearance rate after therapeutic actions than nonbiodegradable UCN/MSNs due to their biocompatibility. Taken together, this work revealed the potential of UCN/MONs for highly efficient and NIR-induced PDT, highlighting the prospects of UCN/MONs in the clinic.

Needle-free cervical cancer treatment using helical multishield intracavitary rotating shield brachytherapy with the 169 Yb Isotope.

PURPOSE: To assess the capability of an intracavitary 169 Yb-based helical multishield rotating shield brachytherapy (RSBT) delivery system to treat cervical cancer. The proposed RSBT delivery system contains a pair of 1.25 mm thick platinum partial shields with 45° and 180° emission angles, which travel in a helical pattern within the applicator. METHODS: A helically threaded tandem applicator with a 45° tandem curvature containing a helically threaded catheter was designed. A 0.6 mm diameter 169 Yb source with a length of 10.5 mm was simulated. A 37-patient treatment planning study, based on Monte Carlo dose calculations using MCNP5, was conducted with high-risk clinical target volumes (HR-CTVs) of 41.2-192.8 cm3 (average ± standard deviation of 79.9 ± 35.8 cm3 ). All patients were assumed to receive 25 fractions of 1.8 Gy of external beam radiation therapy (EBRT) before receiving 5 fractions of high-dose-rate brachytherapy (HDR-BT). For each patient, 192 Ir-based intracavitary (IC) HDR-BT, 192 Ir-based intracavitary/interstitial (IC/IS) HDR-BT using a hybrid applicator with eight IS needles, and 169 Yb-based RSBT plans were generated. RESULTS: For the IC, IC/IS, and RSBT treatment plans, 38%, 84%, and 86% of the plans, respectively, met the planning goal of an HR-CTV D90 (minimum dose to hottest 90%) of 85 GyEQD2 (α/ß = 10 Gy). Median (25th percentile, 75th percentile) treatment times for IC, IC/IS, and RSBT were 11.71 (6.62, 15.40) min, 68.00 (45.02, 80.02) min, and 25.30 (13.87, 35.39) min, respectively. 192 Ir activities ranging from 159.1-370 GBq (4.3-10 Ci) and 169 Yb activities ranging from 429.2-999 GBq (11.6-27 Ci) were used, which correspond to the same clinical ranges of dose rates at 1 cm off-source-axis in water. Extra needle insertion and planning time beyond that needed for intracavitary-only approaches was accounted for in the IC/IS treatment time calculations. CONCLUSION: 169 Yb-based RSBT for cervical cancer met the HR-CTV D90 goal of 85 Gy in a greater percentage of the patients considered than IC/IS (86% vs 84%, respectively) and can reduce overall treatment time relative to IC/IS. 169 Yb-based RSBT could be used to replace IC/IS in instances where IC/IS treatment is not available, especially in instances when HR-CTV volumes are ≥30 cm3 .

Can intermediate-energy sources lead to elevated bone doses for prostate and head & neck high-dose-rate brachytherapy?

PURPOSE: Several radionuclides with high (60Co, 75Se) and intermediate (169Yb, 153Gd) energies have been investigated as alternatives to 192Ir for high-dose-rate brachytherapy. The purpose of this study was to evaluate the impact of tissue heterogeneities for these five high- to intermediate-energy sources in prostate and head & neck brachytherapy. METHODS AND MATERIALS: Treatment plans were generated for a cohort of prostate (n = 10) and oral tongue (n = 10) patients. Dose calculations were performed using RapidBrachyMCTPS, an in-house Geant4-based Monte Carlo treatment planning system. Treatment plans were simulated using 60Co, 192Ir, 75Se, 169Yb, and 153Gd as the active core of the microSelectron v2 source. Two dose calculation scenarios were presented: (1) dose to water in water (Dw,w), and (2) dose to medium in medium (Dm,m). RESULTS: Dw,w overestimates planning target volume coverage compared with Dm,m, regardless of photon energy. The average planning target volume D90 reduction was ∼1% for high-energy sources, whereas larger differences were observed for intermediate-energy sources (1%-2% for prostate and 4%-7% for oral tongue). Dose differences were not clinically relevant (<5%) for soft tissues in general. Going from Dw,w to Dm,m, bone doses were increased two- to three-fold for 169Yb and four- to five-fold for 153Gd, whereas the ratio was close to ∼1 for high-energy sources. CONCLUSIONS: Dw,w underestimates the dose to bones and, to a lesser extent, overestimates the dose to soft tissues for radionuclides with average energies lower than 192Ir. Further studies regarding bone toxicities are needed before intermediate-energy sources can be adopted in cases where bones are in close vicinity to the tumor.

Maximum RBE change in 192Ir, 125I, and 169Yb brachytherapy and the corresponding effect on treatment planning.

PURPOSE: The purpose of this study was to examine RBE variation as a function of distance from the radioactive source, and the potential impact of this variation on a realistic prostate brachytherapy treatment plan. METHODS: Three brachytherapy sources (125I, 192Ir, and 169Yb) were modelled in Geant4 Monte Carlo code, and the resulting electron energy spectrum in water in 3D space around these sources was scored (voxel size of 2 mm3). With this energy spectrum, microdosimetric techniques were used to calculate the maximum RBE, RBEM, as a function of distance from the source. RBEM of 125I relative to 192Ir was calculated in order to validate simulations against literature; all other RBEM calculations were done by normalizing electron fluence at various distances to the source position. In order to examine the impact of RBEM variation in treatment planning, a realistic 192Ir prostate plan was re-evaluated in terms of RBE instead of absorbed dose. RESULTS: The RBEM of 125I, 192Ir, and 169Yb at 8 cm away from the source was 0.994 (+/-0.002), 1.030 (+/-0.003), and 1.066 (+/-0.008), respectively. RBEM in the HDR prostate treatment plan exhibited several hot (+3.6% in RBEM) spots. CONCLUSIONS: The large increase RBEM observed in 169Yb has not yet been described in the literature. Despite the presence of radiobiological hotspots in the HDR treatment, these variations are likely nominal and clinically insignificant.

A novel 169 Yb-based dynamic-shield intensity modulated brachytherapy delivery system for prostate cancer.

PURPOSE: Intensity modulated brachytherapy (IMBT) is a novel high dose rate brachytherapy (HDR BT) technique which incorporates static or dynamic shielding to increase tumor coverage and/or spare healthy tissues. The purpose of this study is to present a novel delivery system (AIM-Brachy) design that can enable dynamic-shield IMBT for prostate cancer. METHODS: The AIM-Brachy system dynamically controls the rotation of platinum shields, placed within interstitial catheters, which partially collimate the radiation emitted from an 169 Yb source. Conventional HDR BT (10 Ci 192 Ir) and IMBT (18 Ci 169 Yb) plans were generated for 12 patients using an in-house column generation-based optimizer, coupled to a Geant4-based dose calculation engine, RapidBrachyMC. Treatment plans were normalized to match the same PTV D90 coverage as the clinical plan. Intershield attenuation effects were taken into account. A sensitivity analysis was performed to evaluate the dosimetric impact of systematic longitudinal source positioning errors ( ± 1 mm, ± 2 mm, and ± 3 mm) and rotational errors ( ± 5 ∘ , ± 10 ∘ , and ± 15 ∘ ) on clinically relevant parameters (PTV D90 and urethra D10 ). RESULTS: The platinum shield reduced the dose rate on the shielded side at 1 cm to 18.1% of the dose rate on the unshielded side. For equal PTV D90 coverage, the urethral D10 was reduced by 13.3%  ±  4.7%, without change to other plan quality indices (PTV V100 , V150, V200 , bladder V75 , rectum V75 , HI, COIN). Delivery times for HDR BT and IMBT were 9.2 ± 1.6 min and 18.6 ± 4.0 min, respectively. In general, the PTV D90 was more sensitive to source positioning errors than rotational errors, while the urethral D10 was more sensitive to rotational errors than source positioning errors. For a typical range of positioning errors ( ± 1 mm, ± 5 ∘ ), the overall tolerance was <2%. CONCLUSIONS: The AIM-Brachy system was proposed to deliver dynamic-shield IMBT for prostate cancer with the potential to create a low dose tunnel within the urethra. The urethra-sparing properties are desirable to minimize the occurrence and severity of urethral strictures or, alternatively, to provide a method for dose escalation.

Evaluation of Antitumor Efficiency of High Intensity Radiation 169Yb Source on Experimental Sarcoma M-1.

Rats with sarcoma M-1 were exposed to high dose rate irradiation with 169Yb source. In 25 days after introduction of a trocar with sealed capsule with 169Yb source into the tumor, complete tumor regression was observed in 70% animals. The results suggest feasibility of using 169Yb source for high-dose rate brachytherapy and development of the personalized medicine approaches.

MONTE CARLO-BASED INVESTIGATION OF MICRODOSIMETRIC DISTRIBUTION OF HIGH ENERGY BRACHYTHERAPY SOURCES.

FLUKA-based Monte Carlo calculations were carried out to study microdosimetric distributions in air and in water for encapsulated high energy brachytherapy sources (60Co, 137Cs, 192Ir and 169Yb) by simulating a Tissue Equivalent Proportional Counter (Model LET1/2) having sensitive diameter of 1. 27 cm for a site size of 1 µm. The study also included microdosimetric distributions of bare sources. When the sources are in air, for a given source, the source geometry does not affect the y¯F and y¯D values significantly. When the encapsulated 192Ir, 137Cs and 60Co sources are in water, y¯F and y¯D values increase with distance in water which is due to degradation in the energy of photons. Using the calculated values of y¯D, relative biological effectiveness (RBE) was obtained for the investigated sources. When 60Co, 137Cs and 192Ir sources are in water, RBE increases from 1.03 ± 0.01 to 1.17 ± 0.01, 1.24 ± 0.01 to 1.46 ± 0.02 and 1.50 ± 0.01 to 1.75 ± 0.03, respectively, when the distance was increased from 3-15 cm, whereas for 169Yb, RBE is about 2, independent of distance in water.

Efficient 169 Yb high-dose-rate brachytherapy source production using reactivation.

PURPOSE: To present and quantify the effectiveness of a method for the efficient production of 169 Yb high-dose-rate brachytherapy sources with 27 Ci activity upon clinical delivery, which have about the same dose rate in water at 1 cm from the source center as 10 Ci 192 Ir sources. MATERIALS: A theoretical framework for 169 Yb source activation and reactivation using thermal neutrons in a research reactor and 168 Yb-Yb2 O3 precursor is derived and benchmarked against published data. The model is dependent primarily on precursor 168 Yb enrichment percentage, active source volume of the active element, and average thermal neutron flux within the active source. RESULTS: Efficiency gains in 169 Yb source production are achievable through reactivation, and the gains increase with active source volume. For an average thermal neutron flux within the active source of 1 × 1014  n cm-2  s-1 , increasing the active source volume from 1 to 3 mm3 decreased reactor-days needed to generate one clinic-year of 169 Yb from 256 days yr-1 to 59 days yr-1 , and 82%-enriched precursor dropped from 80 mg yr-1 to 21 mg yr-1 . A resource reduction of 74%-77% is predicted for an active source volume increase from 1 to 3 mm3 . CONCLUSIONS: Dramatic cost savings are achievable in 169 Yb source production costs through reactivation if active sources larger than 1 mm3 are used.

Microdosimetric Evaluation of Current and Alternative Brachytherapy Sources-A Geant4-DNA Simulation Study.

PURPOSE: Radioisotopes such as 75Se, 169Yb, and 153Gd have photon energy spectra and half-lives that make them excellent candidates as alternatives to 192Ir for high-dose-rate brachytherapy. The aim of the present study was to evaluate the relative biological effectiveness (RBE) of current (192Ir, 125I, 103Pd) and alternative (75Se, 169Yb, 153Gd) brachytherapy radionuclides using Monte Carlo simulations of lineal energy distributions. METHODS AND MATERIALS: Brachytherapy sources (microSelectron v2 [192Ir, 75Se, 169Yb, 153Gd], SelectSeed [125I], and TheraSeed [103Pd]) were placed in the center of a spherical water phantom with a radius of 40 cm using the Geant4 Monte Carlo simulation toolkit. The kinetic energy of all primary, scattered, and fluorescence photons interacting in a scoring volume were tallied at various depths from the source. Electron tracks were generated by sampling the photon interaction spectrum and tracking all the interactions down to 10 eV using the event-by-event capabilities of the Geant4-DNA models. The dose mean lineal energy (y¯D) values were obtained through random sampling of transfer points and overlaying spherical scoring volumes within the associated volume of the tracks. The scoring volume diameter was determined by fitting the y¯D ratio for 125I to its observed RBE. RESULTS: y¯D increased with the increasing distance from the source for 192Ir, 75Se, and 169Yb, remained constant for 153Gd and 125I, and decreased for 103Pd. The diameter at which the y¯D ratio coincided with the RBE of 1.15 to 1.20 for 125I was ∼25 to 40 nm. The RBE (reference 1 MeV photons) at high doses and dose rates for 192Ir, 75Se, 169Yb, 153Gd, 125I, and 103Pd was 1.028 to 1.034, 1.05 to 1.07, 1.12 to 1.15, 1.16 to 1.21, 1.15 to 1.20, and 1.17 to 1.22, respectively. CONCLUSIONS: The radiation quality of the radionuclides under investigation was greater than that of high-energy photons. The present study has provided a set of values to modify the prescription doses for brachytherapy to account for the variation in radiation quality among radionuclides.

Sequential growth of CaF2:Yb,Er@CaF2:Gd nanoparticles for efficient magnetic resonance angiography and tumor diagnosis.

It is a significant challenge to develop nanoscale magnetic resonance imaging (MRI) contrast agents with high performance of relaxation. In this work, Gd3+-doped CaF2-based core-shell nanoparticles (CaF2:Yb,Er@CaF2:Gd) of sub-10 nm size were controllably synthesized by a facile sequential growth method. The as-prepared hydrophilic CaF2:Yb,Er@CaF2:Gd nanoparticles modified using PEG-PAA di-block copolymer benefited from the presence of Gd only in the outer CaF2 layer of the nanoparticles, which exhibited r1 as high as 21.86 mM-1 s-1 under 3.0 T, seven times as high as that of commercially used gadopentetate dimeglumine (Gd-DTPA). Low cytotoxicity, no hemolysis phenomenon and no potential gadolinium ion leakage phenomenon of the hydrophilic CaF2:Yb,Er@CaF2:Gd nanoparticles have been observed and confirmed. Clear vascular details can be observed in magnetic resonance angiography and obvious MR signal of 4T1 tumor area could be significantly improved by intravenous injection of the hydrophilic CaF2:Yb,Er@CaF2:Gd nanoparticles at a low dosage in mice. A series of in vivo biological safety evaluations confirmed the good biocompatibility of the hydrophilic CaF2:Yb,Er@CaF2:Gd nanoparticles, which might be employed in clinical blood pool imaging and tumor diagnosis as a safe and efficient MRI probe.

Direction modulated brachytherapy (DMBT) for treatment of cervical cancer: A planning study with 192 Ir, 60 Co, and 169 Yb HDR sources.

PURPOSE: To evaluate plan quality of a novel MRI-compatible direction modulated brachytherapy (DMBT) tandem applicator using 192 Ir, 60 Co, and 169 Yb HDR brachytherapy sources, for various cervical cancer high-risk clinical target volumes (CTVHR ). MATERIALS AND METHODS: The novel DMBT tandem applicator has six peripheral grooves of 1.3-mm diameter along a 5.4-mm thick nonmagnetic tungsten alloy rod. Monte Carlo (MC) simulations were used to benchmark the dosimetric parameters of the 192 Ir, 60 Co, and 169 Yb HDR sources in a water phantom against the literature data. 45 clinical cases that were treated using conventional tandem-and-ring applicators with 192 Ir source (192 Ir-T&R) were selected consecutively from intErnational MRI-guided BRAchytherapy in CErvical cancer (EMBRACE) trial. Then, for each clinical case, 3D dose distribution of each source inside the DMBT and conventional applicators were calculated and imported onto an in-house developed inverse planning optimization code to generate optimal plans. All plans generated by the DMBT tandem-and-ring (DMBT T&R) from all three sources were compared to the respective 192 Ir-T&R plans. For consistency, all plans were normalized to the same CTVHR D90 achieved in clinical plans. The D2 cm3 for organs at risk (OAR) such as bladder, rectum, and sigmoid, and D90, D98, D10, V100, and V200 for CTVHR were calculated. RESULTS: In general, plan quality significantly improved when a conventional tandem (Con.T) is replaced with the DMBT tandem. The target coverage metrics were similar across 192 Ir-T&R and DMBT T&R plans with all three sources (P > 0.093). 60 Co-DMBT T&R generated greater hot spots and less dose homogeneity in the target volumes compared with the 192 Ir- and 169 Yb-DMBT T&R plans. Mean OAR doses in the DMBT T&R plans were significantly smaller (P < 0.0084) than the 192 Ir-T&R plans. Mean bladder D2 cm3 was reduced by 4.07%, 4.15%, and 5.13%, for the 192 Ir-, 60 Co-, and 169 Yb-DMBT T&R plans respectively. Mean rectum (sigmoid) D2 cm3 was reduced by 3.17% (3.63%), 2.57% (3.96%), and 4.65% (4.34%) for the 192 Ir-, 60 Co-, and 169 Yb-DMBT T&R plans respectively. The DMBT T&R plans with the 169 Yb source generally resulted in the greatest OAR sparing when the CTVHR were larger and irregular in shape, while for smaller and regularly shaped CTVHR (<30 cm3 ), OAR sparing between the sources were comparable. CONCLUSIONS: The DMBT tandem provides a promising alternative to the Con.T design with significant improvement in the plan quality for various target volumes. The DMBT T&R plans generated with the three sources of varying energies generated superior plans compared to the conventional T&R applicators. Plans generated with the 169 Yb-DMBT T&R produced best results for larger and irregularly shaped CTVHR in terms of OAR sparing. Thus, this study suggests that the combination of the DMBT tandem applicator with varying energy sources can work synergistically to generate improved plans for cervical cancer brachytherapy.

Technical Note: Monte Carlo calculations of the AAPM TG-43 brachytherapy dosimetry parameters for a new titanium-encapsulated Yb-169 source.

Due to a number of distinct advantages resulting from the relatively low energy gamma ray spectrum of Yb-169, various designs of Yb-169 sources have been developed over the years for brachytherapy applications. Lately, Yb-169 has also been suggested as an effective and practical radioisotope option for a novel radiation treatment approach often known as gold nanoparticle-aided radiation therapy (GNRT). In a recently published study, the current investigators used the Monte Carlo N-Particle Version 5 (MCNP5) code to design a novel titanium-encapsulated Yb-169 source optimized for GNRT applications. In this study, the original MC source model was modified to accurately match the specifications of the manufactured Yb-169 source. The modified MC model was then used to obtain a complete set of the AAPM TG-43 parameters for the new titanium-encapsulated Yb-169 source. The MC-calculated dose rate constant for this titanium-encapsulated Yb-169 source was 1.19 ± 0.03 cGy·h-1·U-1, indicating no significant change from the values reported for stainless steel-encapsulated Yb-169 sources. The source anisotropy and radial dose function for the new source were also found similar to those reported for the stainless steel-encapsulated Yb-169 sources. The current results suggest that the use of titanium, instead of stainless steel, to encapsulate the Yb-169 core would not lead to any major change in the dosimetric characteristics of the Yb-169 source. The results also show that the titanium encapsulation of the Yb-169 source could be accomplished while meeting the design goals as described in the current investigators' published MC optimization study for GNRT applications.

Monte Carlo calculation of the dose perturbations in a dual-source HDR/PDR afterloader treatment unit.

PURPOSE: Currently, there are high dose rate afterloaders available that can drive two different radioactive sources simultaneously. The source-source and source-cable attenuations are not taken into account by current planning systems. The purpose of this work is to characterize these effects and their overall impact on clinically relevant metrics. METHODS AND MATERIALS: A (192)Ir ((169)Yb) Flexitron source is modeled within a Monte Carlo code, and its water dose distribution is evaluated. A second source (cable) is placed parallel at various distances to quantify the dose perturbations. The dual-source setup is then transposed to clinical prostate plans (n = 11). Each plan D90 is compared to the single-source D90. The worst-case scenario (two sources traveling in closely located positions) establishes the upper bounds of the deviations. Two setups are considered with sources constrained in catheter pairs or freely distributed. A metric proportional to the dwell times and R(-2) (where R is the intersource separation) helps determine the source position in each configuration. RESULTS: The dose profiles vs. R(-2) (3-20 mm) show a maximal dose reduction effect of 65% (25%) for (169)Yb ((192)Ir) at small distances. A shadow region with at least 10% dose difference extends up to 10 cm. A similar study with a steel drive cable shows similar behavior with a maximal decrease of 10% (3%) under irradiation of a (169)Yb ((192)Ir) source. The relative D90 difference with the single source setup is 2.3% on average, up to 3.7%. It is obtained by superimposing the contributions from catheter pairs in the dual-source loading. CONCLUSION: Overall deviations observed in D90 compared to a single source setup are not significant for all cases studied.

Doxorubicin-loaded NaYF4:Yb/Tm-TiO2 inorganic photosensitizers for NIR-triggered photodynamic therapy and enhanced chemotherapy in drug-resistant breast cancers.

The combination therapy has exhibited important potential for the treatment of cancers, especially for drug-resistant cancers. In this report, bi-functional nanoprobes based on doxorubicin (DOX)-loaded NaYF4:Yb/Tm-TiO2 inorganic photosensitizers (FA-NPs-DOX) were synthesized for in vivo near infrared (NIR)-triggered inorganic photodynamic therapy (PDT) and enhanced chemotherapy to overcome the multidrug resistance (MDR) in breast cancers. Using the up-conversion luminescence (UCL) performance of NaYF4:Yb/Tm converting near-infrared (NIR) into ultraviolent (UV) lights, reactive oxygen species (ROS) were triggered from TiO2 inorganic photosensitizers for PDT under the irradiation of a 980 nm laser, by which the deep-penetration and low photo-damage could be reached. Moreover, nanocarrier delivery and folic acid (FA) targeting promoted the cellular uptake, and accelerated the release of DOX in drug-sensitive MCF-7 and resistant MCF-7/ADR cells. The toxicity assessment in vitro and in vivo revealed the good biocompatibility of the as-prepared FA-NPs-DOX nanocomposites. By the combination of enhanced chemotherapy and NIR-triggered inorganic PDT, the viability of MCF-7/ADR cells could decrease by 53.5%, and the inhibition rate of MCF-7/ADR tumors could increase up to 90.33%, compared with free DOX. Therefore, the MDR of breast cancers could be obviously overcome by enhanced chemotherapy and NIR-triggered inorganic PDT of FA-NPs-DOX nanocomposites under the excitation of a 980 nm laser.

Studies on the development of ¹69Yb-brachytherapy seeds: New generation brachytherapy sources for the management of cancer.

This paper describes development of (169)Yb-seeds by encapsulating 0.6-0.65 mm (ϕ) sized (169)Yb2O3 microspheres in titanium capsules. Microspheres synthesized by a sol-gel route were characterized by XRD, SEM/EDS and ICP-AES. Optimization of neutron irradiation was accomplished and (169)Yb-seeds up to 74 MBq of (169)Yb could be produced from natural Yb2O3 microspheres, which have the potential for use in prostate brachytherapy. A protocol to prepare (169)Yb-brachytherapy sources (2.96-3.7 TBq of (169)Yb) with the use of enriched targets was also formulated.

Fractional 1,550 nm Ytterbium/Erbium fiber laser in the treatment of lichen amyloidosis: clinical and histological study.

BACKGROUND AND OBJECTIVE: Lichen amyloidosis is characterized by amyloid deposition in the papillary dermis, presenting clinically with intensely pruritic hyperkeratotic papules. Various treatment modalities have been used but the results are generally unsatisfactory. Several studies show that non-ablative fractional lasers can be used to treat depositional diseases due to their capability of inducing transepidermal elimination of the dermal content. To investigate the efficacy and safety of a non-ablative fractional 1,550 nm Yttrium/Erbium fiber laser for the treatment of lichen amyloidosis. MATERIALS AND METHODS: Ten subjects with a clinical and histological diagnosis of lichen amyloidosis were treated with fractional non-ablative laser using a 7-cm tip, with the parameter of 30 mJ/cm2 and 1,000 microscopic treatment zones (MTZ)/cm2 for three sessions at 4-week intervals. Clinical improvement (in terms of global improvement score, brownish/hyperpigmentation, thickness, and number of papules) was evaluated using a quartile grading scale at baseline, and 4, 12, and 24 weeks after the last treatment. Itch score and subjective satisfaction rates were also assessed. Adverse events were recorded, and pain was scored using a visual analog scale (VAS). Histologic changes were observed using standard staining with hematoxylin and eosin, as well as special stains of alkaline congo red and crystal violet at baseline and 4 weeks after treatment. RESULTS: At 4 and 24 weeks after treatment, the lichen amyloid lesions had statistically significantly improved in all aspects compared to baseline (P = 0.01 and P = 0.016, respectively; Wilcoxon signed-rank test). However, partial recurrence was reported in 2 out of 10 subjects. All subjects rated itching symptom significantly improved after only the first treatment (P < 0.05). Minimal side effects were recorded, including a burning sensation, transient erythema, and edema. Histological evaluation demonstrated decreased epidermal thickness, and degeneration and shrinkage of amyloid material deposition in the papillary dermis. There was no amyloid material deposition noted in two out of eight histopathology studies. CONCLUSIONS: The non-ablative fractional 1,550 nm Ytterbium/Erbium fiber laser is safe and effective for the treatment of lichen amyloidosis. However, larger controlled studies are required to further establish the efficacy of this treatment.

Design of an Yb-169 source optimized for gold nanoparticle-aided radiation therapy.

PURPOSE: To find an optimum design of a new high-dose rate ytterbium (Yb)-169 brachytherapy source that would maximize the dose enhancement during gold nanoparticle-aided radiation therapy (GNRT), while meeting practical constraints for manufacturing a clinically relevant brachytherapy source. METHODS: Four different Yb-169 source designs were considered in this investigation. The first three source models had a single encapsulation made of one of the following materials: aluminum, titanium, and stainless steel. The last source model adopted a dual encapsulation design with an inner aluminum capsule surrounding the Yb-core and an outer titanium capsule. Monte Carlo (MC) simulations using the Monte Carlo N-Particle code version 5 (MCNP5) were conducted initially to investigate the spectral changes caused by these four source designs and the associated variations in macroscopic dose enhancement across the tumor loaded with gold nanoparticles (GNPs) at 0.7% by weight. Subsequent MC simulations were performed using the EGSnrc and norec codes to determine the secondary electron spectra and microscopic dose enhancement as a result of irradiating the GNP-loaded tumor with the mcnp-calculated source spectra. RESULTS: Effects of the source filter design were apparent in the current MC results. The intensity-weighted average energy of the Yb-169 source varied from 108.9 to 122.9 keV, as the source encapsulation material changed from aluminum to stainless steel. Accordingly, the macroscopic dose enhancement calculated at 1 cm away from the source changed from 51.0% to 45.3%. The sources encapsulated by titanium and aluminum/titanium combination showed similar levels of dose enhancement, 49.3% at 1 cm, and average energies of 113.0 and 112.3 keV, respectively. While the secondary electron spectra due to the investigated source designs appeared to look similar in general, some differences were noted especially in the low energy region (<50 keV) of the spectra suggesting the dependence of the photoelectron yield on the atomic number of source filter material, consistent with the macroscopic dose enhancement results. A similar trend was also shown in the so-called microscopic dose enhancement factor, for example, resulting in the maximum values of 138 and 119 for the titanium- and the stainless steel-encapsulated Yb-169 sources, respectively. CONCLUSIONS: The current results consistently show that the dose enhancement achievable from the Yb-169 source is closely related with the atomic number (Z) of source encapsulation material. While the observed range of improvement in the dose enhancement may be considered moderate after factoring all uncertainties in the MC results, the current study provides a reasonable support for the encapsulation of the Yb-core with lower-Z materials than stainless steel, for GNRT applications. Overall, the titanium capsule design can be favored over the aluminum or dual aluminum/titanium capsule designs, due to its superior structural integrity and improved safety during manufacturing and clinical use.