213-Bi-DOTATATE for Targeted Alpha Therapy in Neuroendocrine Tumours

Targeted alpha therapy (TAT) is promising for improvement of current peptide receptor radionuclide therapy for patient with metastatic neuroendocrine tumours. Due to the high LET of alpha particles, the possibility to cause double strand breaks in the DNA of a tumour cell is much higher than after therapy using beta particle emitters. At the same time, healthy tissues can be spared because of the short path length of alpha particles. _213_ Bismuth (_213_ Bi, an alpha emitter with a half-life of 46 min) was eluted from a _225_ Ac/_213_ Bi generator. _213_ Bi was attached to a peptide via a chelator, in our case a somatostatin analogue with the DOTA chelator, DOTA-Tyr3-octreotate (DOTATATE). In this thesis, _213_ Bi-DOTATATE was used for TAT to investigate whether it is superior compared to DOTATATE labelled with beta particle emitters, like _177_ Lu-DOTATATE for treatment of neuroendocrine tumours with somatostatin receptor expression. The stability of _213_ Bi-DOTATATE was investigated; the labelled peptide showed high stability up to 2 h after labelling. _213_ Bi-DOTATATE showed higher therapeutic efficacy in vitro compared to _177_ Lu-DOTATATE; a 5x more tumour cells killing potency was found. _213_ Bi-DOTATATE prolonged survival in xenografted mice with different tumour models with varying somatostatin receptor density and tumour size. Potential renal toxicity could be managed by renal protectant L-lysine application. Furthermore, biodistribution was imaged by a special SPECT camera dedicated to small animals imaging. Overall, _213_ Bi-DOTATATE showed to be promising for TAT for treatment of neuroendocrine tumours with somatostatin expression

Etched distributed Bragg reflectors as three-dimensional photonic crystals: photonic bands and density of states

The photonic band dispersion and density of states (DOS) are calculated for the three-dimensional (3D) hexagonal structure corresponding to a distributed Bragg reflector patterned with a 2D triangular lattice of circular holes. Results for the Si/SiO$_2$ and GaAs/AlGaAs systems determine the optimal parameters for which a gap in the 2D plane occurs and overlaps the 1D gap of the multilayer. The DOS is considerably reduced in correspondence with the overlap of 2D and 1D gaps. Also, the local density of states (i.e., the DOS weighted with the squared electric field at a given point) has strong variations depending on the position. Both results imply substantial changes of spontaneous emission rates and patterns for a local emitter embedded in the structure and make this system attractive for the fabrication of a 3D photonic crystal with controlled radiative properties.Comment: 8 pages, 5 figures; to appear in Phys. Rev.

Influence of tumour size on the efficacy of targeted alpha therapy with 213Bi-[DOTA0,Tyr3]-octreotate

BACKGROUND: Targeted alpha therapy has been postulated to have great potential for the treatment of small clusters of tumour cells as well as small metastases. (213)Bismuth, an α-emitter with a half-life of 46 min, has shown to be effective in preclinical as well as in clinical applications. In this study, we evaluated whether (213)Bi-[DOTA(0), Tyr(3)]-octreotate ((213)Bi-DOTATATE), a (213)Bi-labelled somatostatin analogue with high affinity for somatostatin receptor subtype 2 (SSTR(2)), is suitable for the treatment of larger neuroendocrine tumours overexpressing SSTR(2) in comparison to its effectiveness for smaller tumours. We performed a preclinical targeted radionuclide therapy study with (213)Bi-DOTATATE in animals bearing tumours of different sizes (50 and 200 mm(3)) using two tumour models: H69 (human small cell lung carcinoma) and CA20948 (rat pancreatic tumour). METHODS: Pharmacokinetics was determined for calculation of dosimetry in organs and tumours. H69- or CA20948-xenografted mice with tumour volumes of approximately 120 mm(3) were euthanized at 10, 30, 60 and 120 min post injection of a single dose of (213)Bi-DOTATATE (1.5–4.8 MBq). To investigate the therapeutic efficacy of (213)Bi-DOTATATE, xenografted H69 and CA20948 tumour-bearing mice with tumour sizes of 50 and 200 mm(3) were administered daily with a therapeutic dose of (213)Bi-DOTATATE (0.3 nmol, 2–4 MBq) for three consecutive days. The animals were followed for 90 days after treatment. At day 90, mice were injected with 25 MBq (99m)Tc-DMSA and imaged by SPECT/CT to investigate possible renal dysfunction due to (213)Bi-DOTATATE treatment. RESULTS: Higher tumour uptakes were found in CA20948 tumour-bearing animals compared to those in H69 tumour-bearing mice with the highest tumour uptake of 19.6 ± 6.6 %IA/g in CA20948 tumour-bearing animals, while for H69 tumour-bearing mice, the highest tumour uptake was found to be 9.8 ± 2.4 %IA/g. Nevertheless, as the anti-tumour effect was more pronounced in H69 tumour-bearing mice, the survival rate was higher. Furthermore, in the small tumour groups, no regrowth of tumour was found in two H69 tumour-bearing mice and in one of the CA20948 tumour-bearing mice. No renal dysfunction was observed in (213)Bi-DOTATATE-treated mice after the doses were applied. CONCLUSIONS: (213)Bi-DOTATATE demonstrated a great therapeutic effect in both small and larger tumour lesions. Higher probability for stable disease was found in animals with small tumours. (213)Bi-DOTATATE was effective in different neuroendocrine (H69 and CA20948) tumour models with overexpression of SSTR(2) in mice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13550-016-0162-2) contains supplementary material, which is available to authorized users

Therapeutic application of CCK2R-targeting PP-F11: influence of particle range, activity and peptide amount

Background: Targeted radionuclide therapy with high-energy beta-emitters is generally considered suboptimal to cure small tumours (90Y, 177Lu or 213Bi, accounting for the radionuclide specific activities (SAs), the tumour absorbed doses and tumour (radio) biology. Methods: Tumour uptake of 111In-PP-F11 was determined in nude mice bearing CCK2 receptor-transfected A431 xenografts at 1 and 4 h post-injection for escalating peptide masses of 0.03 to 15 nmol/mouse. The absorbed tumour dose was estimated, assuming comparable biodistributions of the 90Y, 177Lu or 213Bi radiolabelled peptides. The linear-quadratic (LQ) model was used to calculate the tumour control probabilities (TCP) as a function of tumour mass and growth. Results: Practically achievable maximum SAs for PP-F11 labelled with 90Y and 177Lu were 400 MBq 90Y/nmol and 120 MBq177Lu/nmol. Both the large elution volume from the 220 MBq 225Ac generator used and reaction kinetics diminished the maximum achieved 213Bi SA in practice: 40 MBq 213Bi/nmol. Tumour uptakes decreased rapidly with increasing peptide amounts, following a logarithmic curve with ED50 = 0.5 nmol. At 0.03 nmol peptide, the (300 mg) tumour dose was 9 Gy after 12 MBq 90Y-PP-F11, and for 111In and 177Lu, this was 1 Gy. A curative dose of 60 Gy could be achieved with a single administration of 111 MBq 90Y labelled to 0.28 nmol PP-F11 or with 4 × 17 MBq 213Bi (0.41 nmol) when its α-radiation relative biological effectiveness (RBE) was assumed to be 3.4. Repeated dosing is preferable to avoid complete tumour receptor saturation. Tumours larger than 200 mg are curable with 90Y-PP-F11; the other radionuclides perform better in smaller tumours. Furthermore, 177Lu is not optimal for curing fast-growing tumours. Conclusions: Receptor saturation, specific radiopharmaceutical activities and absorbed doses in the tumour together favour therapy with the CCK2 receptor-binding peptide PP-F11 labelled with 90Y, despite its longer β-particle range in tissue, certainly for tumours larger than 300 mg. The predicted TCPs are of theoretical nature and need to be compared with the outcome of targeted radionuclide experiments

Study protocol for "Moving bright, eating smart"- a phase 2 clinical trial on the acceptability and feasibility of a diet and physical activity intervention to prevent recurrence in colorectal cancer survivors

Background: Colorectal cancer is the second most common cancer and cancer-killer in Hong Kong with an alarming increasing incidence in recent years. The latest World Cancer Research Fund report concluded that foods low in fibre, and high in red and processed meat cause colorectal cancer whereas physical activity protects againstcolon cancer. Yet, the influence of these lifestyle factors on cancer outcome is largely unknown even though cancer survivors are eager for lifestyle modifications. Observational studies suggested that low intake of a Western-pattern diet and high physical activity level reduced colorectal cancer mortality. The Theory of PlannedBehaviour and the Health Action Process Approach have guided the design of intervention models targeting a wide range of health-related behaviours.Methods/design: We aim to demonstrate the feasibility of two behavioural interventions intended to improve colorectal cancer outcome and which are designed to increase physical activity level and reduce consumption of a Western-pattern diet. This three year study will be a multicentre, randomised controlled trial in a 2x2 factorialdesign comparing the “Moving Bright, Eating Smart” (physical activity and diet) programme against usual care. Subjects will be recruited over a 12-month period, undertake intervention for 12 months and followed up for a further 12 months. Baseline, interim and three post-intervention assessments will be conducted. Two hundred and twenty-two colorectal cancer patients who completed curative treatment without evidence of recurrence will be recruited into the study. Primary outcome measure will be whether physical activity and dietary targets are met at the end of the 12-month intervention. Secondary outcome measures include the magnitude andmechanism of behavioural change, the degree and determinants of compliance, and the additional health benefits and side effects of the intervention.Discussion: The results of this study will establish the feasibility of targeting the two behaviours (diet and physical activity) and demonstrate the magnitude of behaviour change. The information will facilitate the design of a further larger phase III randomised controlled trial with colorectal cancer outcome as the study endpoint to determine whether this intervention model would reduce colorectal cancer recurrence and mortality

Maintaining radiochemical purity of [177Lu]Lu-DOTA-PSMA-617 for PRRT by reducing radiolysis

[177Lu]Lu-DOTA-PSMA-617 for PRRT is subject to radiolysis and therefore loses receptor affinity. This will be detrimental for treatment efficacy. In this study optimal quencher(s) (combinations) are determined to maintain radiochemical purity with a downscaled model. Downscaled model in terms of activity, but at similar concentrations. DOTA-PSMA-617 was labeled with [177Lu]LuCl3 with different molar- and volume activities. Either methionine, ethanol or both showed superior effects on the stabilizing radiochemical purity of [177Lu]Lu-DOTA-PSMA-617. As a consequence, radiochemical purity of [177Lu]Lu-DOTA-PSMA-617 could be maintained by the addition of methionine and/or ethanol and downscaled model was proven and complementary

Semi-automated system for concentrating 68Ga-eluate to obtain high molar and volume concentration of 68Ga-Radiopharmaca for preclinical applications

Introduction: 68Ga-radiopharmaceuticals are common in the field of Nuclear Medicine to visualize receptor-mediated processes. In contrast to straightforward labeling procedures for clinical applications, preclinical in vitro and in vivo applications are hampered for reasons like e.g. volume restriction, activity concentration, molar activity and osmolality. Therefore, we developed a semi-automatic system specifically to overcome these problems. A difficulty appeared unexpectedly, as intrinsic trace metals derived from eluate (Zn, Fe and Cu) are concentrated as well in amounts that influence radiochemical yield and thus lower molar activity. Methods: To purify Gallium-68 and to reduce the high elution volume of a 68Ga-generator, a NaCl-based method using a column containing PS-H+ was implemented in a low volume PEEK system. Influence on reducing osmolality, acidity and the amount of PS-H+ resin (15–50 mg) was investigated. [68Ga]Ga was desorbed from the PS-H+ resin with acidified 2-5 M NaCl (containing 0.05 M of HCl) and 68Ga-activity was collected. DOTA-TATE was used as a peptide model. All buffers and additives used for labeling were mixed with Chelex 100 (~1 g/50 mL) for >144 h and eventually filtered using a 0.22 μm filter (Millipore). Quantification of metals was performed after labeling by HPLC (UV). Results: Gallium-68 activity could be desorbed from PS-H+ cation column with 3 M NaCl, and >60% (120–180 MBq) of [68Ga]Ga was collected in 99% (ITLC), and a radiochemical purity of >95% (HPLC). Conclusion: With the here described concentration system and metal purification technique, a low activity containing 68Ga-generator can be used to label DOTA-peptide in preclinical applicable amounts >60 MBq/nmol (40–60 MBq/0.1 mL) and within 20 min

Taking off the square root of Nambu-Goto action and obtaining Filippov-Lie algebra gauge theory action

We propose a novel prescription to take off the square root of Nambu-Goto action for a p-brane, which generalizes the Brink-Di Vecchia-Howe-Tucker or also known as Polyakov method. With an arbitrary decomposition as d+n=p+1, our resulting action is a modified d-dimensional Polyakov action which is gauged and possesses a Nambu n-bracket squared potential. We first spell out how the (p+1)-dimensional diffeomorphism is realized in the lower dimensional action. Then we discuss a possible gauge fixing of it to a direct product of $d$-dimensional diffeomorphism and n-dimensional volume preserving diffeomorphism. We show that the latter naturally leads to a novel Filippov-Lie n-algebra based gauge theory action in d-dimensions.Comment: 1+13 pages, No figure; Expanded, published version. Title change

Metallo-dielectric diamond and zinc-blende photonic crystals

It is shown that small inclusions of a low absorbing metal can have a dramatic effect on the photonic band structure. In the case of diamond and zinc-blende photonic crystals, several complete photonic band gaps (CPBG's) can open in the spectrum, between the 2nd-3rd, 5th-6th, and 8th-9th bands. Unlike in the purely dielectric case, in the presence of small inclusions of a low absorbing metal the largest CPBG for a moderate dielectric constant (epsilon<=10) turns out to be the 2nd-3rd CPBG. The 2nd-3rd CPBG is the most important CPBG, because it is the most stable against disorder. For a diamond and zinc-blende structure of nonoverlapping dielectric and metallo-dielectric spheres, a CPBG begins to decrease with an increasing dielectric contrast roughly at the point where another CPBG starts to open--a kind of gap competition. A CPBG can even shrink to zero when the dielectric contrast increases further. Metal inclusions have the biggest effect for the dielectric constant 2<=epsilon<=12, which is a typical dielectric constant at near infrared and in the visible for many materials, including semiconductors and polymers. It is shown that one can create a sizeable and robust 2nd-3rd CPBG at near infrared and visible wavelengths even for a photonic crystal which is composed of more than 97% low refractive index materials (n<=1.45, i.e., that of silica glass or a polymer). These findings open the door for any semiconductor and polymer material to be used as genuine building blocks for the creation of photonic crystals with a CPBG and significantly increase the possibilities for experimentalists to realize a sizeable and robust CPBG in the near infrared and in the visible. One possibility is a construction method using optical tweezers, which is analyzed here.Comment: 25 pp, 23 figs, RevTex, to appear in Phys Rev B. For more information look at http://www.amolf.nl/research/photonic_materials_theory/moroz/moroz.htm

Photonic band gaps in materials with triply periodic surfaces and related tubular structures

We calculate the photonic band gap of triply periodic bicontinuous cubic structures and of tubular structures constructed from the skeletal graphs of triply periodic minimal surfaces. The effect of the symmetry and topology of the periodic dielectric structures on the existence and the characteristics of the gaps is discussed. We find that the C(I2-Y**) structure with Ia3d symmetry, a symmetry which is often seen in experimentally realized bicontinuous structures, has a photonic band gap with interesting characteristics. For a dielectric contrast of 11.9 the largest gap is approximately 20% for a volume fraction of the high dielectric material of 25%. The midgap frequency is a factor of 1.5 higher than the one for the (tubular) D and G structures