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The radiation-induced releasing of the liquid-core of the microcapsules was improved using H2O2, which produced O2 generation of H2O2 after irradiation. Further, we tested whether these microcapsules enhanced the antitumor effects and decreased the adverse effects in vivo in C3He/J mice. The capsules were produced by spraying a mixture of 3.0% hyaluronic acid, 2.0% alginate, 3.0% H2O2, and 0.3 mmol of carboplatin on a mixture of 0.3 molFeCl2 and 0.15 molCaCl2. The microcapsules were subcutaneously injected into MM46 tumors that had been inoculated in the left hind legs of C3He/J mice. The radiotherapy comprised tumor irradiation with 10 Gy or 20 Gy 60Co. The antitumor effect of the microcapsules was tested by measuring tumor size and monitoring tumor growth. Three types of adverse effects were considered: fuzzy hair, loss of body weight, and death. The size of the capsule size was 23 ± 2.4 µmɸ and that of the liquid core, 20.2 ± 2.2 µmɸ. The injected microcapsules localized drugs around the tumor. The production of O2 by radiation increased the release of carboplatin from the microcapsules. The antitumor effects of radiation, carboplatin, and released oxygen were synergistic. Localization of the carboplatin decreased its adverse effects. However, the H2O2 caused ulceration of the skin in the treated area. The use of our microcapsules enhanced the antitumor effects and decreased the adverse effects of carboplatin. However, the skin-ulceration caused by H2O2 must be considered before these microcapsules can be used clinically.
Microencapsulated anti-RLIP76 was tested in vivo using C3He/J mice to determine the increasing of antitumor effects by chemotherapeutic agent efflux inhibition during chemoradiotherapy. Microcapsules were produced by spraying a mixture of 3.0% hyaluronic acid, 2.0% alginate, 3.0% H2O2, and 0.3 mmol carboplatin onto a mixture of 0.3 mol FeCl2 and 0.15 mol CaCl2. Microcapsules were subcutaneously injected into MM46 tumors previously inoculated into the left hind legs of C3He/J mice. Subsequent radiotherapy consisted of tumor irradiation with 10 Gy or 20 Gy60Co. The antitumor effects of microcapsules were tested by measuring tumor size and monitoring tumor growth. Three types of adverse effects were considered: fuzzy hair, loss of body weight, and mortality. Carboplatin levels were monitored using particle-induced X-ray emission (PIXE) and a micro-PIXE camera. Anti-RLIP76 inhibited the efflux of carboplatin from tumor tissue, which led to an increase in the concentration of carboplatin. Higher carboplatin concentration significantly increased the combined antitumor effect of radiation and chemotherapy. A significant decrease in adverse effects was also observed with microencapsulated anti-RLIP76.
We have been developing microcapsules that release anticancer drug with response to radiation. We attempted to decrease the diameter of capsules. Then, two categories were tested in VIVO in C3He mice: (1) the antitumor effect in combination with radiation and subcutaneously injected nanocapsules, (2) the kidnetics of nanocapsules when they were injected intravenously.
Microcapsules were produced by spraying a mixture of 3.0 % hyaluronic acid, 2.0 % alginate, 3.0 % H2O2, and 0.3 mmol carboplatin (Pt containing anticancer drug) onto a mixture of vibrated 0.3 mol FeCl2 and 0.15 mol CaCl2. The antitumor effect was measured by measuring tumor diameter every day. The kinetics of microcapsules were expressed as the numbers of capsules in 5 views (25 × 25 μm) of micro PIXE camera and Pt concentration of quantiative PIXE.
The generated microcapsules 752 ± 64 nm, which were significantly downsized relative to previous capsules. The accumulations of capsules in lungs, liver, and kidneys were decreased by downsizing, whereas those of tumors were increased. By adjusting Pt concentration in tumor, there were no significant differences in antitumor effect between not downsized and downsized microcapsules with combination with radiation.
Decreased trapping of downsized microcapsules to lungs, liver, and kidneys, also increased trapping in tumors will lead to new targeted chemoradiotherapy via intravenous injection of microcapsules.
The aim of this study was to determine whether oxygen-releasing microcapsules could be used to sensitize cancer cells to kill by radiation. The microcapsules were generated by spraying a mixture of 0.1% alginate and hyaluronic acid into a 0.3 mmol/l solution of CaCl2 and FeCl2. These were then subcutaneously injected around a MM48 tumor (a cell line derived from human breast cancer) in the left hind legs of C3H/HeN mice, and tumors were dosed with 60Co γ-ray radiation. We showed that the oxygen released from the microcapsules enhanced the anti-tumor effect of radiation treatment via the generation of oxygen radicals.
We have been developing microcapsules that release anticancer drugs in response to radiation with an aim of targeted delivery and increasing the efficacy of anticancer drugs by a combination of these drugs with radiation. The aim of this study was to micronize microcapsules by adding carbonated water to the core material of microcapsules, which releases the anticancer drugs in response to radiation. The core material of microcapsules was prepared by mixing 0.1 g of hyaluronic acid and 0.2 g of alginate into 5 mL of carbonated water. The mixture was sprayed onto a 0.3 mmoL/L solution of calcium chloride (CaCl2) and ferrous chloride (FeCl2) using an ultrasound disintegrator. The vibration of the ultrasound disintegrator generated microbubbles in the carbonated water, which micronized the microcapsules. Intravenous injection of the micronized microcapsules to tumor-bearing mice showed that the micronized microcapsules passed more efficiently through the capillaries of lungs or kidneys, which resulted in increased delivery of microcapsules to the tumors and increased the anticancer effect.
In this paper, we used microcapsules releasing liposome-protamine-hyaluronic acid nanoparticles (LPH-NP) with/without carboplatin in response to radiation to image and treat MM48 breast cancer in C3He/N mice in two radiation sessions. The micro-particle-induced X-ray emission (PIXE) camera and quantitative PIXE were used to image and measure the release of nanoparticles from the microcapsules. In session one, iopamiron and computed tomography (CT)-detectable microcapsules containing P-selectin and LPH-NP were mixed with a solution of alginate, hyaluronate, ascorbate, and P-selectin. This solution was sprayed into an FeCl2 solution containing VEGFR-1/2 antibodies (Abs). The microcapsules obtained were injected intravenously into mice, and after 9 h, the mice were exposed to 10 or 20 Gy (140 keV) of X-ray radiation. Anti-VEGFR-1/VEGFR-2 microcapsules accumulated around tumors and released P-selectin and the iopamiron-labeled LPH-NP in response to the first radiation. The iopamiron-containing nanoparticles were detected by CT, allowing detection of MM48 tumors by CT. In the second session, the microcapsules released LPH-NH that delivered carboplatin into the tumor cells. This treatment had a significant antitumor effect (P<0.05). The micro-PIXE camera and quantitative PIXE successfully imaged and measured the release of contents from microcapsules. Our results indicate that targeted nanoparticles allow for accurate detection and treatment of tumors.
We aimed to image and treat the lung metastases of MM48 breast cancer cells in C3He/N mice by using microcapsules that release liposome-protamine-hyaluronic acid nanoparticles (LPH-NP) in response to two radiation sessions. In session one, computed tomography (CT)-detectable microcapsules containing P-selectin and 5% iopamiron were mixed with a 1 mL solution of 4% alginate, 3% hyaluronate, 1 mg ascorbate, and 1 μg/mL P-selectin. This was sprayed into 0.5 mmol/L FeCl2 containing 1 μg/mL VEGFR-1/2 antibodies (Abs). The mice were intravenously injected with microcapsules, which released the P-selectin, and then a CT study was performed to detect lung metastases. After the CT evaluation, the mice received 10 or 20 Gy (140 keV) of X-ray radiation to the lungs. In session two, carboplatin-LPH-NP was released into the tumor, which was treated with another dose of radiation. To do this, carboplatin LPH-NP was mixed with the cocktail used in session one and sprayed into 0.5 mmol/L FeCl2 containing 1 μg/mL anti-P-selectin Abs. Microcapsules (1 × 1010) were injected intravenously and then interacted with the P-selectin. The released carboplatin LPH-NP attacked lung metastases synergistically with radiation, which resulted in further reduction of the lung metastases.
The nanoparticles, which releases anticancer drug with response to radiation, were developed. Also, two categories were tested: (i) their ability to release anticancer drug in vitro; and (ii) their kinetics in the body, when they were injected through tail vein of BALB/c mice in vivo. To prepare the particles, hyaluronic acid and protamine were mixed into carboplatin solution, and reacted for 30 min in room temperature. Those particles were exposed to a single dose of 10 Gy of 140 KeV X-ray. Their ability to release carboplatin with response to radiation was expressed as the percentage of ruptured particles, basing on images of particles, using micro PIXE camera. The amount of released carboplatin was measured by quantitative PIXE method. The kinetics of particles in body was assessed by counting the number of particles, which were trapped in lungs, using micro PIXE camera. The mean diameter of particles was 743 ± 34 nm. By irradiation, 59.3 ± 7.23% of particles ruptured, and 95.9 ± 2.3% carboplatin was released from particles. The trapped particles in lungs were significantly reduced, when compared with previous alginate-hyaluronic particles.
Encapsulated protamine-hyaluronic acid particles containing carboplatin were prepared and their ability to release carboplatin was tested in vivo. Protamine–hyaluronic acid particles containing carboplatin were prepared by mixing protamine (1.6 mg) and hyaluronic acid (1.28 mg) into a 5 mg/mL carboplatin solution for 30 min at room temperature. A 1 mL solution of protamine–hyaluronic acid particles was poured into an ampule of COATSOME® EL-010 (Nichiyu, Tokyo, Japan), shaken three times by hand, and allowed to incubate at room temperature for 15 min. Following that, 10 or 20 Gy of 100 kiloelectronvolt (KeV) soft X-ray was applied. The release of carboplatin was imaged using a microparticle-induced X-ray emission (PIXE) camera. The amount of carboplatin released was expressed as the amount of platinum released and measured via quantitative micro-PIXE analysis. The diameter of the generated encapsulated particles measured 574±23 nm (mean ± standard error).
The release of carboplatin from the encapsulated protamine–hyaluronic acid particles was observed under a micro-PIXE camera. The amount of carboplatin released was 3.0±0.3 μg under 10 Gy of radiation, and 7.3±0.8 μg under 20 Gy of radiation, which was a sufficient dose for cancer treatment. However, 10 or 20 Gy of radiation is much greater than the dose used for clinical cancer treatment (2 Gy). Further research to reduce the radiation dose to 2 Gy in order to release sufficient carboplatin for cancer treatment is required.
Cancer is a dreadful disease that will affect one in three people at some point in their life; radiotherapy is used in more than half of all cancer treatment, and contributes about 40% to the successful treatment of cancer. Charged Particle Therapy uses protons and other light ions to deliver the lethal dose to the tumor while being relatively sparing of healthy tissue and, because of the finite range of the particles, is able to avoid giving any dose to vital organs. While there are adequate technologies currently available to deliver the required energies and fluxes, the two main technologies (cyclotrons and synchrotrons) have limitations. PAMELA (the Particle Accelerator for MEdicaLApplications) uses the newly-developed non-scaling Fixed Field Alternating Gradient accelerator concepts to deliver therapeutically relevant beams. The status of the development of the PAMELA conceptual design is discussed.
In the external radiation therapy the source of radiation is from outside. The healthy tissue and some organs, called critical organs which are quite intolerable for radiation, are always irradiated, too. Therefore, the careful treatment plan has to be constructed to ensure high and homogeneous dose in the tumor, but on the other hand to spare the normal tissue and critical organs possibly well.
In the radiation therapy treatment planning one tries to optimize the dose distribution in the way that the above aim is satisfied. The dose distributions can be generated with different techniques. The most recent of them is the so-called multileaf collimator (MLC) delivery technique. Calculation of the dose distribution demands some dose calculation model. The paper gives a model and theoretical basis of planning applying the Boltzmann-transport equation in dose calculation and MLC delivery technique. The existence of solutions and the optimal treatment planning are considered. A preliminary artificial computer simulation is included.
A Boltzmann transport model for dose calculation in radiation therapy is considered. We formulate an optimal control problem for the desired dose. We prove existence and uniqueness of a minimizer. Based on this model, we derive optimality conditions. The PN discretization in angle of the full model is considered. We show that the PN approximation of the optimality system is in fact the optimality system of the PN approximation, provided that, instead of the usually used Marshak boundary conditions, Mark's boundary conditions are used. Numerical results in one and two dimensions are presented.
In this paper we study a problem in radiotherapy treatment planning. This problem is formulated as an optimization problem of a functional of the radiative flux. It is constrained by the condition that the radiative flux, which depends on position, energy and direction of the particles, is governed by a Boltzmann integro-differential equation. We show the existence, uniqueness and regularity of solutions to this constrained optimization problem in an appropriate function space. The main new difficulty is the treatment of the energy loss term. Furthermore, we characterize optimal controls by deriving first-order optimality conditions.
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