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With their low immunogenicity and excellent deliverability, extracellular vesicles (EVs) are promising platforms for drug delivery systems. In this study, hydrophobic molecule loading techniques were developed via an exchange reaction based on supramolecular chemistry without using organic solvents that can induce EV disruption and harmful side effects. To demonstrate the availability of an exchanging reaction to prepare drug-loading EVs, hydrophobic boron cluster carborane (CB) was introduced to EVs (CB@EVs), which is expected as a boron agent for boron neutron capture therapy (BNCT). The exchange reaction enabled the encapsulation of CB to EVs without disrupting their structure and forming aggregates. Single-particle analysis revealed that an exchanging reaction can uniformly introduce cargo molecules to EVs, which is advantageous in formulating pharmaceuticals. The performance of CB@EVs as boron agents for BNCT was demonstrated in vitro and in vivo. Compared to L-BPA, a clinically available boron agent, and CB delivered with liposomes, CB@EV systems exhibited the highest BNCT activity in vitro due to their excellent deliverability of cargo molecules via an endocytosis-independent pathway. The system can deeply penetrate 3D cultured spheroids even in the presence of extracellular matrices. The EV-based system could efficiently accumulate in tumor tissues in tumor xenograft model mice with high selectivity, mainly via the enhanced permeation and retention effect, and the deliverability of cargo molecules to tumor tissues in vivo enhanced the therapeutic benefits of BNCT compared to the L-BPA/fructose complex. All of the features of EVs are also advantageous in establishing anticancer agent delivery platforms.
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Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B-NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy-resistant advanced-stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti-PD-1 antibody immunotherapy group did not show tumor suppression. Only the B-NIT group showed strong tumor growth inhibition at both BNCT-treated and shielded distant sites. Intratumoral CD8+ T-cell infiltration and serum high mobility group box 1 (HMGB1) levels were higher in the B-NIT group. Analysis of CD8+ T cells in tumor-infiltrating lymphocytes (TILs) showed that CD62L- CD44+ effector memory T cells and CD69+ early-activated T cells were predominantly increased in the B-NIT group. Administration of CD8-depleting mAb to the B-NIT group completely suppressed the augmented therapeutic effects. This indicated that B-NIT has a potent immune-induced abscopal effect, directly destroying tumors with BNCT, inducing antigen-spreading effects, and protecting normal tissue. B-NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy-resistant malignancies, B-NIT can become a new treatment candidate for advanced-stage cancers.
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Multidisciplinary therapy centered on radical surgery for resectable pancreatic cancer is expected to prolong prognosis, but relies on CA19-9 biomarker levels to determine treatment strategy. Boron neutron capture therapy (BNCT) is a chemoradiotherapy using tumor hyperaccumulator boron drugs and neutron irradiation. The purpose of this study is to investigate novel boron drug agents for BNCT for pancreatic cancer. Bioinformatics was used to evaluate the uptake of current boron amino acid (BPA) drugs for BNCT into pancreatic cancer. The expression of the amino acid transporter LAT1, a BPA uptake transporter, was low in pancreatic cancer and even lower in high CA19-9 pancreatic cancer. In contrast, the glucose transporter was high in high CA19-9 pancreatic cancers and inversely correlated with LAT1 expression. Considering the low EPR effect in pancreatic cancer, we synthesized a small molecule Glucose-BSH, which is boron BSH bound to glucose, and confirmed its specific uptake in pancreatic cancer. uptake of Glucose-BSH was confirmed in an environment compatible with the tumor microenvironment. The therapeutic efficacy and safety of Glucose-BSH by therapeutic neutron irradiation were confirmed with BNCT. We report Glucose-BSH boron drug discovery study of a Precision Medicine BNCT with application to high CA19-9 pancreatic cancer.
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Terapia por Captura de Neutrón de Boro , Glucosa , Neoplasias Pancreáticas , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patología , Humanos , Glucosa/metabolismo , Línea Celular Tumoral , Animales , Compuestos de Boro/química , Compuestos de Boro/uso terapéutico , Boro/química , Femenino , Ratones DesnudosRESUMEN
PURPOSE: Boron neutron capture therapy (BNCT) is a tumor cell-selective particle-radiation therapy. In BNCT, administered p-boronophenylalanine (BPA) is selectively taken up by tumor cells, and the tumor is irradiated with thermal neutrons. High-LET α-particles and recoil 7Li, which have a path length of 5-9 µm, are generated by the capture reaction between 10B and thermal neutrons and selectively kill tumor cells that have uptaken 10B. Although BNCT has prolonged the survival time of malignant glioma patients, recurrences are still to be resolved. miRNAs, that are encapsulated in small extracellular vesicles (sEVs) in body fluids and exist stably may serve critical role in recurrence. In this study, we comprehensively investigated microRNAs (miRNAs) in sEVs released from post-BNCT glioblastoma cells. METHOD: Glioblastoma U87 MG cells were treated with 25 ppm of BPA in the culture media and irradiated with thermal neutrons. After irradiation, they were plated into dishes and cultured for 3 days in the 5% CO2 incubator. Then, sEVs released into the medium were collected by column chromatography, and miRNAs in sEVs were comprehensively investigated using microarrays. RESULT: An increase in 20 individual miRNAs (ratio > 2) and a decrease in 2 individual miRNAs (ratio < 0.5) were detected in BNCT cells compared with non-irradiated cells. Among detected miRNAs, 20 miRNAs were associated with worse prognosis of glioma in Kaplan Meier Survival Analysis of overall survival in TCGA. CONCLUSION: These miRNA after BNCT may proceed tumors, modulate radiation resistance, or inhibit invasion and affect the prognosis of glioma.
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Terapia por Captura de Neutrón de Boro , Neoplasias Encefálicas , Vesículas Extracelulares , Glioblastoma , MicroARNs , Terapia por Captura de Neutrón de Boro/métodos , Humanos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/efectos de la radiación , MicroARNs/metabolismo , MicroARNs/genética , Glioblastoma/radioterapia , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/genética , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de la radiaciónRESUMEN
Although boron neutron capture therapy (BNCT) causes minor damage to normal cells owing to the nuclear reactions induced by neutrons with major elements of tissues such as hydrogen and nitrogen, it is useful to estimate the accurate exposure dose for radiation protection. This study aims to estimate the contribution of internal exposure in radiation exposure dose for BNCT. The study was performed by referring to clinical studies at a reactor-based BNCT facility on the basis of computational dosimetry. Five irradiation regions of head and neck were selected for the estimation. The results suggest that external exposure occurred primarily in and around the irradiation field. Furthermore, during the exposure dose estimation in BNCT, internal exposure was found to be not negligible, implying that the irradiation regions in treatment planning must be considered for avoiding damage to certain critical organs that are susceptible to internal exposure.
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Terapia por Captura de Neutrón de Boro , Terapia por Captura de Neutrón de Boro/métodos , Humanos , Dosificación Radioterapéutica , Neutrones , Dosis de Radiación , Radiometría/métodos , Protección Radiológica/métodos , Exposición a la Radiación/análisis , Planificación de la Radioterapia Asistida por Computador/métodos , Método de Montecarlo , Neoplasias de Cabeza y Cuello/radioterapia , Fantasmas de Imagen , Simulación por ComputadorRESUMEN
BACKGROUND: In Japan, the clinical treatment of boron neutron capture therapy (BNCT) has been applied to unresectable, locally advanced, and recurrent head and neck carcinomas using an accelerator-based neutron source since June of 2020. Considering the increase in the number of patients receiving BNCT, efficiency of the treatment planning procedure is becoming increasingly important. Therefore, novel and rapid dose calculation algorithms must be developed. We developed a novel algorithm for calculating neutron flux, which comprises of a combination of a Monte Carlo (MC) method and a method based on the removal-diffusion (RD) theory (RD calculation method) for the purpose of dose calculation of BNCT. PURPOSE: We present the details of our novel algorithm and the verification results of the calculation accuracy based on the MC calculation result. METHODS: In this study, the "MC-RD" calculation method was developed, wherein the RD calculation method was used to calculate the thermalization process of neutrons and the MC method was used to calculate the moderation process. The RD parameters were determined by MC calculations in advance. The MC-RD calculation accuracy was verified by comparing the results of the MC-RD and MC calculations with respect to the neutron flux distributions in each of the cubic and head phantoms filled with water. RESULTS: Comparing the MC-RD calculation results with those of MC calculations, it was found that the MC-RD calculation accurately reproduced the thermal neutron flux distribution inside the phantom, with the exception of the region near the surface of the phantom. CONCLUSIONS: The MC-RD calculation method is useful for the evaluation of the neutron flux distribution for the purpose of BNCT dose calculation, except for the region near the surface.
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Algoritmos , Terapia por Captura de Neutrón de Boro , Método de Montecarlo , Neutrones , Planificación de la Radioterapia Asistida por Computador , Terapia por Captura de Neutrón de Boro/métodos , Neutrones/uso terapéutico , Planificación de la Radioterapia Asistida por Computador/métodos , Difusión , Dosificación Radioterapéutica , Fantasmas de Imagen , HumanosRESUMEN
Noninvasive monitoring of boron agent biodistribution is required in advance of neutron capture therapy. In this study, we developed a gadolinium-boron-conjugated albumin (Gd-MID-BSA) for MRI-guided neutron capture therapy. Gd-MID-BSA was prepared by labeling bovine serum albumin with a maleimide-functionalized gadolinium complex and a maleimide-functionalized closo-dodecaborate orthogonally. The accumulation of Gd-MID-BSA in tumors in CT26 tumor-bearing mice reached a maximum at 24 h after the injection, as confirmed by T1-based MRI and biodistribution analysis using inductively coupled plasma optical emission spectrometry. The concentrations of boron and gadolinium in the tumors exceeded the thresholds required for boron neutron capture therapy (BNCT) and gadolinium neutron capture therapy (GdNCT), respectively. The boron concentration ratios of tumor to blood and tumor to normal tissues satisfied the clinical criteria, indicating the reduction of undesired nuclear reactions of endogenous nuclei. The molar ratio of boron to gadolinium in the tumor was close to that of Gd-MID-BSA, demonstrating that the accumulation of Gd-MID-BSA in the tumor can be evaluated by MRI. Thermal neutron irradiation with Gd-MID-BSA resulted in significant suppression of tumor growth compared to the group injected with a boron-conjugated albumin without gadolinium (MID-BSA). The neutron irradiation with Gd-MID-BSA did not cause apparent side effects. These results demonstrate that the conjugation of gadolinium and boron within the albumin molecule offers a novel strategy for enhancing the therapeutic effect of BNCT and the potential of MRI-guided neutron capture therapy as a promising treatment for malignant tumors.
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Terapia por Captura de Neutrón de Boro , Neoplasias , Terapia por Captura de Neutrón , Ratones , Animales , Boro , Gadolinio , Distribución Tisular , Neoplasias/diagnóstico por imagen , Neoplasias/radioterapia , Neoplasias/tratamiento farmacológico , Terapia por Captura de Neutrón/métodos , Imagen por Resonancia Magnética/métodos , Terapia por Captura de Neutrón de Boro/métodos , MaleimidasRESUMEN
Boron neutron capture therapy (BNCT) is a promising modality for cancer treatment because of its minimal invasiveness. To maximize the therapeutic benefits of BNCT, the development of efficient platforms for the delivery of boron agents is indispensable. Here, carborane-integrated immunoliposomes were prepared via an exchanging reaction to achieve HER-2-targeted BNCT. The conjugation of an anti-HER-2 antibody to carborane-integrated liposomes successfully endowed these liposomes with targeting properties toward HER-2-overexpressing human ovarian cancer cells (SK-OV3); the resulting BNCT activity toward SK-OV3 cells obtained using the current immunoliposomal system was 14-fold that of the l-BPA/fructose complex, which is a clinically available boron agent. Moreover, the growth of spheroids treated with this system followed by thermal neutron irradiation was significantly suppressed compared with treatment with the l-BPA/fructose complex.
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Boranos , Terapia por Captura de Neutrón de Boro , Humanos , Liposomas , Terapia por Captura de Neutrón de Boro/métodos , Boro , Compuestos de Boro , FructosaRESUMEN
The development of boron agents with integrated functionality, including biocompatibility, high boron content, and cancer cell targeting, is desired to exploit the therapeutic efficacy of boron neutron capture therapy (BNCT). Here, we report the therapeutic efficacy of BNCT using a HER-2-targeted antibody-conjugated boron nitride nanotube/ß-1,3-glucan complex. The anticancer effect of BNCT using our system was 30-fold that of the clinically available boron agent l-BPA/fructose complex.
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As function preservation cancer therapy, targeted radiation therapies have been developed for the quality of life of cancer patients. However, preclinical animal studies evaluating the safety and efficacy of targeted radiation therapy is challenging from the viewpoints of animal welfare and animal protection, as well as the management of animal in radiation-controlled areas under the regulations. We fabricated the human 3D oral cancer model that considers the time axis of the follow up in cancer treatment. Therefore, in this study, the 3D model with human oral cancer cells and normal oral fibroblasts was treated based on clinical protocol. After cancer treatment, the histological findings of the 3D oral cancer model indicated the clinical correlation between tumor response and surrounding normal tissue. This 3D model has potential as a tool for preclinical studies alternative to animal studies.
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The boron neutron capture therapy treatment planning systems such as SERA and TSUKUBA Plan, which are mainly based on the Monte Carlo method, require the lung physical density and composition of the tissue for the dose calculation. However, the physical density and composition of lungs may change because of diseases such as pneumonia and emphysema. We investigated the effect of the lung physical density on the neutron flux distribution and dose for the lung and tumor.
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Terapia por Captura de Neutrón de Boro , Mesotelioma Maligno , Humanos , Terapia por Captura de Neutrón de Boro/métodos , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/métodos , Pulmón , Método de MontecarloRESUMEN
To treat superficial tumors using accelerator-based boron neutron capture therapy (ABBNCT), a technique was investigated, based on which, a single-neutron modulator was placed inside a collimator and was irradiated with thermal neutrons. In large tumors, the dose was reduced at their edges. The objective was to generate a uniform and therapeutic intensity dose distribution. In this study, we developed a method for optimizing the shape of the intensity modulator and irradiation time ratio to generate a uniform dose distribution to treat superficial tumors of various shapes. A computational tool was developed, which performed Monte Carlo simulations using 424 different source combinations. We determined the shape of the intensity modulator with the highest minimum tumor dose. The homogeneity index (HI), which evaluates uniformity, was also derived. To evaluate the efficacy of this method, the dose distribution of a tumor with a diameter of 100 mm and thickness of 10 mm was evaluated. Furthermore, irradiation experiments were conducted using an ABBNCT system. The thermal neutron flux distribution outcomes that have considerable impacts on the tumor's dose confirmed a good agreement between experiments and calculations. Moreover, the minimum tumor dose and HI improved by 20 and 36%, respectively, compared with the irradiation case wherein a single-neutron modulator was used. The proposed method improves the minimum tumor volume and uniformity. The results demonstrate the method's efficacy in ABBNCT for the treatment of superficial tumors.
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Terapia por Captura de Neutrón de Boro , Neoplasias , Humanos , Terapia por Captura de Neutrón de Boro/métodos , Neoplasias/radioterapia , Neutrones , Dosificación Radioterapéutica , Método de MontecarloRESUMEN
Minimally invasive boron neutron capture therapy (BNCT) is an elegant approach for cancer treatment. The highly selective and efficient deliverability of boron agents to cancer cells is the key to maximizing the therapeutic benefits of BNCT. In addition, enhancement of the frequencies to achieve boron neutron capture reaction is also significant in improving therapeutic efficacy by providing a highly concentrated boron agent in each boron nanoparticle. As the density of the thermal neutron beam remains low, it is unable to induce high-efficiency cell destruction. Herein, we report phospholipid-coated boronic oxide nanoparticles as agents for BNCT that can provide a highly concentrated boron atom in each nanoparticle. The current system exhibited inâ vitro BNCT activity seven times higher than that of commercial boron agents. Furthermore, the system could penetrate cancer spheroids deeply, efficiently suppressing thermal neutron irradiation-induced growth.
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Terapia por Captura de Neutrón de Boro , Nanopartículas , Boro , Fosfolípidos , Compuestos de Boro/uso terapéutico , ÓxidosRESUMEN
We developed a 'hybrid algorithm' that combines the Monte Carlo (MC) and point-kernel methods for fast dose calculation in boron neutron capture therapy. The objectives of this study were to experimentally verify the hybrid algorithm and to verify the calculation accuracy and time of a 'complementary approach' adopting both the hybrid algorithm and the full-energy MC method. In the latter verification, the results were compared with those obtained using the full-energy MC method alone. In the hybrid algorithm, the moderation process of neutrons is simulated using only the MC method, and the thermalization process is modeled as a kernel. The thermal neutron fluxes calculated using only this algorithm were compared with those measured in a cubic phantom. In addition, a complementary approach was used for dose calculation in a geometry simulating the head region, and its computation time and accuracy were verified. The experimental verification indicated that the thermal neutron fluxes calculated using only the hybrid algorithm reproduced the measured values at depths exceeding a few centimeters, whereas they overestimated those at shallower depths. Compared with the calculation using only the full-energy MC method, the complementary approach reduced the computation time by approximately half, maintaining nearly same accuracy. When focusing on the calculation only using the hybrid algorithm only for the boron dose attributed to the reaction of thermal neutrons, the computation time was expected to reduce by 95% compared with the calculation using only the full-energy MC method. In conclusion, modeling the thermalization process as a kernel was effective for reducing the computation time.
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Terapia por Captura de Neutrón de Boro , Dosificación Radioterapéutica , Terapia por Captura de Neutrón de Boro/métodos , Planificación de la Radioterapia Asistida por Computador/métodos , Neutrones , AlgoritmosRESUMEN
In boron neutron capture therapy (BNCT), treatment planning images are acquired in the recumbent position. However, treatment is occasionally performed in the sitting position. For BNCT treatment planning, we investigated the usability of cone-beam computed tomography (CBCT) images using digital radiography equipment that allows imaging in the sitting position. The dose calculation results in both CBCT and fan beam CT were in good agreement. This method will eliminate the posture difference between planning and treatment.
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Terapia por Captura de Neutrón de Boro , Intensificación de Imagen Radiográfica , Terapia por Captura de Neutrón de Boro/métodos , Sedestación , Fantasmas de Imagen , Tomografía Computarizada de Haz Cónico , Planificación de la Radioterapia Asistida por Computador/métodosRESUMEN
New carborane-bearing hydroxamate matrix metalloproteinase (MMP) ligands have been synthesized for boron neutron capture therapy (BNCT) with nanomolar potency against MMP-2, -9 and -13. New analogs are based on MMP inhibitor CGS-23023A, and two previously reported MMP ligands 1 (B1) and 2 (B2) were studied in vitro for BNCT activity. The boronated MMP ligands 1 and 2 showed high in vitro tumoricidal effects in an in vitro BNCT assay, exhibiting IC50 values for 1 and 2 of 2.04 × 10-2 mg/mL and 2.67 × 10-2 mg/mL, respectively. The relative killing effect of 1 to L-boronophenylalanine (BPA) is 0.82/0.27 = 3.0, and that of 2 is 0.82/0.32 = 2.6, whereas the relative killing effect of 4 is comparable to boronophenylalanine (BPA). The survival fraction of 1 and 2 in a pre-incubation boron concentration at 0.143 ppm 10B and 0.101 ppm 10B, respectively, were similar, and these results suggest that 1 and 2 are actively accumulated through attachment to the Squamous cell carcinoma (SCC)VII cells. Compounds 1 and 2 very effectively killed glioma U87 delta EGFR cells after BNCT. This study is noteworthy in demonstrating BNCT efficacy through binding to MMP enzymes overexpressed at the surface of the tumor cell without tumor cell penetration.
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Terapia por Captura de Neutrón de Boro , Glioma , Humanos , Terapia por Captura de Neutrón de Boro/métodos , Ligandos , Internalización del Virus , Compuestos de Boro/farmacologíaRESUMEN
BACKGROUND/AIM: To investigate the long-term influence of head-neutron irradiation on mice spleens, post-radiation late effects were examined in three types of mice: Balb/c and severe combined immunodeficiency (SCID) mice, which have high radio-sensitivities, and C3H mice. MATERIALS AND METHODS: Neutron irradiation was performed with the neutron beam of the Kyoto University Research Reactor. Survival fractions and the change in spleen size after head-neutron irradiation were investigated in three different types of mice. Physical condition after neutron irradiation was observed for eighteen months. RESULTS: The onset of primary splenic malignant lymphoma was recognized in many of the Balb/c mice 18 months after head-neutron irradiation. Eight months after head-neutron irradiation, many SCID mice developed an abscess in the part exposed to radiation and spleen swelling. The swollen spleen of SCID mice had hematopoiesis from the marrow. CONCLUSION: Low energy head-neutron irradiation damages immune organs in radiosensitive SCID and Balb/c mice. A combination of boron neutron capture therapy and immunotherapy may be less toxic than low-energy neutron-irradiation alone.
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Terapia por Captura de Neutrón de Boro , Bazo , Ratones , Animales , Ratones SCID , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Carcinogénesis , NeutronesRESUMEN
Boron neutron capture therapy shows is a promising approach to cancer therapy, but the delivery of effective boron agents is challenging. To address the requirements for efficient boron delivery, we used a hybrid nanoparticle comprising a carborane = bearing pullulan nanogel and hydrophobized boron oxide nanoparticle (HBNGs) enabling the preparation of highly concentrated boron agents for efficient delivery. The HBNGs showed better anti-cancer effects on Colon26 cells than a clinically boron agent, L-BPA/fructose complex, by enhancing the accumulation and retention amount of the boron agent within cells in vitro. The accumulation of HBNGs in tumors, due to the enhanced permeation and retention effect, enabled the delivery of boron agents with high tumor selectivity, meeting clinical demands. Intravenous injection of boron neutron capture therapy (BNCT) using HBNGs decreased tumor volume without significant body weight loss, and no regrowth of tumor was observed three months after complete regression. The therapeutic efficacy of HBNGs was better than that of L-BPA/fructose complex. BNCT with HBNGs is a promising approach to cancer therapeutics.
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Terapia por Captura de Neutrón de Boro , Neoplasias , Humanos , Nanogeles , Boro , Neoplasias/radioterapia , Neoplasias/tratamiento farmacológico , Compuestos de Boro , FructosaRESUMEN
Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or neo vector (SAS/neo) were inoculated subcutaneously into left hind legs of nude mice. After the subcutaneous administration of a 10B-carrier, boronophenylalanine-10B (BPA) or sodium mercaptododecaborate-10B (BSH), at two separate concentrations, the 10B concentrations in tumors were measured using γ-ray spectrometry. The tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) tumor cells, then were administered with BPA or BSH. Subsequently, the tumors were irradiated with reactor neutron beams during the time of which 10B concentrations were kept at levels similar to each other. Following irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of BrdU-unlabeled quiescent (Q) and total (= P + Q) tumor cells were assessed based on the frequencies of micronucleation using immunofluorescence staining for BrdU. In both SAS/neo and SAS/mp53 tumors, the compound biological effectiveness (CBE) values were higher in Q cells and in the use of BPA than total cells and BSH, respectively. The higher the administered concentrations were, the smaller the CBE values became, with a clearer tendency in SAS/neo tumors and the use of BPA than in SAS/mp53 tumors and BSH, respectively. The values for BPA that delivers into solid tumors more dependently on uptake capacity of tumor cells than BSH became more alterable. Tumor micro-environmental heterogeneity might partially influence on the CBE value. The CBE value can be regarded as one of the indices showing the level of intratumor heterogeneity.