In vivo fluorescence imaging of nanocarriers in near-infrared window II based on aggregation-caused quenching.

Accurate fluorescence imaging of nanocarriers in vivo remains a challenge owing to interference derived mainly from biological tissues and free probes. To address both issues, the current study explored fluorophores in the near-infrared (NIR)-II window with aggregation-caused quenching (ACQ) properties to improve imaging accuracy. Candidate fluorophores with NIR-II emission, ACQ984 (λem = 984 nm) and IR-1060 (λem = 1060 nm), from the aza-BODIPY and cyanine families, respectively, were compared with the commercial fluorophore ICG with NIR-II tail emission and the NIR-I fluorophore P2 from the aza-BODIPY family. ACQ984 demonstrates high water sensitivity with complete fluorescence quenching at a water fraction greater than 50%. Physically embedding the fluorophores illuminates various nanocarriers, while free fluorophores cause negligible interference owing to the ACQ effect. Imaging based on ACQ984 revealed fine structures in the vascular system at high resolution. Moreover, good in vivo and ex vivo correlations in the monitoring of blood nanocarriers can be established, enabling real-time noninvasive in situ investigation of blood pharmacokinetics and dynamic distribution in various tissues. IR-1060 also has a good ACQ effect, but the lack of sufficient photostability and steady post-labeling fluorescence undermines its potential for nanocarrier bioimaging. P2 has an excellent ACQ effect, but its NIR-I emission only provides nondiscriminative ambiguous images. The failure of the non-ACQ probe ICG to display the biodistribution details serves as counterevidence for the improved imaging accuracy by NIR-II ACQ probes. Taken together, it is concluded that fluorescence imaging of nanocarriers based on NIR-II ACQ probes enables accurate in vivo bioimaging and real-time in situ pharmacokinetic analysis.

Evaluation of sodium borocaptate (BSH) and boronophenylalanine (BPA) as boron delivery agents for neutron capture therapy (NCT) of cancer: an update and a guide for the future clinical evaluation of new boron delivery agents for NCT.

Boron neutron capture therapy (BNCT) is a cancer treatment modality based on the nuclear capture and fission reactions that occur when boron-10, a stable isotope, is irradiated with neutrons of the appropriate energy to produce boron-11 in an unstable form, which undergoes instantaneous nuclear fission to produce high-energy, tumoricidal alpha particles. The primary purpose of this review is to provide an update on the first drug used clinically, sodium borocaptate (BSH), by the Japanese neurosurgeon Hiroshi Hatanaka to treat patients with brain tumors and the second drug, boronophenylalanine (BPA), which first was used clinically by the Japanese dermatologist Yutaka Mishima to treat patients with cutaneous melanomas. Subsequently, BPA has become the primary drug used as a boron delivery agent to treat patients with several types of cancers, specifically brain tumors and recurrent tumors of the head and neck region. The focus of this review will be on the initial studies that were carried out to define the pharmacokinetics and pharmacodynamics of BSH and BPA and their biodistribution in tumor and normal tissues following administration to patients with high-grade gliomas and their subsequent clinical use to treat patients with high-grade gliomas. First, we will summarize the studies that were carried out in Japan with BSH and subsequently at our own institution, The Ohio State University, and those of several other groups. Second, we will describe studies carried out in Japan with BPA and then in the United States that have led to its use as the primary drug that is being used clinically for BNCT. Third, although there have been intense efforts to develop new and better boron delivery agents for BNCT, none of these have yet been evaluated clinically. The present report will provide a guide to the future clinical evaluation of new boron delivery agents prior to their clinical use for BNCT.

Active control of pharmacokinetics using light-responsive polymer-drug conjugates for boron neutron capture therapy.

In boron neutron capture therapy (BNCT), boron drugs should exhibit high intratumoral boron concentrations during neutron irradiation, while being cleared from the blood and normal organs. However, it is usually challenging to achieve such tumor accumulation and quick clearance simultaneously in a temporally controlled manner. Here, we developed a polymer-drug conjugate that can actively control the clearance of the drugs from the blood. This polymer-drug conjugate is based on a biocompatible polymer that passively accumulates in tumors. Its side chains were conjugated with the low-molecular-weight boron drugs, which are immediately excreted by the kidneys, via photolabile linkers. In a murine subcutaneous tumor model, the polymer-drug conjugate could accumulate in the tumor with the high boron concentration ratio of the tumor to the surrounding normal tissue (∼10) after intravenous injection while a considerable amount remained in the bloodstream as well. Photoirradiation to blood vessels through the skin surface cleaved the linker to release the boron drug in the blood, allowing for its rapid clearance from the bloodstream. Meanwhile, the boron concentration in the tumor which was not photoirradiated could be maintained high, permitting strong BNCT effects. In clinical BNCT, the dose of thermal neutrons to solid tumors is determined by the maximum radiation exposure to normal organs. Thus, our polymer-drug conjugate may enable us to increase the therapeutic radiation dose to tumors in such a practical situation.

Fluorine-18 labeling PEGylated 6-boronotryptophan for PET scanning of mice for assessing the pharmacokinetics for boron neutron capture therapy of brain tumors.

Two tryptophan compound classes 5- and 6-borono PEGylated boronotryptophan derivatives have been prepared for assessing their aqueous solubility as formulation of injections for boron neutron capture therapy (BNCT). The PEGylation has improved their aqueous solubility thereby increasing their test concentration in 1 mM without suffering from toxicity. In-vitro uptake assay of PEGylated 5- and 6-boronotryptophan showed that the B-10 concentration can reach 15-50 ppm in U87 cell whereas the uptake in LN229 cell varies. Shorter PEG compound 6-boronotryptophanPEG200[18F] was obtained in 1.7 % radiochemical yield and the PET-derived radioradioactivity percentage in 18 % was taken up by U87 tumor at the limb of xenograft mouse. As high as tumor to normal uptake ratio in 170 (T/N) was obtained while an inferior radioactivity uptake of 3 % and T/N of 8 was observed in LN229 xenografted mouse.

Carborane-FAPI conjugate: A potential FAP-targeted boron agent with improved boron content.

Boron neutron capture therapy (BNCT) has received extensive attention as an advanced binary radiotherapy method. However, BNCT still faces poor selectivity of boron agent and is insufficient boron content in tumor tissues. To improve the tumor-targeted ability and boron content, this research aims to design, synthesize and preliminary evaluate a new borane agent Carborane-FAPI, which coupling the o-carborane to the compound skeleton of a mature fibroblast activating protein (FAP) inhibitor (FAPI). FAP is a tumor-associated antigen. FAP expressed lowly in normal organs and highly expressed in tumors, so it is a potential target for diagnosis and treatment. Boronophenylalanine (BPA) is the most widely investigated BNCT drug in present. Compared with BPA, the boron content of a single molecule is increased and drug targeting is enhanced. The results show that Carboaren-FAPI has low toxicity to normal cells, and selective enrichment in tumor tissues. It is a promising boron drug that has the potential to be used in BNCT.

A bis-boron boramino acid PET tracer for brain tumor diagnosis.

PURPOSE: Boramino acids are a class of amino acid biomimics that replace the carboxylate group with trifluoroborate and can achieve the 18F-labeled positron emission tomography (PET) and boron neutron capture therapy (BNCT) with identical chemical structure. METHODS: This study reports a trifluoroborate-derived boronophenylalanine (BBPA), a derived boronophenylalanine (BPA) for BNCT, as a promising PET tracer for tumor imaging. RESULTS: Competition inhibition assays in cancer cells suggested the cell accumulation of [18F]BBPA is through large neutral amino acid transporter type-1 (LAT-1). Of note, [18F]BBPA is a pan-cancer probe that shows notable tumor uptake in B16-F10 tumor-bearing mice. In the patients with gliomas and metastatic brain tumors, [18F]BBPA-PET shows good tumor uptake and notable tumor-to-normal brain ratio (T/N ratio, 18.7 ± 5.5, n = 11), higher than common amino acid PET tracers. The [18F]BBPA-PET quantitative parameters exhibited no difference in diverse contrast-enhanced status (P = 0.115-0.687) suggesting the [18F]BBPA uptake was independent from MRI contrast-enhancement. CONCLUSION: This study outlines a clinical trial with [18F]BBPA to achieve higher tumor-specific accumulation for PET, provides a potential technique for brain tumor diagnosis, and might facilitate the BNCT of brain tumors.

Boron neutron capture therapy in cancer: past, present and future

Undifferentiated thyroid cancer (UTC) is a very aggressive tumor with no effective treatment, since it lacks iodine uptake and does not respond to radio or chemotherapy. The prognosis of these patients is bad, due to the rapid growth of the tumor and the early development of metastasis. Boron neutron capture therapy (BNCT) is based on the selective uptake of certain boron non-radioactive compounds by a tumor, and the subsequent irradiation of the area with an appropriate neutron beam. 10B is then activated to 11B, which will immediately decay releasing alpha particles and 7Li, of high linear energy transfer (LET) and limited reach. Clinical trials are being performed in patients with glioblastoma multiforme and melanoma. We have explored its possible application to UTC. Our results demonstrated that a cell line of human UTC has a selective uptake of borophenylalanine (BPA) both in vitro and after transplantation to nude mice. Treatment of mice by BNCT led to a complete control of growth and cure of 100 percent of the animals. Moreover dogs with spontaneous UTC also have a selective uptake of BPA. At the present we are studying the biodistribution of BPA in patients with UTC before its application in humans.

O câncer indiferenciado de tiróide (CIT) é um tumor muito agressivo sem tratamento efetivo, uma vez que não capta iodo e não responde à radio ou quimioterapia. O prognóstico desses pacientes é ruim, devido ao rápido crescimento do tumor e surgimento precoce de metástases. A terapia por captura de nêutrons de boro (TCNB) é baseada na captação seletiva de certos compostos de boro não-radioativos pelo tumor, e à subsequente irradiação da área com um feixe de nêutrons apropriado. O 10B é então ativado para 11B, cujo decaimento imediato libera partículas alfa e 7Li, de alta transferência linear de energia (TLE) e alcance limitado. Ensaios clínicos estão sendo conduzidos em pacientes com glioblastoma multiforme e melanoma, e nós estamos explorando sua possível aplicação no CIT. Nossos resultados demonstram que uma linhagem celular do CIT humano mostra captação seletiva de borofenilalanina (BPA) tanto in vitro como após transplante em camundongos "nude". O tratamento de camundongos com TCNB leva a um controle completo do crescimento tumoral e à cura em 100 por cento dos animais. Além disso, cães com CIT espontâneo também apresentam captação seletiva de BPA. No momento, estamos estudando a biodistribuição de BPA em pacientes com CIT, antes de sua aplicação em humanos.