A Novel Boron Dipyrromethene-Erlotinib Conjugate for Precise Photodynamic Therapy against Liver Cancer.

Photodynamic Therapy (PDT) is recognized for its exceptional effectiveness as a promising cancer treatment method. However, it is noted that overexposure to the dosage and sunlight in traditional PDT can result in damage to healthy tissues, due to the low tumor selectivity of currently available photosensitizers (PSs). To address this challenge, we introduce herein a new strategy where the small molecule-targeted agent, erlotinib, is integrated into a boron dipyrromethene (BODIPY)-based PS to form conjugate 6 to enhance the precision of PDT. This conjugate demonstrates optical absorption, fluorescence emission, and singlet oxygen generation efficiency comparable to the reference compound 7, which lacks erlotinib. In vitro studies reveal that, after internalization, conjugate 6 predominantly accumulates in the lysosomes of HepG2 cells, exhibiting significant photocytotoxicity with an IC50 value of 3.01 µM. A distinct preference for HepG2 cells over HELF cells is observed with conjugate 6 but not with compound 7. In vivo experiments further confirm that conjugate 6 has a specific affinity for tumor tissues, and the combination treatment of conjugate 6 with laser illumination can effectively eradicate H22 tumors in mice with outstanding biosafety. This study presents a novel and potential PS for achieving precise PDT against cancer.

Photodynamic Therapy with Targeted Release of Boron-Dipyrromethene Dye from Cobalt(III) Prodrugs in Red Light.

Boron-dipyrromethene (BODIPY) dyes are promising photosensitizers for cellular imaging and photodynamic therapy (PDT) owing to their excellent photophysical properties and the synthetically tunable core. Metalation provides a convenient way to overcome the drawbacks arising from their low aqueous solubility. New photo-/redox-responsive Co(III) prodrug chaperones are developed as anticancer PDT agents for efficient cellular delivery of red-light-active BODIPY dyes. The photobiological activity of heteroleptic Co(III) complexes derived from tris(2-pyridylmethyl)amine (TPA) and acetylacetone-conjugated PEGylated distyryl BODIPY (HL1) or its dibromo analogue (HL2), [CoIII(TPA)(L1/L2)](ClO4)2 (1 and 2), are investigated. The Co(III)/Co(II) redox potential is tuned using the Co(III)-TPA scaffold. Complex 1 displays the in vitro release of BODIPY on red light irradiation. Complex 2, having good singlet oxygen quantum yield (ΦΔ âˆ¼ 0.28 in DMSO), demonstrates submicromolar photocytotoxicity to HeLa cancer cells (IC50 ≈ 0.23 µM) while being less toxic to HPL1D normal cells in red light. Cellular imaging using the emissive complex 1 shows mitochondrial localization and significant penetration into the HeLa tumor spheroids. Complex 2 shows supercoiled DNA photocleavage activity and apoptotic cell death through phototriggered generation of reactive oxygen species. The Co(III)-BODIPY prodrug conjugates exemplify new type of phototherapeutic agents with better efficacy than the organic dyes alone in the phototherapeutic window.

Porphyrin precursors and risk of primary liver cancer in acute intermittent porphyria: A case-control study of 188 patients.

Acute intermittent porphyria (AIP) is a rare hereditary metabolic disease characterized by acute attacks and accumulation of the porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Patients with AIP have a high risk of primary liver cancer (PLC). We aimed to assess the association between porphyrin precursor excretion and the risk for PLC in patients with AIP. We studied 48 patients with AIP who developed PLC between 1987 and 2015 and 140 age and sex matched controls with AIP but no PLC. Data on all available urinary PBG and ALA samples collected from 1975 until 1 year before PLC diagnosis were analyzed and compared between cases and controls using logistic regression. Porphyrin precursor excretion was higher in patients with PLC (PBG median 7.9 [IQR 4.4-21.9] mmol/mol creatinine) than in controls (3.8 [1.2-9.8]) (adjusted odds ratio 1.07, 95% confidence interval: 1.02-1.12). None of the 28 patients with all registered samples below the upper limit of normal (ULN) developed PLC, and only one of the 45 patients with all samples <2× ULN developed PLC. Among non-PLC controls, ALA and PBG levels decreased after age 50-60 while an increasing trend was observed after age 65 among those who developed PLC. Increased urinary porphyrin precursors are associated with a high risk of developing PLC. Patients with normal levels appear to have a low risk while high or increasing ALA and PBG after age 65 indicates high risk, which should be considered in surveillance decisions.

A Tetrazine-Caged Carbon-Dipyrromethene as a Bioorthogonally Activatable Fluorescent Probe.

A water-soluble 1,2,4,5-tetrazine-substituted carbon-dipyrromethene (C-DIPY) was synthesized from the previously reported carbonyl pyrrole dimer through a two-step procedure. Owing to the presence of a tetrazine moiety, the fluorescence emission of this compound was largely quenched in phosphate-buffered saline at pH 7.4. Upon addition of a bicyclo[6.1.0]non-4-yne (BCN) derivative, the tetrazine-based quenching component of the compound was disrupted through the inverse electron-demand Diels-Alder reaction to restore the fluorescence in up to 6.6-fold. This bioorthogonal activation was also demonstrated using U-87 MG human glioblastoma cells, in which the fluorescence intensity of this C-DIPY could be enhanced by 8.7-fold upon post-incubation with the BCN derivative. The results showed that this tetrazine-caged C-DIPY can serve as a bioorthogonally activatable fluorescent probe for bioimaging. The compound, however, was found to reside preferentially in the lysosomes instead of the mitochondria of the cells as predicted based on its cationic character, which could be attributed to its energy-dependent endocytic cellular uptake pathway, for which lysosomes are the end station.

AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review.

DESCRIPTION: The acute hepatic porphyrias (AHP) are rare, inborn errors of heme-metabolism and include acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and porphyria due to severe deficiency of 5-aminolevulinic acid dehydratase. Acute intermittent porphyria is the most common type of AHP, with an estimated prevalence of patients with symptoms of approximately 1 in 100,000. The major clinical presentation involves attacks of severe pain, usually abdominal and generalized, without peritoneal signs or abnormalities on cross-sectional imaging. Acute attacks occur mainly in women in their childbearing years. AHP should be considered in the evaluation of all patients, and especially women aged 15-50 years with recurrent severe abdominal pain not ascribable to common causes. The screening tests of choice include random urine porphobilinogen and δ-aminolevulinic acid corrected to creatinine. All patients with elevations in urinary porphobilinogen and/or δ-aminolevulinic acid should initially be presumed to have AHP. The cornerstones of management include discontinuation of porphyrinogenic drugs and chemicals, administration of oral or intravenous dextrose and intravenous hemin, and use of analgesics and antiemetics. Diagnosis of AHP type can be confirmed after initial treatment by genetic testing for pathogenic variants in HMBS, CPOX, PPOX, and ALAD genes. AHP is also associated with chronic symptoms and long-term risk of systemic arterial hypertension, chronic renal and liver disease, and hepatocellular carcinoma. Patients who have recurrent acute attacks (4 or more per year) should be considered for prophylactic therapy with intravenous hemin or subcutaneous givosiran. Liver transplantation is curative and reserved for patients with intractable symptoms who have failed other treatment options. METHODS: This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Women aged 15-50 years with unexplained, recurrent severe abdominal pain without a clear etiology after an initial workup should be considered for screening for an AHP. BEST PRACTICE ADVICE 2: Initial diagnosis of AHP should be made by biochemical testing measuring δ-aminolevulinic acid, porphobilinogen, and creatinine on a random urine sample. BEST PRACTICE ADVICE 3: Genetic testing should be used to confirm the diagnosis of AHP in patients with positive biochemical testing. BEST PRACTICE ADVICE 4: Acute attacks of AHP that are severe enough to require hospital admission should be treated with intravenous hemin, given daily, preferably into a high-flow central vein. BEST PRACTICE ADVICE 5: In addition to intravenous hemin, management of acute attacks of AHP should include pain control, antiemetics, management of systemic arterial hypertension, tachycardia, and hyponatremia, and hypomagnesemia, if present. BEST PRACTICE ADVICE 6: Patients should be counseled to avoid identifiable triggers that may precipitate acute attacks, such as alcohol and porphyrinogenic medications. BEST PRACTICE ADVICE 7: Prophylactic heme therapy or givosiran, administered in an outpatient setting, should be considered in patients with recurrent attacks (4 or more per year). BEST PRACTICE ADVICE 8: Liver transplantation for AHP should be limited to patients with intractable symptoms and significantly decreased quality of life who are refractory to pharmacotherapy. BEST PRACTICE ADVICE 9: Patients with AHP should be monitored annually for liver disease. BEST PRACTICE ADVICE 10: Patients with AHP, regardless of the severity of symptoms, should undergo surveillance for hepatocellular carcinoma, beginning at age 50 years, with liver ultrasound every 6 months. BEST PRACTICE ADVICE 11: Patients with AHP on treatment should undergo surveillance for chronic kidney disease annually with serum creatinine and estimated glomerular filtration rate. BEST PRACTICE ADVICE 12: Patients should be counseled on the chronic and long-term complications of AHP, including neuropathy, chronic kidney disease, hypertension, and hepatocellular carcinoma, and need for long-term monitoring.

Mitochondria-Targeting Boron Dipyrromethene Based Photosensitizers for Enhanced Photodynamic Therapy: Synthesis, Optical Properties, and in†vitro Biological Activity.

Increasing Investigations show that photosensitizers (PSs) which target mitochondria are useful for enhancing photodynamic therapy (PDT) efficacy. Herein, we carefully designed and synthesized four triphenylphosphonium (TPP)-modified boron dipyrromethene (BDP)-based PSs through Cu(I)-assisted "3+2" cycloaddition reaction. All of them exhibit intense red light absorption with maxima between 659 and 663 nm, considerable fluorescence emission with quantum yields of 0.16-0.23, high singlet oxygen generation efficiency ranging from 0.22 to 0.34, excellent mitochondria-targeting ability, and good biocompatibility. Upon illumination, they induce significant cancer cell death through a mitochondria-related apoptosis pathway. The IC50 values of these BDP dyes against MCF-7 cells were determined to be as low as 0.046-0.113 µM under rather low dosage of light irradiation (1.5 J ⋅ cm-2 ).

A Hypoxia-Activated Prodrug Conjugated with a BODIPY-Based Photothermal Agent for Imaging-Guided Chemo-Photothermal Combination Therapy.

Hypoxia-activated prodrugs (HAPs) have drawn increasing attention for improving the antitumor effects while minimizing side effects. However, the heterogeneous distribution of the hypoxic region in tumors severely impedes the curative effect of HAPs. Additionally, most HAPs are not amenable to optical imaging, and it is difficult to precisely trace them in tissues. Herein, we carefully designed and synthesized a multifunctional therapeutic BAC prodrug by connecting the chemotherapeutic drug camptothecin (CPT) and the fluorescent photothermal agent boron dipyrromethene (BODIPY) via hypoxia-responsive azobenzene linkers. To enhance the solubility and tumor accumulation, the prepared BAC was further encapsulated into a human serum albumin (HSA)-based drug delivery system to form HSA@BAC nanoparticles. Since the CPT was caged by a BODIPY-based molecule at the active site, the BAC exhibited excellent biosafety. Importantly, the activated CPT could be quickly released from BAC and could perform chemotherapy in hypoxic cancer cells, which was ascribed to the cleavage of the azobenzene linker by overexpressed azoreductase. After irradiation with a 730 nm laser, HSA@BAC can efficiently generate hyperthermia to achieve irreversible cancer cell death by oxygen-independent photothermal therapy. Under fluorescence imaging-guided local irradiation, both in vitro and in vivo studies demonstrated that HSA@BAC exhibited superior antitumor effects with minimal side effects.

Boron Dipyrromethene-Based Phototheranostics for Near Infrared Fluorescent and Photoacoustic Imaging-Guided Synchronous Photodynamic and Photothermal Therapy of Cancer.

The regulation of photochemical properties of phototheranostics, especially the absorption, fluorescence, singlet oxygen (1O2) generation, and photothermal conversion efficiency, is a hot research topic. Here, we designed and synthesized four boron dipyrromethene (BODIPY) derivatives with high absorption coefficients and intense fluorescence in the near-infrared (NIR) region. The substituted electron-donating group significantly improved 1O2 generation and fluorescence of BODIPYs, whereas the electron-withdrawing group boosts photothermal conversion. These hydrophobic BODIPYs were further coated with DSPE-PEG-2000 to form water dispersible nanoparticles (NPs). Among these BODIPY NPs, the B-OMe-NPs with methoxyl substituted at the meso-position showed the highest 1O2 generation, a photothermal conversion efficiency of 66.5%, and an NIR fluorescence peak at 809 nm. In vitro and in vivo experiments demonstrated that B-OMe-NPs might be used for NIR fluorescent and photoacoustic imaging-guided photodynamic and photothermal therapy of cancer.

Self-Assembled Aza-Boron-Dipyrromethene for Ferroptosis-Boosted Sonodynamic Therapy.

The presence of apoptosis inhibition proteins renders the cancer cells resistant to apoptosis, severely compromising the antitumor efficacy of sonodynamic therapy (SDT). Here, an intelligent anticancer nanoplatform based on an Aza-boron-dipyrromethene dye (denoted as Aza-BDY) is elaborately established for ferroptosis augmented SDT through cysteine (Cys) starvation. After endocytosis by tumor cells, Aza-BDY serves as both a ferroptosis inducing agent and a sonosensitizer for tumor treatment. The specific Cys response facilitates the disruption of redox homeostasis and initiation of cellular ferroptosis. Meanwhile, the released sonosensitizer causes efficient SDT and augments ferroptosis under ultrasound irradiation. Detailed in vitro and in vivo investigations demonstrate that the synergistic effect of Cys depletion and singlet oxygen (1 O2 ) generation significantly induces cancer-cell death and suppresses tumor proliferation with a high inhibition rate of 97.5 %.

Phenylthiol-BODIPY-based supramolecular metallacycles for synergistic tumor chemo-photodynamic therapy.

The development of more effective tumor therapy remains challenging and has received widespread attention. In the past decade, there has been growing interest in synergistic tumor therapy based on supramolecular coordination complexes. Herein, we describe two triangular metallacycles (1 and 2) constructed by the formation of pyridyl boron dipyrromethene (BODIPY)-platinum coordination. Metallacycle 2 had considerable tumor penetration, as evidenced by the phenylthiol-BODIPY ligand imparting red fluorescent emission at ∼660 nm, enabling bioimaging, and transport visualization within the tumor. Based on the therapeutic efficacy of the platinum(II) acceptor and high singlet oxygen (1O2) generation ability of BODIPY, 2 was successfully incorporated into nanoparticles and applied in chemo-photodynamic tumor therapy against malignant human glioma U87 cells, showing excellent synergistic therapeutic efficacy. A half-maximal inhibitory concentration of 0.35 µM was measured for 2 against U87 cancer cells in vitro. In vivo experiments indicated that 2 displayed precise tumor targeting ability and good biocompatibility, along with strong antitumor effects. This work provides a promising approach for treating solid tumors by synergistic chemo-photodynamic therapy of supramolecular coordination complexes.

Bi-allelic hydroxymethylbilane synthase inactivation defines a homogenous clinico-molecular subtype of hepatocellular carcinoma.

BACKGROUND & AIMS: Acute intermittent porphyria (AIP), caused by heterozygous germline mutations of the heme synthesis pathway enzyme HMBS (hydroxymethylbilane synthase), confers a high risk of hepatocellular carcinoma (HCC) development. Yet, the role of HMBS in liver tumorigenesis remains unclear. METHODS: Herein, we explore HMBS alterations in a large series of 758 HCC cases, including 4 patients with AIP. We quantify the impact of HMBS mutations on heme biosynthesis pathway intermediates and we investigate the molecular and clinical features of HMBS-mutated tumors. RESULTS: We identify recurrent bi-allelic HMBS inactivation, both in patients with AIP acquiring a second somatic HMBS mutation and in sporadic HCC with 2 somatic hits. HMBS alterations are enriched in truncating mutations, in particular in splice regions, leading to abnormal transcript structures. Bi-allelic HMBS inactivation results in a massive accumulation of its toxic substrate porphobilinogen and synergizes with CTNNB1-activating mutations, leading to the development of well-differentiated tumors with a transcriptomic signature of Wnt/ß-catenin pathway activation and a DNA methylation signature related to ageing. HMBS-inactivated HCC mostly affects females, in the absence of fibrosis and classical HCC risk factors. CONCLUSIONS: These data identify HMBS as a tumor suppressor gene whose bi-allelic inactivation defines a homogenous clinical and molecular HCC subtype. LAY SUMMARY: Heme (the precursor to hemoglobin, which plays a key role in oxygen transport around the body) synthesis occurs in the liver and involves several enzymes including hydroxymethylbilane synthase (HMBS). HMBS mutations cause acute intermittent porphyria, a disease caused by the accumulation of toxic porphyrin precursors. Herein, we show that HMBS inactivation is also involved in the development of liver cancers with distinct clinical and molecular characteristics.

Near-Infrared Emitting Ir(III) Complexes Bearing a Dipyrromethene Ligand for Oxygen Imaging of Deeper Tissues In Vivo.

Phosphorescence lifetime imaging microscopy (PLIM) using a phosphorescent oxygen probe is an innovative technique for elucidating the behavior of oxygen in living tissues. In this study, we designed and synthesized an Ir(III) complex, PPYDM-BBMD, that exhibits long-lived phosphorescence in the near-infrared region and enables in vivo oxygen imaging in deeper tissues. PPYDM-BBMD has a π-extended ligand based on a meso-mesityl dipyrromethene structure and phenylpyridine ligands with cationic dimethylamino groups to promote intracellular uptake. This complex gave a phosphorescence spectrum with a maximum at 773 nm in the wavelength range of the so-called biological window and exhibited an exceptionally long lifetime (18.5 µs in degassed acetonitrile), allowing for excellent oxygen sensitivity even in the near-infrared window. PPYDM-BBMD showed a high intracellular uptake in cultured cells and mainly accumulated in the endoplasmic reticulum. We evaluated the oxygen sensitivity of PPYDM-BBMD phosphorescence in alpha mouse liver 12 (AML12) cells based on the Stern-Volmer analysis, which gave an O2-induced quenching rate constant of 1.42 × 103 mmHg-1 s-1. PPYDM-BBMD was administered in the tail veins of anesthetized mice, and confocal one-photon PLIM images of hepatic tissues were measured at different depths from the liver surfaces. The PLIM images visualized the oxygen gradients in hepatic lobules up to a depth of about 100 µm from the liver surfaces with a cellular-level resolution, allowing for the quantification of oxygen partial pressure based on calibration results using AML12 cells.

Galactose conjugated boron dipyrromethene and hydrogen bonding promoted J-aggregates for efficiently targeted NIR-II fluorescence assistant photothermal therapy.

It is essential to develop novel multifunctional and easily synthesized stable NIR-II fluorescent probes to guide photothermal therapy for tumors. Here, we propose a new strategy to construct boron dipyrromethene (BODIPY) J-aggregates by intermolecular hydrogen bonding (H-bond) and π-π stacking interactions to achieve fluorescence emission in the second near-infrared window (NIR-II, 1000-1700 nm). A novel meso-benzamide galactose hexanoate-BODIPY (Gal-OH-BDP) amphiphilic small molecular dye was synthesized and it formed nanoparticles spontaneously in aqueous solution with a maximum emission wavelength near 1060 nm, which works as a smart nanomedicine for targeting NIR-II imaging-guided photothermal therapy (PTT) of hepatocellular carcinoma. Galactose not only provided hydrogen bonds to regulate the aggregation pattern of the molecules but also effectively targeted hepatocellular carcinoma cells and promoted the formation of well-dispersed nanoparticles of dye molecules due to their hydrophilicity. Moreover, due to high photothermal conversion efficiency (PCE = 55%), Gal-OH-BDP NPs achieve galactose-targeted NIR-II imaging and PTT, which is important for the precise diagnosis and treatment of tumors (Scheme 1). In the present research work, H-bond was introduced for the first time into BODIPY for building J-aggregates to achieve the NIR-II fluorescence.

Acute hepatic porphyria: when to perform liver transplantation?

. (AU)Acute hepatic porphyrias (AHPs) are inborn errors of hemebiosynthesis and its most common and severe type is the acute intermittent porphyria (AIP). AIP is an hereditary autosomal dominant disease caused by accumulated porphobilinogen deaminase (PBG) and delta aminolevulin acid (ALA) products. The main symptoms are severe abdominal pain, neuromuscular and psychiatric disturbances, nausea, vomiting, encephalopathy, tachycardia, seizures, tremors and hypertension, that usually are manifested by acute crises. The treatment is based on clinical management and in cases which the patient's quality of life is affected liver transplantation (LT) may be an alternative choice. We report the case of a patient with AHP presenting recurrent crisis leading to chronic symptoms occurrence and poor quality of life with progressive unresponsiveness to hemin treatment. Patient was submitted to LT as curative therapy proposal, but patient still presents some clinical manifestations that may indicate the possibility of a secondary cause to explain persistence of her symptoms despite of biochemical normalization of ALA and PBG. (AU)

As porfirias hepáticas agudas (PHA) compreendem um grupo de porfirias que apresentam erros inatos na biossíntese do grupo heme, sendo a mais severa e o tipo mais comum da PHA, a porfiria aguda intermitente (PAI). A PAI é uma doença autossômica dominante causada pelo acúmulo dos produtos porfobilinogênio deaminase (PBG) e ácido delta-aminolevulínico (ALA). Os principais sintomas são dor abdominal intensa, distúrbios neuromusculares e psiquiátricos, náuseas, vômitos, encefalopatia, taquicardia, febre, tremores e hipertensão, os quais normalmente são manifestados durante as crises agudas. O tratamento é baseado no manejo clínico de todos pacientes durante a crise. Para os casos em que a qualidade de vida do paciente é afetada negativamente, a terapêutica de transplante hepático poderá ser indicada. O objetivo do relato de caso é introduzir o tratamento de uma paciente com recorrentes crises agudas de porfiria e danos em sua qualidade de vida. Uma vez que a paciente não apresentou melhora após tratamento com hematina, foi submetida ao transplante hepático visando a cura da doença. Após o transplante, a paciente ainda apresentou alguns sintomas clínicos, necessitando reformular uma segunda hipótese para explicar a persistência de tais sintomas apesar da normalização dos níveis de ALA e PBG. (AU)

Tracking Labile Copper Fluctuation In Vivo/Ex Vivo: Design and Application of a Ratiometric Near-Infrared Fluorophore Derived from 4-Aminostyrene-Conjugated Boron Dipyrromethene.

Specimen differences, tissue-dependent background fluorescence and scattering, and deviated specimen position and sensor concentration make optical imaging for labile copper fluctuation in animals questionable, and a signal comparison between specimens is infeasible. We proposed ratiometric optical imaging as an alternative to overcome these disadvantages, and a near-infrared (NIR) ratiometric sensor, BDPS1, was devised therefore by conjugating boron dipyrromethene (BODIPY) with 4-aminostyrene and modifying the 4-amino group as a Cu+ chelator. BDPS1 possessed an excitation ratiometric copper-sensing ability to show the ratio of NIR emission (710 nm) upon excitation at 600 nm to that at 660 nm, Fex600/Fex660, increasing from 2.8 to 10.7. This sensor displayed still the opposite copper response of its internal charge transfer (ICT; 670 nm) and local (581 nm) emission bands. Ratiometric imaging with this sensor disclosed a higher labile copper region near the nucleus apparatus, and HEK-293T cells were more sensitive to copper incubation than MCF-7 cells. Dual excitation ratiometric imaging with this sensor realized tracking of labile copper fluctuation in mice, and the whole-body imaging found that tail intravenous injection of CUTX-101, a therapeutical agent for Menkes disease, led to a distinct labile copper increase in the upper belly. The ex vivo imaging of the resected viscera of mice revealed that CUTX-101 injection enhanced the labile copper level in the liver, intestine, lung, and gall bladder in sequence, yet the kidney, heart, and spleen showed almost no response. This study indicated that modifying BODIPY as an extended ICT fluorophore, with its electron-donating group being derived as a metal chelator, is an effective design rationale of NIR ratiometric sensors for copper tracking in vivo/ex vivo.

Synergistic photodynamic and photothermal therapy of BODIPY-conjugated hyaluronic acid nanoparticles.

The combination of photodynamic therapy (PDT) and photothermal therapy (PTT) has emerged as a promising strategy for complete tumor ablation therapy. Herein, a boron dipyrromethene (BODIPY)-conjugated hyaluronic acid polymer that can self-assemble to form the nanoparticles (BODIPY-HA NPs) was prepared for combined cancer PDT and PTT. The fluorescence emission and reactive oxygen species (ROS) generation of BODIPY-HA NPs were inhibited because of the π-π stacking behavior of BODIPY, resulting in photothermal effect under 808 nm light irradiation. Upon the internalization by cancer cells, the BODIPY-HA NPs could disassemble into BODIPY-HA molecules, with the recovery of the fluorescence and ROS generation for PDT. Importantly, in vitro results confirmed that combined PTT and PDT have exhibited better anticancer effect than PTT alone upon 808 nm laser irradiation. These results showed that the self-assembled BODIPY-HA NPs may be a promising nanomedicine for synergistic cancer PDT and PTT.

Hierarchical nano-to-molecular disassembly of boron dipyrromethene nanoparticles for enhanced tumor penetration and activatable photodynamic therapy.

The development of activatable photosensitizers (PSs) is of particular interest for achieving tumor photodynamic therapy (PDT) with minimal side effects. However, the in vivo applications of PSs are limited by complex physiological and biological delivery barriers. Herein, boron dipyrromethene (BDP)-based nanoparticles are developed through the self-assembly of a multifunctional "one-for-all" building block for enhanced tumor penetration and activatable PDT. The nanoparticles show excellent colloidal stability and long circulation lifetime in blood. Once they reach the tumor site, the first-stage size reduction occurs due to the hydrolysis of the Schiff base bond between polyethylene glycol and the cyclic Arg-Gly-Asp peptide in the acidic tumor microenvironment (pH~6.5), facilitating tumor penetration and specific recognition by cancer cells overexpressing integrin ανß3 receptors. Upon the endocytosis by cancer cells, the second-stage size reduction is triggered by more acidic pH in lysosomes (pH~4.5). Importantly, the protonated diethylamino groups can block photoinduced electron transfer from the amine donor to the excited PSs and accelerate complete disassembly of the nanoparticles into single PS molecule, with the recovery of the fluorescence and photoactivity for efficient PDT. This study presents a smart PS delivery strategy involving acidity-triggered hierarchical disassembly from the nano to molecular scale for precise tumor PDT.

Near-Infrared absorbing J-Aggregates of boron dipyrromethene for high efficient photothermal therapy.

Constructing bioactive materials remains a big challenge through the aggregates of molecules. Herein, a boron dipyrromethene (BODIPY) derivative containing three nitro groups (BDP-(NO2)3) was synthesized, which displays the characteristic of J-aggregate with pronounced red-shifted absorption in nonpolar solvent and aqueous media. The bathochromic shift from 635 to 765 nm facilitates photothermal transition upon the irradiation of near-infrared (NIR) light. Interestingly, BDP-(NO2)3 nanoparticles (NPs) fabricated from BDP-(NO2)3 and poly(oxyethylene)-poly(oxypropylene) copolymer (F-127), still exhibit obvious J-aggregate, which possess the merits of hydrophilicity, NIR absorption, high photothermal conversion efficiency, excellent biosafety, and can behave as unique candidates for photothermal therapy. In vitro and in vivo experiments validate that BDP-(NO2)3 NPs can effectively suppress the proliferation of cancer cells and lead to tumor ablation. This assembly method would be a generic and efficient mode for reasonable design of functional nanomaterials, and could inspire more study on aggregates of organic molecules.

Immobilising hairpin DNA-conjugated distyryl boron dipyrromethene on gold@polydopamine core-shell nanorods for microRNA detection and microRNA-mediated photodynamic therapy.

A novel nanosystem of polydopamine-coated gold nanorods (AuNR@PDA) immobilised with molecules of hairpin DNA-conjugated distyryl boron dipyrromethene (DSBDP) was designed and fabricated for detection of microRNA-21 (miR-21). By using this oncogenic stimulus, the photodynamic effect of the DSBDP-based photosensitiser was also activated. In the presence of miR-21, the fluorescence intensity of the nanosystem was increased due to the dissociation of the conjugate from AuNR@PDA upon hybridisation. The intracellular fluorescence intensity triggered by intracellular miR-21 was in the order: MCF-7 > HeLa > HEK-293, which was in accordance with their miR-21 expression levels. The specificity was demonstrated by comparing the results with those of an analogue with a scrambled DNA sequence. The nanosystem could also result in miR-21-mediated photodynamic eradication of miR-21-overexpressed MCF-7 cells. After intravenous injection of the nanosystem into HeLa tumour-bearing nude mice, the fluorescence intensity of the tumour was increased over 24 h and was about 3-fold stronger than that of the scrambled analogue. Upon irradiation, the nanosystem could also greatly reduce the size of the tumour without causing significant tissue damage in the major organs. The overall results showed that this nanoplatform can serve as a specific and potent theranostic agent for simultaneous miR-21 detection and miR-21-mediated photodynamic therapy.

Dual Color Imaging from a Single BF2-Azadipyrromethene Fluorophore Demonstrated in vivo for Lymph Node Identification.

Dual emissions at ~700 and 800 nm have been achieved from a single NIR-AZA fluorophore 1 by establishing parameters in which it can exist in either its isolated molecular or aggregated states. Dual near infrared (NIR) fluorescence color lymph node (LN) mapping with 1 was achieved in a large-animal porcine model, with injection site, channels and nodes all detectable at both 700 and 800 nm using a preclinical open camera system. The fluorophore was also compatible with imaging using two clinical instruments for fluorescence guided surgery. Methods: An NIR-AZA fluorophore with hydrophilic and phobic features was synthesised in a straightforward manner and its aggregation properties characterised spectroscopically and by TEM imaging. Toxicity was assessed in a rodent model and dual color fluorescence imaging evaluated by lymph node mapping in a large animal porcine models and in ex-vivo human tissue specimen. Results: Dual color fluorescence imaging has been achieved in the highly complex biomedical scenario of lymph node mapping. Emissions at 700 and 800 nm can be achieved from a single fluorophore by establishing molecular and aggregate forms. Fluorophore was compatible with clinical systems for fluorescence guided surgery and no toxicity was observed in high dosage testing. Conclusion: A new, biomedical compatible form of NIR-dual emission wavelength imaging has been established using a readily accessible fluorophore with significant scope for clinical translation.