Type-I Photodynamic Therapy Induced by Pt-Coordination of Type-II Photosensitizers into Supramolecular Complexes.

Platinum supramolecular complexes based on photosensitizers have garnered great interest in photodynamic therapy (PDT) due to Pt (II) centers as chemotherapeutic agents to eliminate tumor cells completely, which greatly improve the antitumor efficacy of PDT. However, in comparison to precursor photosensitizer ligand, the formed platinum supramolecular complexes typically exhibit inferior outcomes in terms of reactive oxygen species (ROS) generation. How to boost ROS generation in the formed platinum supramolecular complexes for enhanced PDT is an enticing yet highly challenging task. Here we report a Pt-coordination-based dimeric photosensitizer complex (Cz-BTZ-Py)2Pt(OTf)2. It is found that comparing with photosensitizer ligand Cz-BTZ-Py, the formed supramolecular complex exhibit redshifts of absorption wavelength as well as enhanced ROS generation efficiency. Moreover, type-I ROS generation (O2⋅-) is produced in the formed platinum supramolecular complexes mainly due to a reduced energy gap ΔEST resulting from exciton coupling between two photosensitizer ligands. And type-I ROS (O2⋅-) generation significantly amplifies the photodynamic therapy (PDT) outcomes. In vitro evaluation shows excellent photochemotherapy performance of (Cz-BTZ-Py)2Pt(OTf)2 nanoparticles. We anticipate this work would provide a novel approach to design type-I photosensitizers for efficient PDT.

Integration of TADF Photosensitizer as "Electron Pump" and BSA as "Electron Reservoir" for Boosting Type I Photodynamic Therapy.

Type I photosensitization provides an effective solution to the problem of unsatisfactory photodynamic therapeutic (PDT) effects caused by the tumor hypoxia. The challenge in the development of Type I mode is to boost the photosensitizer's own electron transfer capacity. Herein, we found that the use of bovine serum albumin (BSA) to encapsulate a thermally activated delayed fluorescence (TADF) photosensitizer PS can significantly promote the Type I PDT process to generate a mass of superoxide anions (O2•-). This Type I photosensitization opened a new strategy by employing BSA as "electron reservoir" and TADF photosensitizer as "electron pump". We integrated these roles of BSA and PS in one system by preparing nanophotosensitizer PS@BSA. The Type I PDT performance was demonstrated with tumor cells under hypoxic conditions. Furthermore, PS@BSA took full advantage of the tumor-targeting role of BSA and achieved efficient PDT for tumor-bearing mice in the in vivo experiments. This work provides an effective route to improve the PDT efficiency of hypoxic tumors.

Jointly Depleting Glutathione Based on Self-Assembled Nanomicelles for Enhancing Photodynamic Therapy.

Photodynamic therapy (PDT) is one common ROS-generating therapeutic method with high tumor selectivity and low side effects. But the GSH-upregulation often alleviates its therapeutic efficiency. Here, we proposed a new strategy of jointly depleting GSH to enhance the therapeutic effect of PDT by preparing a nanomicelle by self-assembly method from GSH-activated photosensitizer DMT, curcumin, and amphiphilic polymer TPGS.

Metal-Coordination-Mediated H-Aggregates of Cyanine Dyes for Effective Photothermal Therapy.

Integration of cyanine dyes and metal ions into one nanoplatform via metal-coordination interactions is an effective strategy to build multimodality phototheranostics. The multifunctionalities of the formed nanoscale metal-organic particles (NMOPs) have been widely explored. However, the effect of metal-coordination interaction on the aggregation behavior of cyanine dyes is rarely reported. Herein, we reported the H-aggregation behavior of cyanine dye Cy-3COOH induced by different metal ions M (Fe2+ or Mn2+ ). Moreover, the extent of H-aggregates varied with different metal-coordination interactions. Upon NIR irradiation, H-aggregates of Cy-3COOH remarkably promoted photothermal conversion efficiency. Interestingly, we also find that H-aggregates of Cy-3COOH induced by metal ions can generate the reactive oxygen species (ROS) involving singlet oxygen (1 O2 ) and superoxide anion radical (O2 - ⋅) upon light irradiation. In addition, the ROS efficiency varies depending on the extent of H-aggregates. Additionally, the photoinduced ROS could disassemble aggregates and decompose cyanine dye Cy-3COOH, which limits the photothermal capability of Cy-3COOH/M NPs. Therefore, the photothermal performance of Cy-3COOH/M NPs could be manipulated by the degree of H-aggregation. This would provide a new insight to develop efficient phototheranostics NMOPs for cancer treatment.

Boosting Type-I and Type-II ROS Production of Water-Soluble Porphyrin for Efficient Hypoxic Tumor Therapy.

As the most successful clinically approved photosensitizers, porphyrins have been extensively employed in the photodynamic therapy (PDT) of cancers. However, their poor water solubility, aggregation-induced self-quenching on ROS generation, and a low tolerance for a hypoxic condition usually result in unsatisfied therapeutic outcomes. Therefore, great efforts have been dedicated to improving the PDT efficacy of porphyrin-type photosensitizers in treating hypoxic tumors, including combination with additional active components or therapies, which can significantly complicate the therapeutic process. Herein, we report a novel water-soluble porphyrin with O-linked cationic side chains, which exhibits good water solubility, high photostability, and significantly enhanced ROS generation efficacy in both type-I and type-II photodynamic pathways. We have also found that the end charges of side chains can dramatically affect the ROS generation of the porphyrin. The cationic porphyrin exhibited high in vitro PDT efficacy with low IC50 values both in normoxia and hypoxia. Hence, during in vivo PDT study, the cationic porphyrin displayed highly effective tumor ablation capability. This study demonstrates the power of side-chain chemistry in tuning the photodynamic property of porphyrin, which offers a new effective strategy to enhance the anticancer performance of photosensitizers for fulfilling the increasing demands for cancer therapy in clinics.

[Clinical characteristics and genetic analysis of two children with Autosomal dominant mental retardation type 21 due to variants of CTCF gene].

OBJECTIVE: To explore the clinical and genetic characteristics of two children with developmental delay. METHODS: Two children who had presented at the Children's Hospital Affiliated to Shandong University on August 18, 2021 were enrolled as the study subjects. Clinical and laboratory examination, chromosomal karyotyping and high-throughput sequencing were carried out for both children. RESULTS: Both children had a 46,XX karyotype. High-throughput sequencing showed that they have respectively carried a c.489delG (p.Q165Rfs*14) and a c.1157_1158delAT (p.Y386Cfs*22) frameshifting variant of the CTCF gene, both had a de novo origin and were unreported previously. CONCLUSION: The CTCF gene variants probably underlay the development delay in the two children. Above discovery has enriched the mutational spectrum of the CTCF gene and has important implications for revealing the genotype-phenotype correlation for similar patients.

A Selenium-Substituted Heptamethine Cyanine Photosensitizer for Near-Infrared Photodynamic Therapy.

Photodynamic therapy (PDT) is a relatively safe approach to cancer treatment without significant systemic side effects or drug resistance. However, the current PDT efficiency is unsatisfactory due to the lack of near-infrared (NIR) photosensitizers. Heptamethine cyanine (Cy7) dyes are well-known NIR fluorophores and are also used as photosensitizers. But their singlet oxygen quantum yields (ΦΔ ) are not ideal. Herein, we developed an NIR photosensitizer with a long-lived excited triplet state (τ=4.3 µs) by introducing a selenium atom into the structure of a Cy7 dye. The new NIR photosensitizer exhibits a significantly high singlet oxygen quantum yield (ΦΔ =0.11). Its good PDT effect was demonstrated in the living cells. Considering that the selenium-substituted photosensitizer has a very low dark cytotoxicity and good chemical stability, we conclude that it will have a promising future in biomedical and clinical applications.

A Novel D-A-D Photosensitizer for Efficient NIR Imaging and Photodynamic Therapy.

Photodynamic therapy (PDT) has attracted great interest in cancer theranostics owing to its minimal invasiveness and low side effect. In PDT, photosensitizers are indispensable components that generate cytotoxic reactive oxygen species (ROS). Tremendous efforts have been devoted to optimizing the photosensitizer with enhanced ROS efficiency. However, to improve the precision and controllability for PDT, developing NIR imaging-guided photosensitizers are still urgent and challenging. Here, we have designed a novel photosensitizer 2Cz-BTZ which integrated with intense NIR emission and photoinduced singlet oxygen 1 O2 generation capabilities. Moreover, after loading the photosensitizers 2Cz-BTZ into biocompatible amphiphilic polymers F127, the formed 2Cz-BTZ@F127 nanoparticles (NPs) exhibited good photoinduced therapy as well as long-term in vivo imaging capabilities. Under these merits, the 2Cz-BTZ@F127 NPs showed NIR imaging-guided PDT, which paves a promising way for spatiotemporally precise tumor theranostics.

Self-Assembled Platinum Supramolecular Metallacycles Based on a Novel TADF Photosensitizer for Efficient Cancer Photochemotherapy.

Recently, supramolecular coordination complexes (SCCs) based on photosensitizers as bridging ligands have attracted great attention in cancer therapy owing to their synergistic effect between photodynamic therapy (PDT) and chemotherapy. Herein, a highly emissive supramolecular platinum triangle BTZPy-Pt based on a novel type of photosensitizer BTZPy with thermally activated delayed fluorescence (TADF) was fabricated. The BTZPy and BTZPy-Pt exhibited strong luminescence emission in the visible range with high quantum yields (quantum yields (QYs) for BTZPy and BTZPy-Pt were about 78 and 62% in ethanol solutions, respectively). Additionally, BTZPy had been proved to be an excellent photosensitizer with superior 1O2 generation capability (the 1O2 generation quantum yield reached up to ca. 95%) for PDT. By the combination of the excellent phototoxicity of BTZPy and the antitumor activity of the Pt center, the platinum triangle BTZPy-Pt demonstrated a highly efficient anticancer performance toward HeLa cells (IC50: 0.5 µg mL-1). This study not only provides a blueprint to fabricate new types of photosensitizers but also paves a way to design novel SCCs for efficient PDT.

Synthesis of Noble Metal M@YSiO2 Yolk-Shell Nanoparticles with Thin Organic/Inorganic Hybrid Outer Shells via an Aqueous Medium Phase.

A simple method is proposed for the synthesis of noble metal M@YSiO2 (M = Au, Pd, Ag) yolk-shell nanoparticles. The effects of synthesis conditions on the preparation of yolk-shell nanoparticles were discussed in detail. According to the different corrosion resistances between inorganic silica and organosilicone in a selective etching solution, yolk-shell nanoparticles with large cavity and thin shell were prepared using the same aqueous medium in a step-by-step synthesis process. Different from traditional methods, this method is facile and efficient because the main synthesis process is carried out in an aqueous phase. This extended method may benefit the synthesis and application of other nanomaterials with a similar yolk-shell structure.

Smart Bimodal Imaging of Hypochlorous Acid In Vivo Using a Heterobimetallic Ruthenium(II)-Gadolinium(III) Complex Probe.

A unique heterobimetallic Ru(II)-Gd(III) complex, Ru-AN-Gd, is reported to serve as an effective probe for bimodal phosphorescence-magnetic resonance (MR) imaging of hypochlorous acid (HClO) in vitro and in vivo. The probe was designed by incorporating a MR contrast agent, Gd-DOTA, into a HClO-responsive bipyridine-Ru(II) complex derivative. The specific reaction between Ru-AN-Gd and HClO triggers the cleavage of an ether bond in the probe molecule, resulting in phosphorescence turn-on and MR turn-off responses to HClO. The integration of MR and phosphorescence detection modes allows the probe to be employed for detecting HClO in a quite wide concentration range (0.6-2000 µM) and for imaging HClO at various resolutions ranging from the subcellular level to the whole body without a depth limit. Its applicability was demonstrated by phosphorescence imaging of lysosomal HClO in live cells, visualization of HClO generation in a mouse arthritis model, and bimodal phosphorescence-MR imaging of HClO in drug-induced acute liver and kidney injury of a mouse. The research achievements suggested the potential of Ru-AN-Gd for diagnosis and treatment monitoring of HClO-related disease.

Recent Development of Photothermal Agents (PTAs) Based on Small Organic Molecular Dyes.

Photothermal therapy (PTT) has attracted great attention due to its noninvasive and effective use against cancer. Various photothermal agents (PTAs) including organic and inorganic PTAs have been developed in the last decades. Organic PTAs based on small-molecule dyes exhibit great potential for future clinical applications considering their good biocompatibility and easy chemical modification or functionalization. In this review, we discuss the recent progress of organic PTAs based on small-molecule dyes for enhanced PTT. We summarize the strategies to improve the light penetration of PTAs, methods to enhance their photothermal conversion efficiency, how to optimize PTAs' delivery into deep tumors, and how to resist photobleaching under repeated laser irradiation. We hope that this review can rouse the interest of researchers in the field of PTAs based on small-molecule dyes and help them to fabricate next-generation PTAs for noninvasive cancer therapy.

[Analysis of clinical and genetic characteristics of a child with ring chromosome 4 syndrome].

OBJECTIVE: To explore the genetic basis for a child featuring short stature. METHODS: G-banded karyotyping, chromosomal microarray analysis (CMA) and high-throughput sequencing were carried out on peripheral blood sample from the child. RESULTS: The karyotype of the child was ascertained as 45,XY,-4[3]/46,XY,r(4)(p16q35)[84]/47,XY,-4,r(4)(p16q25)*2[7]/48,XY,-4,r(4)(p16q35)*3[1]/46,XY,dic r(4;4)(p16q35;p16q35)[2]/46,XY,add(4)(p16)[3]. A 647 kb deletion at 4p16.3 was identified by CMA, which encompassed 6 OMIM genes including ZNF141, PIGG, PDE6B, ATP5I, PCGF3 and MYL5. High-throughput sequencing has identified no pathogenic/likely pathogenic variants consistent with the clinical symptoms. CONCLUSION: A rare ring chromosome 4 syndrome was identified by combined chromosomal karyotyping, CMA and high-throughput sequencing. Conventional cytogenetic analysis and genetic testing in combine have enabled the diagnosis in this case.

Knockdown of long noncoding RNA urothelial carcinoma associated 1 inhibits colorectal cancer cell proliferation and promotes apoptosis via modulating autophagy.

Long noncoding RNA urothelial carcinoma associated 1 (UCA1) has been implicated in the growth and metastasis of colorectal cancer (CRC), and autophagy contributes to tumorigenesis and cancer cell survival. However, the regulatory role of UCA1 in CRC cell viability by modulating autophagy remains unclear. In the present study, a significant positive correlation was observed between UCA1 and microtubule-associated protein 1 light chain 3 (LC3) levels, and the elevated UCA1 was negatively correlated with the PKB/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway in 293T cells. Downregulation of UCA1 inhibited autophagy activation and cell proliferation, whereas the apoptosis was increased and the cell cycle was arrested in G2 stage. The next results showed that UCA1 was markedly upregulated in Caco-2 cells. Knockdown of UCA1 significantly decreased the LC3-II and autophagy-related gene 5 (ATG5) protein levels and resulted in an increase in p62 expression. Conversely, the autophagy activator rapamycin (RAPA) reversed the effects. Furthermore, downregulated UCA1 decreased Caco-2 cells population in the G1 phase and increased the cells number in G2 phage. The cell proliferation was inhibited, and apoptosis rate was promoted. More important, RAPA could also abrogate the changes induced by knockdown of UCA1. Collectively, these data demonstrated that downregulated UCA1 induced autophagy inhibition, resulting in suppressing cell proliferation and promoting apoptosis, which suggested that UCA1 might serve as a potential new oncogene to regulate CRC cells viability by modulating autophagy.

Uniparental Disomy of Chromosome 15 in Two Cases by Chromosome Microarray: A Lesson Worth Thinking.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurogenetic disorders caused by loss of function of the imprinted genes at 15q11q13. A 5-7 Mb paternal/maternal deletion of chromosomal region 15q11.2q13 is the major genetic cause of PWS/AS, but in a small group of patients, the PWS/AS phenotype can result from maternal/paternal uniparental disomy (UPD) of chromosome 15. Various mechanisms leading to UPD include gametic complementation, trisomy rescue, and compensatory UPD, which can be inferred from the pattern of uniparental heterodisomy (heteroUPD) or uniparental isodisomy (isoUPD). However, heteroUPD and isoUPD, especially mixed heteroUPD and isoUPD, are very rare in patients with PWS/AS. Here, we report 2 children with PWS/AS caused by mixed segmental heteroUPD 15 and isoUPD 15 which failed to be identified by chromosome microarray (CMA) but could be detected by other molecular genetic methods. The present report unravels the mechanism of mixed iso/heteroUPD 15 in PWS/AS and phenotype-genotype correlations. Moreover, our study suggests that CMA is prone to misdiagnosis for imprinting disorders such as PWS/AS, though it is considered a highly useful tool for copy number variations. As a result, other molecular detection methods, such as methylation analysis and STR marker analysis for UPD, should be supplementary used in this situation.

Chromosome r(3)(p25.3q29) in a Patient with Developmental Delay and Congenital Heart Defects: A Case Report and a Brief Literature Review.

Ring chromosome 3, r(3), is an extremely rare cytogenetic abnormality with clinical heterogeneity and only 12 cases reported in the literature. Here, we report a 1-year-old girl presenting distinctive facial features, developmental delay, and congenital heart defects with r(3) and a ∼10-Mb deletion of chromosome 3pterp25.3 (61,891-9,979,408) involving 42 known genes which was detected using G-banding karyotyping and CytoScan 750K-Array. The breakpoints in r(3) were mapped at 3p25.3 and 3q29. We also analyzed the available information on the clinical features of the reported cases with r(3) and 3p deletion syndrome in order to provide more valuable information of genotype-phenotype correlations. To our knowledge, this is the largest detected fragment described in r(3) cases and the second r(3) study using whole-genome microarray.

[Molecular cytogenetic analysis of a case with ring chromosome 3 syndrome].

OBJECTIVE: To investigate the genetic cause for a child with developmental delay and congenital heart disease through molecular cytogenetic analysis. METHODS: G-banded karyotyping and chromosomal microarray analysis (CMA) were performed for the patient and his parents. RESULTS: The proband's karyotype was detected as ring chromosome 3, and a 3q26.3-25.3 deletion encompassing 45 genes has been found with CMA. Testing of both parents was normal. CONCLUSION: Clinical phenotype of the patient with ring chromosome 3 mainly depends on the involved genes. It is necessary to combine CMA and karyotyping for the diagnosis of ring chromosome, as CMA can provide more accurate information for variations of the genome.

Thermally activated delayed fluorescence of fluorescein derivative for time-resolved and confocal fluorescence imaging.

Compared with fluorescence imaging utilizing fluorophores whose lifetimes are in the order of nanoseconds, time-resolved fluorescence microscopy has more advantages in monitoring target fluorescence. In this work, compound DCF-MPYM, which is based on a fluorescein derivative, showed long-lived luminescence (22.11 µs in deaerated ethanol) and was used in time-resolved fluorescence imaging in living cells. Both nanosecond time-resolved transient difference absorption spectra and time-correlated single-photon counting (TCSPC) were employed to explain the long lifetime of the compound, which is rare in pure organic fluorophores without rare earth metals and heavy atoms. A mechanism of thermally activated delayed fluorescence (TADF) that considers the long wavelength fluorescence, large Stokes shift, and long-lived triplet state of DCF-MPYM was proposed. The energy gap (ΔEST) of DCF-MPYM between the singlet and triplet state was determined to be 28.36 meV by the decay rate of DF as a function of temperature. The ΔE(ST) was small enough to allow efficient intersystem crossing (ISC) and reverse ISC, leading to efficient TADF at room temperature. The straightforward synthesis of DCF-MPYM and wide availability of its starting materials contribute to the excellent potential of the compound to replace luminescent lanthanide complexes in future time-resolved imaging technologies.

Self-assembly-integrated tumor targeting and electron transfer programming towards boosting tumor type I photodynamic therapy.

Type I photodynamic therapy (PDT) is attracting increasing interest as an effective solution to the poor prognosis of patients with hypoxic tumors. The development of functional type I photosensitizers is limited by a lack of feasible strategies to systematically modulate electron transfer (ET) in photosensitization. Herein, we present an easily accessible approach for the preparation of nanophotosensitizers with self-assembly-integrated tumor-targeting and ET programming towards boosting tumor type I PDT. Specifically, a dual functional amphiphile PS-02 was designed with a ligand (6-NS) that had the ability to not only target tumor cell marker carbonic anhydrase IX (CAIX) but also regulate the ET process for type I PDT. The amphiphile PS-02 tended to self-assemble into PS-02 nanoparticles (NPs), which exhibited a local "ET-cage effect" due to the electron-deficient nature of 6-NS. It is noteworthy that when PS-02 NPs selectively targeted the tumor cells, the CAIX binding enabled the uncaging of the inhibited ET process owing to the electron-rich characteristic of CAIX. Therefore, PS-02 NPs integrated tumor targeting and CAIX activation towards boosting type I PDT. As a proof of concept, the improved PDT performance of PS-02 NPs was demonstrated with tumor cells under hypoxic conditions and solid tumor tissue in mouse in vivo experiments. This work provides a practical paradigm to develop versatile type I PDT nano-photosensitizers by simply manipulating ET and easy self-assembling.

Dual-Responsive hollow mesoporous organosilicon nanocarriers for photodynamic therapy.

HYPOTHESIS: The nano-delivery platform, -SS-HMONs@MB@MnO2 nanoparticles (SMM NPs) loaded with methylene blue (MB) as photosensitizer have excellent photodynamic therapy (PDT) effect. The disulfide bond and MnO2 give the shell redox-responsive properties. SMM NPs consume glutathione (GSH) in tumor cells, reducing the scavenging of reactive oxygen species (ROS) by GSH and enhancing the PDT effect of MB. EXPERIMENTS: The GSH dual-responsive nano-delivery platform, was designed and constructed by using disulfide-doped hollow mesoporous organosilicon nanoparticles (-SS-HMONs) as intermediate responsive layer, loaded with MB as photosensitizer and coated with MnO2 as shells. The MB photosensitizer release and GSH response were characterized. The PDT effect of nanoparticles was evaluated. FINDINGS: The SMM NPs were uniform in size and well dispersed. The nanoparticles could react with GSH, leading to the decomposition of MnO2 shells and the breakage of disulfide bonds in -SS-HMONs, resulted in the release of MB photosensitizer. The cell experiment showed that SMM NPs had good ROS generating ability and PDT effect after being sucked by tumor cells, which could effectively kill tumor cells. However, in vivo experiments demonstrated that SMM NPs showed slight inhibition on tumor growth. The actual effect in animals was different from the effect in cells.