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1.
Analyst ; 149(12): 3288-3292, 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38808583

ABSTRACT

An acetal-linked dimeric phthalocyanine has been synthesised and immobilised on the surface of gold nanobipyramids. The resulting nanocomposite serves as a highly sensitive probe for intracellular pH through its acid-responsive fluorescence and surface-enhanced Raman scattering signals. The phthalocyanine units released in the acidic intracellular environment can also effectively eliminate the cancer cells upon light irradiation, rendering this simple fabricated nanosystem a bimodal and bifunctional theranostic agent.


Subject(s)
Gold , Indoles , Isoindoles , Photochemotherapy , Indoles/chemistry , Indoles/radiation effects , Gold/chemistry , Humans , Hydrogen-Ion Concentration , Photochemotherapy/methods , Metal Nanoparticles/chemistry , Metal Nanoparticles/radiation effects , Photosensitizing Agents/chemistry , Photosensitizing Agents/radiation effects , Spectrum Analysis, Raman/methods , Neoplasms , Dimerization , Cell Line, Tumor
2.
J Med Chem ; 64(23): 17455-17467, 2021 12 09.
Article in English | MEDLINE | ID: mdl-34846143

ABSTRACT

Two dual stimuli-activated photosensitizers were developed, in which two or three glutathione (GSH)-responsive 2,4-dinitrobenzenesulfonate (DNBS)-substituted zinc(II) phthalocyanine units were connected via one or two cathepsin B-cleavable Gly-Phe-Leu-Gly peptide linker(s). These dimeric and trimeric phthalocyanines were fully quenched in the native form due to the photoinduced electron transfer to the DNBS substituents and the self-quenching of the phthalocyanine units. In the presence of GSH and cathepsin B, or upon internalization into A549 and HepG2 cancer cells, these probes were activated through the release of free phthalocyanine units. The intracellular fluorescence intensity was increased upon post-incubation with GSH ester or reduced upon pre-treatment with a cathepsin B inhibitor. Upon light irradiation, these photosensitizers became highly cytotoxic with IC50 values of 0.21-0.39 µM. The photocytotoxicity was also dependent on the intracellular GSH and cathepsin B levels. The results showed that these conjugates could serve as smart photosensitizers for targeted photodynamic therapy.


Subject(s)
Antineoplastic Agents/pharmacology , Biopolymers/metabolism , Cathepsin B/metabolism , Glutathione/metabolism , Isoindoles/metabolism , Photochemotherapy , Photosensitizing Agents/pharmacology , Cell Line, Tumor , Fluorescence , Humans
3.
Curr Med Chem ; 28(21): 4283-4294, 2021.
Article in English | MEDLINE | ID: mdl-33292110

ABSTRACT

BACKGROUND: We report herein the synthesis of a novel dicationic boron dipyrromethene derivative (compound 3) which is symmetrically substituted with two trimethylammonium styryl groups. METHODS: The antibacterial photodynamic activity of compound 3 was determined against sixteen methicillin-resistant Staphylococcus aureus (MRSA) strains, including four ATCC type strains (ATCC 43300, ATCC BAA-42, ATCC BAA-43, and ATCC BAA-44), two mutant strains [AAC(6')-APH(2") and RN4220/pUL5054], and ten nonduplicate clinical strains of hospital- and community-associated MRSA. Upon light irradiation, the minimum bactericidal concentrations of compound 3 were in the range of 1.56-50 µM against all the sixteen MRSA strains. Interestingly, compound 3 was not only more active than an analogue in which the ammonium groups are not directly connected to the n-conjugated system (compound 4), but also showed significantly higher (p < 0.05) antibacterial potency than the clinically approved photosensitizer methylene blue. The skin irritation of compound 3 during topical application was tested on human 3-D skin constructs and proven to be non-irritant in vivo at concentrations below 1.250 mM. In the murine MRSA infected wound study, the colony forming unit reduction of compound 3 + PDT group showed significantly (p < 0.05) higher value (>2.5 log10) compared to other test groups except for the positive control. CONCLUSION: In conclusion, the present study provides a scientific basis for future development of compound 3 as a potent photosensitizer for photodynamic therapy for MRSA wound infection.


Subject(s)
Anti-Infective Agents , Methicillin-Resistant Staphylococcus aureus , Photochemotherapy , Animals , Anti-Bacterial Agents/pharmacology , Boron , Humans , Mice , Microbial Sensitivity Tests , Photosensitizing Agents/therapeutic use , Porphobilinogen/analogs & derivatives
4.
Acta Biomater ; 116: 329-343, 2020 10 15.
Article in English | MEDLINE | ID: mdl-32890751

ABSTRACT

By using an oil-in-water single emulsion method, a series of multifunctional hybrid nanoparticles (NPs) were prepared which consisted of a core of poly(lactic-co-glycolic acid) (PLGA) with a lipoid shell of n-hexadecylamine-substituted hyaluronic acid (HA), encapsulating a zinc(II) phthalocyanine-based photosensitizer (ZnPc). As determined by laser light scattering, these hybrid NPs labeled as ZnPc@PLGA-HA NPs possessed a hydrodynamic diameter of 280 nm and a surface charge of -30 mV, showing high stability in serum. The Q-band absorption of ZnPc exhibited a large red-shift from 674 nm for free ZnPc in dimethylsulfoxide to 832 nm for this nanosystem in water. Upon light irradiation at 808 nm, the encapsulated ZnPc induced a strong photothermal effect instead of photodynamic action, which is usually observed for ZnPc-containing NPs. The tumor-targeting effect of these NPs due to the HA coating was investigated against the human colorectal adenocarcinoma HT29 cells and human lung carcinoma A549 cells, both of which overexpress cluster determinant 44 (CD44) receptors, using the CD44-negative human normal hepatic LO2 cells as a negative control. The photothermal cell-killing effect of these NPs was significantly higher for the two CD44-positive cell lines than that for the negative control. Their in vivo photothermal efficacy was also examined on HT29 tumor-bearing nude mice. Upon irradiation, the NPs caused significant temperature increase at the tumor site and ablation of the tumor. The results showed that these multifunctional NPs could serve as an effective photothermal agent for targeted photothermal therapy. Statement of significance Phthalocyanines are well-known photosensitizers for photodynamic therapy. By encapsulating these molecules into various nanoplatforms, a range of multifunctional photosensitizing systems have been developed for cancer therapy. In this study, we have demonstrated that by careful selection of phthalocyanines and the nanocarriers, as well as the self-assembly and encapsulation methods, the encapsulated phthalocyanine molecules could switch the photoinduced action from photodynamic therapy to photothermal therapy as a result of the enhanced aggregation of the macrocyclic molecules in the nanoparticles. The unique packing of the molecules also resulted in a large red-shift of the Q-band absorption to 832 nm, facilitating the in vitro and in vivo photothermal treatment.


Subject(s)
Nanoparticles , Photochemotherapy , Animals , Cell Line, Tumor , Glycols , Hyaluronic Acid/pharmacology , Indoles , Isoindoles , Mice , Mice, Nude , Organometallic Compounds , Polylactic Acid-Polyglycolic Acid Copolymer , Zinc , Zinc Compounds
5.
Org Lett ; 22(18): 7098-7102, 2020 09 18.
Article in English | MEDLINE | ID: mdl-32806143

ABSTRACT

A phthalaldehyde-substituted phthalocyanine has been synthesized that can conjugate with a range of biomolecules, including peptides, monosaccharides, lipids, and DNAs, and be immobilized on the surface of bovine serum album nanoparticles and glass slides using the versatile and efficient phthalaldehyde-amine capture reactions. The light-induced cytotoxic effects of the latter two materials have also been examined against cancer cells and bacteria, respectively, showing that they are highly efficient photosensitizing systems for photodynamic therapy.

6.
Cell ; 182(3): 734-743.e5, 2020 08 06.
Article in English | MEDLINE | ID: mdl-32643603

ABSTRACT

COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >290,000 deaths as of May 15, 2020. It is critical that vaccines and therapeutics be developed very rapidly. Mice, the ideal animal for assessing such interventions, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells, and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and disease resolution in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis and to evaluate new therapies and vaccines.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/pathology , Coronavirus Infections/prevention & control , Disease Models, Animal , Pandemics/prevention & control , Pneumonia, Viral/pathology , Pneumonia, Viral/prevention & control , Vaccination , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/virology , Drug Evaluation, Preclinical/methods , Female , Humans , Interferon-gamma/genetics , Interferon-gamma/metabolism , Lung/pathology , Lung/virology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/metabolism , SARS-CoV-2 , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolism , Specific Pathogen-Free Organisms , Transduction, Genetic , Vero Cells , Viral Load , Virus Replication
7.
Emerg Microbes Infect ; 9(1): 1628-1637, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32619386

ABSTRACT

Antimicrobial photodynamic therapy (aPDT) is an innovative approach to combat multi-drug resistant bacteria. It is known that cationic Zn(II) phthalocyanines (ZnPc) are effective in mediating aPDT against methicillin-resistant Staphylococcus aureus (MRSA). Here we used ZnPc-based photosensitizer named ZnPcE previously reported by our research group to evaluate its aPDT efficacy against broad spectrum of clinically relevant MRSAs. Remarkably, in vitro anti-MRSA activity was achieved using near-infrared (NIR, >610 nm) light with minimal bactericidal concentrations ranging <0.019-0.156 µM against the panel of MRSAs. ZnPcE was not only significantly (p < .05) more potent than methylene blue, which is a clinically approved photosensitizer but also demonstrated low cytotoxicity against human fibroblasts cell line (Hs-27) and human immortalized keratinocytes cell line (HaCaT). The toxicity was further evaluated on human 3-D skin constructs and found ZnPcE did not manifest in vivo skin irritation at ≤7.8 µM concentration. In the murine MRSA wound model, ZnPcE with PDT group demonstrated > 4 log10 CFU reduction and the value is significantly higher (p < .05) than all test groups except positive control. To conclude, results of present study provide a scientific basis for future clinical evaluation of ZnPcE-PDT on MRSA wound infection.


Subject(s)
Indoles/administration & dosage , Methicillin-Resistant Staphylococcus aureus/drug effects , Organometallic Compounds/administration & dosage , Photochemotherapy/methods , Photosensitizing Agents/administration & dosage , Staphylococcal Infections/drug therapy , Administration, Topical , Animals , Cell Line , Disease Models, Animal , Humans , Indoles/chemistry , Indoles/pharmacology , Isoindoles , Male , Methicillin-Resistant Staphylococcus aureus/pathogenicity , Mice , Microbial Sensitivity Tests , Molecular Structure , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Zinc Compounds
8.
Biomedicines ; 8(6)2020 May 29.
Article in English | MEDLINE | ID: mdl-32485946

ABSTRACT

A series of cationic boron dipyrromethene (BODIPY) derivatives were synthesized and characterized with various spectroscopic methods. Having the ability to generate singlet oxygen upon irradiation, these compounds could potentially serve as photosensitizers for antimicrobial photodynamic therapy. Of the five BODIPYs being examined, the dicationic aza-BODIPY analogue (compound 5) demonstrated the highest potency against a broad spectrum of clinically relevant methicillin-resistant Staphylococcus aureus (MRSA), including four ATCC-type strains (ATCC 43300, ATCC BAA-42, ATCC BAA-43, and ATCC BAA-44), two strains carrying specific antibiotic resistance mechanisms [-AAC(6')-APH(2") and RN4220/pUL5054], and ten non-duplicate clinical strains from hospital- and community-associated MRSAs of the important clonal types ST239, ST30, and ST59, which have previously been documented to be prevalent in Hong Kong and its neighboring countries. The in vitro anti-MRSA activity of compound 5 was achieved upon irradiation with near-infrared light (>610 nm) with minimal bactericidal concentrations (MBCs) ranging from 12.5 to 25 µM against the whole panel of MRSAs, except the hospital-associated MRSAs for which the MBCs were in the range of 50-100 µM. Compound 5 was significantly (p < 0.05) more potent than methylene blue, which is a clinically approved photosensitizer, indicating that it is a promising antimicrobial agent that is worthy of further investigation.

9.
J Mater Chem B ; 8(20): 4460-4468, 2020 05 28.
Article in English | MEDLINE | ID: mdl-32369087

ABSTRACT

A combined stimulus-responsive photosensitiser and drug release system based on mesoporous silica nanoparticles was prepared. This nanoplatform encapsulated molecules of zinc(ii) phthalocyanine substituted with a glutathione-cleavable 2,4-dinitrobenzenesulfonate quencher and doxorubicin linked via a singlet-oxygen-cleavable 9,10-dialkoxyanthracene linker. In the presence of glutathione (in mM range) and upon irradiation (λ > 610 nm), the phthalocyanine units were activated by detaching from the quenching component to emit fluorescence and generate singlet oxygen. The latter subsequently cleaved the 9,10-dialkoxyanthracene linker to trigger the release of a doxorubicin derivative. The glutathione- and light-controlled activation and drug-release processes on this nanoplatform were demonstrated in phosphate buffered saline. The activation in fluorescence emission by intracellular thiols was also shown inside HepG2 human hepatocellular carcinoma cells. Upon irradiation, the nanosystem exhibited high cytotoxicity due to the photodynamic effect of the activated phthalocyanine units, but the cytotoxic effect of the released Dox moieties was not notable probably due to their reduced cytotoxicity as a result of the pendant substituent and the low drug loading in the nanoparticles.


Subject(s)
Delayed-Action Preparations/metabolism , Glutathione/metabolism , Indoles/metabolism , Nanoparticles/metabolism , Organometallic Compounds/metabolism , Silicon Dioxide/metabolism , Singlet Oxygen/metabolism , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/pharmacokinetics , Antibiotics, Antineoplastic/pharmacology , Benzenesulfonates/metabolism , Doxorubicin/administration & dosage , Doxorubicin/pharmacokinetics , Doxorubicin/pharmacology , Drug Liberation , Hep G2 Cells , Humans , Isoindoles , Light , Porosity , Zinc Compounds
10.
ACS Appl Bio Mater ; 3(9): 5463-5473, 2020 Sep 21.
Article in English | MEDLINE | ID: mdl-35021785

ABSTRACT

Two zinc(II) phthalocyanines (ZnPcs) substituted with a short peptide (Gly-Gly-Lys) with either a carboxyl or a carbamoyl group at the C-terminus and an appended biotin moiety were prepared and characterized. They could self-assemble into spherical nanoparticles, namely ZnPc-GGK(B)-COOH NP and ZnPc-GGK(B)-CONH2 NP, through noncovalent interactions, which encapsulated the hydrophobic ZnPc units in the core and exposed the biotin moieties on the surface. The zeta potential of ZnPc-GGK(B)-COOH NP in water was found to be -28 mV, whereas that of ZnPc-GGK(B)-CONH2 NP was in opposite sign (+15 mV), reflecting the different functionality at the C-terminus, which also greatly affected the stability of the self-assembled nanoparticles. The targeting effect of ZnPc-GGK(B)-COOH NP was examined against human hepatocellular carcinoma HepG2 cells, which overexpress biotin receptor, and Chinese Hamster Ovary CHO-K1 cells, which have a low expression of biotin receptor. This nanosystem was also coassembled with the chemotherapeutic doxorubicin (DOX) to form ZnPc-GGK(B)-COOH/DOX NP. Both ZnPc-GGK(B)-COOH NP and ZnPc-GGK(B)-COOH/DOX NP could induce photocytotoxicity and apoptosis on HepG2 cells with an IC50 value of 1.48 and 0.49 µM ZnPc, respectively. For the latter nanosystem, the ZnPc and DOX components induced cytotoxicity in a synergistic manner. The photodynamic and chemotherapeutic effects of these two nanosystems were also examined on nude mice bearing a human colorectal adenocarcinoma HT29 tumor. The ZnPc-GGK(B)-COOH/DOX NP exhibited a stronger tumor inhibition effect upon irradiation, demonstrating the presence of dual chemo-photodynamic therapeutic actions.

11.
Chem Commun (Camb) ; 56(7): 1078-1081, 2020 Jan 23.
Article in English | MEDLINE | ID: mdl-31872834

ABSTRACT

A boron dipyrromethene based photosensitiser substituted with a 1,2,4,5-tetrazine moiety has been prepared of which the photoactivity can be activated upon an inverse-electron-demand Diels-Alder reaction with trans-cyclooctene derivatives. By using a biotin-conjugated trans-cyclooctene to tag the biotin-receptor-positive HeLa cells, this photosensitiser exhibits site-specific activation through cycloaddition, leading to high photocytotoxicity.


Subject(s)
Boron Compounds/pharmacology , Heterocyclic Compounds, 1-Ring/pharmacology , Photosensitizing Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/radiation effects , Biotin/analogs & derivatives , Biotin/chemical synthesis , Biotin/pharmacology , Boron Compounds/chemical synthesis , Boron Compounds/radiation effects , Cell Line, Tumor , Cycloaddition Reaction , Cyclooctanes/chemical synthesis , Cyclooctanes/chemistry , Cyclooctanes/pharmacology , Heterocyclic Compounds, 1-Ring/chemical synthesis , Heterocyclic Compounds, 1-Ring/radiation effects , Humans , Light , Photochemotherapy , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/radiation effects , Singlet Oxygen/metabolism
12.
Chem Commun (Camb) ; 55(90): 13518-13521, 2019 Nov 07.
Article in English | MEDLINE | ID: mdl-31608902
13.
Eur J Med Chem ; 179: 828-836, 2019 Oct 01.
Article in English | MEDLINE | ID: mdl-31295715

ABSTRACT

A ferrocenyl boron dipyrromethene (BODIPY) has been developed and utilized as a dark quencher to construct a cathepsin B-responsive fluorescent probe and photosensitizer. The smart fluorescent probe and photosensitizer (Pc-FcQ) contains a zinc(II) phthalocyanine as the fluorescent and photosensitizing unit which is conjugated to the ferrocenyl BODIPY dark quencher via a cathepsin B-cleavable peptide substrate [Gly-Phe-Leu-Gly-Lys]. The photosensitizing properties of Pc-FcQ, including fluorescence and singlet oxygen generation, are significantly quenched through energy transfer to the BODIPY unit and subsequently by the photoinduced electron transfer from the nearby ferrocenyl moiety. Upon exposure of cathepsin B in human hepatocellular carcinoma HepG cells, the fluorescence emission of Pc-FcQ could be restored, indicating the cleavage of the peptide substrate and the separation of the phthalocyanine and ferrocenyl BODIPY unit. However, the intracellular fluorescence intensity of Pc-FcQ was largely diminished after the cells were pre-treated with cathepsin B inhibitor. Its intracellular fluorescence intensity was comparable to that of the control compound in which the peptide substrate was replaced by the non-cleavable one [Gly-Gly-Gly-Gly-Lys]. The singlet oxygen generation of Pc-FcQ was also examined in HepG2 cells as reflected by the cytotoxicity assay. The Pc-FcQ exhibited higher potency when compared with the non-cleavable analogue due to the cleavage of peptide substrate and the detachment of the BODIPY dark quencher from the phthalocyanine. The activation of the Pc-FcQ was also demonstrated in tumor-bearing nude mice. After intratumoral injection of Pc-FcQ, the fluorescence intensity at the tumor region increased gradually over 10 h as a result of the detachment of the dark quencher upon the action of cathepsin B. All the results suggest that this ferrocenyl BODIPY could serve as an efficient dark quencher and the resulting Pc-FcQ could act as the cathepsin B-responsive fluorescent probe and activatable photosensitizer.


Subject(s)
Boron/pharmacology , Cathepsin B/pharmacology , Ferrous Compounds/pharmacology , Fluorescent Dyes/pharmacology , Photosensitizing Agents/pharmacology , Porphobilinogen/analogs & derivatives , Animals , Boron/chemistry , Cathepsin B/chemistry , Cell Survival/drug effects , Dose-Response Relationship, Drug , Female , Ferrous Compounds/chemistry , Fluorescent Dyes/chemistry , HT29 Cells , Hep G2 Cells , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Optical Imaging , Photosensitizing Agents/chemistry , Porphobilinogen/chemistry , Porphobilinogen/pharmacology , Structure-Activity Relationship , Tumor Cells, Cultured
14.
Eur J Med Chem ; 174: 56-65, 2019 Jul 15.
Article in English | MEDLINE | ID: mdl-31029944

ABSTRACT

A zinc(II) phthalocyanine substituted with three 2,4-dinitrobenzenesulfonate (DNBS) groups and a cyclic arginine-glycine-aspartic acid (cRGDfK) moiety was prepared and characterized. With three strongly electron-withdrawing DNBS groups, this compound was fully quenched in terms of fluorescence emission and singlet oxygen generation in N,N-dimethylformamide and phosphate buffered saline due to the strong photoinduced electron transfer effect. In the presence of glutathione (GSH), which is the most abundant intracellular thiol particularly in tumor cells, the DNBS moieties were cleaved, thereby restoring these photoactivities and making the conjugate as a GSH-activated photosensitizer. Being a well-known integrin antagonist, the cyclic RGD peptide sequence could enhance the localization of the conjugate in integrin-upregulated tumor cells. As shown by confocal laser scanning microscopy and flow cytometry, the intracellular fluorescence intensity of the conjugate was significantly higher in the integrin-positive A549 and MDA-MB-231 cells than in the integrin-negative MCF-7 and HEK293 cells. The photocytotoxicity of the conjugate against MDA-MB-231 cells was also higher than that toward MCF-7 cells. The results suggest that this dual-functional photosensitizer is a promising candidate for targeted photodynamic therapy.


Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Glutathione/metabolism , Indoles/pharmacology , Peptides, Cyclic/pharmacology , Photosensitizing Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Antineoplastic Agents/radiation effects , Benzenesulfonates/chemical synthesis , Benzenesulfonates/metabolism , Benzenesulfonates/pharmacology , Benzenesulfonates/radiation effects , Cell Line, Tumor , Coordination Complexes/chemical synthesis , Coordination Complexes/metabolism , Coordination Complexes/radiation effects , Fluorescence , HEK293 Cells , Humans , Indoles/chemical synthesis , Indoles/metabolism , Indoles/radiation effects , Integrins/metabolism , Light , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/metabolism , Peptides, Cyclic/radiation effects , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/metabolism , Photosensitizing Agents/radiation effects , Singlet Oxygen/metabolism , Zinc/chemistry
15.
RSC Adv ; 9(36): 20652-20662, 2019 Jul 01.
Article in English | MEDLINE | ID: mdl-35515550

ABSTRACT

A peptide-conjugated zinc(ii) phthalocyanine containing the epidermal growth factor receptor-targeted heptapeptide QRHKPRE has been prepared. The conjugate labelled as ZnPc-QRH* can selectively bind to the cell membrane of HT29 human colorectal adenocarcinoma cells in 10 min followed by internalisation upon prolonged incubation via receptor-mediated endocytosis, leading to localisation in lysosomes eventually. By manipulating the incubation time, the subcellular localisation of the conjugate can be varied and the cell-death pathways induced upon irradiation can also be altered. It has been found that photosensitisation initiated at the cell membrane and in the lysosomes would trigger cell death mainly through necrosis and apoptosis respectively. Intravenous administration of the conjugate into HT29 tumour-bearing nude mice resulted in higher accumulation in the tumour than in most major organs. The selective binding of this conjugate to tumour has also been demonstrated by comparing the results with those of the analogue with a scrambled peptide sequence (EPRQRHK). The overall results indicate that ZnPc-QRH* is a promising EGFR-targeted photosensitiser for photodynamic therapy.

16.
Chemistry ; 24(22): 5779-5789, 2018 Apr 17.
Article in English | MEDLINE | ID: mdl-29356199

ABSTRACT

A series of disulfide-linked dendritic phthalocyanines were synthesized by using the CuI -catalyzed alkyne-azide cycloaddition reaction as the key step. Whereas these compounds were essentially nonaggregated in N,N-dimethylformamide, they were stacked in citrate solution (pH 7.4, with 1 % Cremophor EL), as shown by the broad appearance of their Q-band absorption. Having two-to-six zinc(II) phthalocyanine units in a molecule, these compounds were significantly self-quenched, particularly in citrate solution. Both the fluorescence intensity and singlet-oxygen generation efficiency were significantly lower than those of the monomeric counterparts, and the self-quenching efficiency increased as the number of phthalocyanine units increased. Upon interaction with 5 mm glutathione (GSH) in citrate solution, the fluorescence intensity of these compounds increased as a result of cleavage of the disulfide linkages and separation of the phthalocyanine units, which thereby reduced the self-quenching effect. The "on/off" ratios were found to be 7, 18, 23, and 21 for the dimeric (PC2), trimeric (PC3), tetrameric (PC4), and hexameric (PC6) systems, respectively. GSH also enhanced the fluorescence emission inside human colon adenocarcinoma HT29 cells and promoted the formation of singlet oxygen of these compounds. Upon irradiation, their half maximal inhibitory concentration (IC50 ) values were found to be in the range of 0.18 to 0.38 µm. Finally, the biodistribution and activation of PC2 and PC6 were also examined in HT29 tumor-bearing nude mice. For both compounds, the fluorescence intensity per unit area at the tumor was found to grow gradually during the first 24 h. Whereas the intensity then dropped for PC2, the intensity for PC6 remained steady over the following 6 d, which might have been a result of the enhanced permeability and retention effect arising from the larger molecular mass of the hexameric system.


Subject(s)
Disulfides/chemistry , Glutathione/chemistry , Indoles/chemical synthesis , Photosensitizing Agents/chemical synthesis , Animals , Cycloaddition Reaction , Dimethylformamide/chemistry , Fluorescence , Glutathione/metabolism , HT29 Cells , Humans , Hydrogen-Ion Concentration , Indoles/chemistry , Isoindoles , Mice, Nude , Organometallic Compounds/chemistry , Photochemotherapy , Photosensitizing Agents/chemistry , Photosensitizing Agents/therapeutic use , Singlet Oxygen/chemistry , Structure-Activity Relationship , Tissue Distribution , Zinc
17.
Chemistry ; 23(65): 16505-16515, 2017 Nov 21.
Article in English | MEDLINE | ID: mdl-28771861

ABSTRACT

Doxorubicin (Dox) was conjugated to a zinc(II) phthalocyanine (ZnPc) through an acid-cleavable hydrazone linker. This azido-containing conjugate was then anchored to the nanochannels of an alkyne-modified mesoporous silica nanoparticle (MSN) system via copper(I)-catalyzed azide-alkyne cycloaddition. An analogous nanosystem was also prepared by immobilization of a hydrazine-substituted ZnPc to the MSN followed by coupling with Dox. The release of Dox under acidic conditions was studied in phosphate-buffered saline. After internalization into human hepatocellular carcinoma HepG2 cells, these nanoparticles showed fluorescence not only for ZnPc, but also for Dox, suggesting that release of Dox was triggered by the acidic intracellular environment. The chemocytotoxic Dox together with singlet oxygen generated upon irradiation on the encapsulated ZnPc in these MSNs could kill the cells effectively. A synergistic cytotoxicity was suggested by a less-than-unity combination index. These nanoparticles function as both nanophotosensitizers for photodynamic therapy and as nanoplatforms for pH-controlled drug release.


Subject(s)
Doxorubicin/chemistry , Drug Carriers/chemistry , Indoles/chemistry , Nanoparticles/chemistry , Organometallic Compounds/chemistry , Silicon Dioxide/chemistry , Alkynes/chemistry , Cycloaddition Reaction , Doxorubicin/metabolism , Drug Liberation , Dynamic Light Scattering , Hep G2 Cells , Humans , Hydrogen-Ion Concentration , Isoindoles , Light , Microscopy, Confocal , Microscopy, Electron, Transmission , Photochemotherapy , Porosity , Singlet Oxygen/metabolism , Zinc Compounds
18.
ACS Appl Mater Interfaces ; 9(28): 23487-23496, 2017 Jul 19.
Article in English | MEDLINE | ID: mdl-28661122

ABSTRACT

An acid-cleavable acetal-linked zinc(II) phthalocyanine dimer with an azido terminal group (cPc) was prepared and conjugated to alkyne-modified mesoporous silica nanoparticles via copper(I)-catalyzed alkyne-azide cycloaddition reaction. For comparison, an amine-linked analogue (nPc) was also prepared as a non-acid-cleavable counterpart. These dimeric phthalocyanines were significantly self-quenched due to the close proximity of the phthalocyanine units inside the mesopores, resulting in much weaker fluorescence emission and singlet oxygen generation, both in N,N-dimethylformamide and in phosphate-buffered saline (PBS), compared with the free molecular counterparts. Under acidic conditions in PBS, the cPc-encapsulated nanosystem was activated in terms of fluorescence emission and singlet oxygen production. After internalization into human colon adenocarcinoma HT29 cells, it exhibited much higher intracellular fluorescence and photocytotoxicity compared to the nanosystem entrapped with nPc. The activation of this nanosystem was also demonstrated in tumor-bearing nude mice. The intratumoral fluorescence intensity increased gradually over 24 h, while for the nPc counterpart the fluorescence remained very weak. The results suggest that this nanosystem serves as a promising activatable nanophotosensitizing agent for photodynamic therapy.


Subject(s)
Nanoparticles , Animals , Humans , Hydrogen-Ion Concentration , Indoles , Isoindoles , Mice , Mice, Nude , Organometallic Compounds , Photochemotherapy , Photosensitizing Agents , Silicon Dioxide , Zinc Compounds
19.
Dalton Trans ; 45(44): 17798-17806, 2016 Nov 28.
Article in English | MEDLINE | ID: mdl-27774548

ABSTRACT

An efficient ferrocenyl BODIPY based dark quencher has been developed and employed to construct a FRET-based fluorescent probe that contains a biotin moiety as a potential directing ligand for cancer cells and a glutathione-cleavable disulfide linker connecting the quencher and a distyryl BODIPY fluorophore. This molecular probe is deactivated in the native form through FRET followed by intramolecular charge transfer due to the ferrocenyl unit. However, upon interaction with glutathione in phosphate buffered saline and inside cancer cells, the fluorescence emission is significantly increased due to detachment of the fluorophore from the quencher. As shown by flow cytometry, this probe also exhibits preferential uptake by the biotin-receptor-expressing A549 human lung adenocarcinoma epithelial cells over the Chinese hamster ovary CHO-K1 cells used as the negative control. On the basis that both biotin receptor and GSH level are often overexpressed or elevated in cancer cells, this dual functional fluorescent probe serves as a promising agent for cancer imaging.


Subject(s)
Biotin/chemistry , Boron Compounds/chemistry , Fluorescent Dyes/chemistry , Glutathione/analysis , A549 Cells , Animals , CHO Cells , Cricetulus , Ferrous Compounds/chemistry , Fluorescence Resonance Energy Transfer , Humans , Neoplasms/chemistry
20.
Clin Gastroenterol Hepatol ; 13(5): 867-73, 2015 May.
Article in English | MEDLINE | ID: mdl-25445765

ABSTRACT

BACKGROUND & AIMS: Patients with suspected gastroesophageal reflux disease (GERD) often are treated empirically with proton pump inhibitors (PPIs). Patients whose symptoms are not reduced during the PPI trial are referred for further tests. We investigated whether patients referred for the evaluation of reflux symptoms had GERD. We also aimed to categorize patients with a poor response to PPIs into groups with hypersensitive esophagus or functional heartburn. METHODS: We performed a retrospective study, searching a clinical database of patients referred for GERD testing from 2006 through 2011. We collected data on all patients who underwent upper endoscopy, esophageal manometry, and 24-hour pH-impedance monitoring, and were off PPIs for at least 1 week. Evidence of GERD was determined by an abnormal upper endoscopy or 24-hour pH-impedance monitoring. Further categorization was determined by impedance results and the symptom association probability index. RESULTS: We identified 221 patients (mean age, 47.6 ± 13.3 y; 56% male; 61% Caucasians); 97% previously had been prescribed PPIs, before they were tested. The patients had erosive esophagitis (n = 21; 10%), nonerosive reflux disease with increased pH (n = 61; 27%), nonerosive reflux disease with abnormal impedance (n = 18; 8%), hypersensitive esophagus (n = 30; 14%), functional heartburn (n = 18; 8%), functional disorders other than heartburn (n = 30; 14%), and undetermined disorders (n = 43; 19%). CONCLUSIONS: In a retrospective analysis of 221 patients, roughly half of the patients referred for testing did not have evidence of GERD. Further categorization of patients can help guide diagnosis and management.


Subject(s)
Gastroesophageal Reflux/diagnosis , Gastroesophageal Reflux/pathology , Proton Pump Inhibitors/therapeutic use , Adult , Electric Impedance , Female , Humans , Hydrogen-Ion Concentration , Male , Middle Aged , Retrospective Studies , Treatment Failure
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