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1.
Sci Adv ; 6(10): eaaz0575, 2020 03.
Article in English | MEDLINE | ID: mdl-32181355

ABSTRACT

Although photodynamic therapy (PDT) has been clinically applied tumor hypoxia still greatly restricts the performance of this oxygen-dependent oncological treatment. The delivery of oxygen donors to tumor may produce excessive reactive oxygen species (ROS) and damage the peripheral tissues. Herein, we developed a strategy to solve the hypoxia issue by enhancing the lethality of ROS. Before PDT, the ROS-defensing system of the cancer cells was obstructed by an inhibitor to MTH1, which is a key for the remediation of ROS-caused DNA damage. As a result, both nuclei and mitochondrial DNA damages were increased, remarkably promoting cellular apoptosis. The therapeutic results demonstrated that the performance of PDT can be improved by the MTH1 inhibitor, leading to efficient cancer cell killing effect in the hypoxic tumor. This strategy makes better use of the limited oxygen, holding the promise to achieve satisfactory therapeutic effect by PDT without generating redundant cytotoxic ROS.


Subject(s)
Antineoplastic Agents/pharmacology , DNA Repair Enzymes/genetics , DNA, Neoplasm/genetics , Enzyme Inhibitors/pharmacology , Melanoma, Experimental/drug therapy , Phosphoric Monoester Hydrolases/genetics , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Chlorophyllides , DNA Repair/drug effects , DNA Repair/genetics , DNA Repair Enzymes/antagonists & inhibitors , DNA Repair Enzymes/metabolism , DNA, Neoplasm/antagonists & inhibitors , DNA, Neoplasm/metabolism , Drug Carriers/administration & dosage , Drug Carriers/chemical synthesis , Drug Compounding/methods , Enzyme Inhibitors/chemistry , Female , Gene Expression , HCT116 Cells , HeLa Cells , Humans , Light , MCF-7 Cells , Melanoma, Experimental/enzymology , Melanoma, Experimental/pathology , Mice, Nude , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Phosphoric Monoester Hydrolases/antagonists & inhibitors , Phosphoric Monoester Hydrolases/metabolism , Photochemotherapy/methods , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacokinetics , Porphyrins/chemistry , Porphyrins/pharmacokinetics , Pyrimidines/chemistry , Reactive Oxygen Species/metabolism , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
2.
Angew Chem Int Ed Engl ; 58(23): 7641-7646, 2019 06 03.
Article in English | MEDLINE | ID: mdl-30980463

ABSTRACT

The co-delivery of photosensitizers with prodrugs sensitive to reactive oxygen species (ROS) for light-triggered ROS generation and cascaded prodrug activation has drawn tremendous attention. However, the absence of a feasible method to deliver the two components at a precise ratio has impaired the application potential. Herein, we report an efficient method to produce a nanosized platform for the delivery of an optimized ratio of the two components by the means of host-guest strategy for maximizing the combination therapy efficacy of cancer treatment. The key features of this host-guest strategy for the combination therapy are that the ratio between photosensitizer and ROS-sensitive prodrug can be easily tuned, near-infrared (NIR) irradiation can sensitize the photosensitizer and activate the paclitaxel prodrug for its release, and the accumulation process can be tracked by NIR imaging to maximize the efficacy of photodynamic and chemotherapy.


Subject(s)
Paclitaxel/pharmacology , Photochemotherapy/methods , Photosensitizing Agents/administration & dosage , Phototherapy/methods , Prodrugs/pharmacology , Reactive Oxygen Species/metabolism , Uterine Cervical Neoplasms/therapy , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Cell Proliferation , Combined Modality Therapy , Drug Delivery Systems , Female , Humans , Infrared Rays , Mice , Mice, Nude , Prodrugs/chemistry , Tumor Cells, Cultured , Uterine Cervical Neoplasms/pathology , Xenograft Model Antitumor Assays
3.
ACS Nano ; 12(12): 11936-11948, 2018 12 26.
Article in English | MEDLINE | ID: mdl-30444343

ABSTRACT

Topical treatment using photodynamic therapy (PDT) for many types of skin cancers has largely been limited by the inability of existing photosensitizers to penetrate into the deep skin tissue. To overcome these problems, we developed a mesoporous nanovehicle with dual loading of photosensitizers and clinically relevant drugs for combination therapy, while utilizing microneedle technology to facilitate their penetration into deep skin tissue. Sub-50 nm photodynamically active mesoporous organosilica nanoparticles were synthesized with photosensitizers covalently bonded to the silica matrix, which dramatically increased the quantum yield and photostability of these photosensitizers. The mesopores of the nanoparticles were further loaded with small-molecule inhibitors, i. e., dabrafenib and trametinib, that target the hyperactive mitogen-activated protein kinase (MAPK) pathway for melanoma treatment. As-prepared empty nanovehicle was cytocompatible with normal skin cells in the dark, while NIR-irradiated drug-loaded nanovehicle showed a synergistic killing effect on skin cancer cells mainly through reactive oxygen species and caspase-activated apoptosis. The nanovehicle could significantly inhibit the proliferation of tumor cells in a 3D spheroid model in vitro. Porcine skin fluorescence imaging demonstrated that microneedles could facilitate the penetration of nanovehicle across the epidermis layer of skin to reach deep-seated melanoma sites. Tumor regression studies in a xenografted melanoma mouse model confirmed superior therapeutic efficacy of the nanovehicle through combinational PDT and targeted therapy.


Subject(s)
Antineoplastic Agents/chemistry , Melanoma/therapy , Nanostructures/chemistry , Photosensitizing Agents/chemistry , Skin Neoplasms/therapy , Administration, Topical , Animals , Antineoplastic Agents/administration & dosage , Apoptosis/drug effects , Cell Line, Tumor , Combined Modality Therapy , Drug Delivery Systems , Female , Heterografts , Humans , Imidazoles/administration & dosage , Imidazoles/chemistry , Indoles/chemistry , Isoindoles , Mice, Nude , Needles , Oxidative Stress , Oximes/administration & dosage , Oximes/chemistry , Photochemotherapy/methods , Pyridones/administration & dosage , Pyridones/chemistry , Pyrimidinones/administration & dosage , Pyrimidinones/chemistry , Silicon Dioxide/chemistry
4.
ACS Appl Mater Interfaces ; 10(19): 16344-16351, 2018 May 16.
Article in English | MEDLINE | ID: mdl-29697957

ABSTRACT

Achieving an integrated system for combinational therapy of cancer with enhanced efficacy is always a challenge. A multifunctional system (CCeT nanoparticles (NPs)) for a synergistic photodynamic and photothermal cancer therapy was successfully developed. This system is composed of Cu2- xS nanoclusters functionalized with chlorin e6 (Ce6)-conjugated branched polyethylenimine (PEI-Ce6) and mitochondria-targeting 3-(carboxypropyl)triphenylphosphonium bromide (TPP-COOH). The colocalization of the resulted CCeT NPs inside the mitochondria of cancer cells was proven. The CCeT NPs exhibited significant photodynamic therapy (PDT) efficacy due to efficient singlet oxygen (1O2) generation triggered by a 630 nm laser. This system also showed excellent photothermal conversion capability upon the irradiation of 808 nm laser for photothermal therapy (PTT). In particular, the platform achieved nearly 100% inhibitory rate of the tumor growth in vivo through combinational PDT and PTT. Thus, the CCeT NPs could efficiently inhibit the tumor growth in vitro and in vivo by combinational PDT and PTT, offering synergistic therapeutic efficiency as compared to PTT or PDT alone.


Subject(s)
Nanoparticles , Chlorophyllides , Copper , Photochemotherapy , Photosensitizing Agents , Polyethyleneimine , Porphyrins
5.
Adv Sci (Weinh) ; 5(1): 1700552, 2018 01.
Article in English | MEDLINE | ID: mdl-29375976

ABSTRACT

Manipulating the property transfer in nanosystems is a challenging task since it requires switchable molecular packing such as separate aggregation (self-sorting) or synergistic aggregation (coassembly). Herein, a unique manipulation of self-sorting/coassembly aggregation and the observation of switchable stimulus-responsiveness transfer in a two component self-assembly system are reported. Two building blocks bearing the same cholesterol group give versatile topological structures in polar and nonpolar solvents. One building block (cholesterol conjugated cynanostilbene, CCS) consists of cholesterol conjugated with a cynanostilbene unit, and the other one (C10CN) is comprised of cholesterol connected with a naphthalimide group having a flexible long alkyl chain. Their assemblies including gel, crystalline plates, and vesicles are obtained. In gel and crystalline plate phases, the self-sorting behavior dominates, while synergistic coassembly occurs in vesicle phase. Since CCS having the cyanostilbene group can respond to the light irradiation, it undergoes light-induced chiral amplification. C10CN is thermally responsive, whereby its supramolecular chirality is inversed upon heating. In coassembled vesicles, it is interestingly observed that their responsiveness can be transferred by each other, i.e., the C10CN segment is sensitive to the light irradiation, while CCS is thermoresponsive. This unprecedented behavior of the property transfer may shine a light to the precise fabrication of smart materials.

6.
ACS Appl Mater Interfaces ; 9(33): 27553-27562, 2017 Aug 23.
Article in English | MEDLINE | ID: mdl-28749655

ABSTRACT

The integration of chemotherapy and photodynamic therapy (PDT) in a single delivery system is highly desirable for enhancing anticancer therapeutic efficacy. Herein, two cyclometalated Ir(III) complex-constructed micelles FIr-1 and FIr-2 were demonstrated for glutathione (GSH) activated targeted chemotherapy and PDT. The cyclometalated Ir(III) complexes were prepared by conjugating phosphorescent Ir(III) compounds with chemotherapeutic drug camptothecin (CPT) through GSH responsive disulfide bond linkages, and the Ir(III) complexes were then assembled with amphiphilic surfactant pluronic F127 via noncovalent encapsulation to afford micelles. The surfaces of the micelles were further decorated with folic acid as a targeting group. The micelles showed intense fluorescence that renders them with excellent real-time imaging capability. The release of free anticancer drug CPT from the micelles was realized through GSH-activated disulfide bond cleavage in tumor cells. In addition, the micelles were capable of generating singlet oxygen used for PDT upon visible light irradiation. On account of having folic acid targeting ligand, the micelles displayed greater cellular accumulation in folate receptor (FR) overexpressed HeLa cells than FR low-expressed MCF-7 cells, leading to selective cancer cell killing effect. As compared with solo therapeutic systems, the micelles with targeted combinational chemotherapy and PDT presented superior potency and efficacy in killing tumor cells at a low dosage. On the basis of these findings, the multifunctional micelles could serve as a versatile theranostic nanoplatform for cancer cell targeted imaging and combinational therapy.


Subject(s)
Iridium/chemistry , Cell Line, Tumor , Glutathione , Humans , Micelles , Photochemotherapy
7.
ACS Appl Mater Interfaces ; 9(28): 23536-23543, 2017 Jul 19.
Article in English | MEDLINE | ID: mdl-28657709

ABSTRACT

The construction of prodrugs has been a popular strategy to overcome the limitations of chemotherapeutic drugs. However, complicated synthesis procedures and laborious purification steps make the fabrication of amphiphilic prodrugs rather difficult. By harnessing the concept of host-guest interaction, we designed and prepared a supra-amphiphile consisting of a dendritic cyclodextrin host and an adamantane/naphthalimide-modified camptothecin guest through glutathione-responsive disulfide linkage. This host-guest complex could self-assemble in aqueous solution to give nanosized vesicles. When the disulfide bond in adamantane/naphthalimide-modified camptothecin was cleaved by glutathione, the fluorescence of the freed adamantane/naphthalimide unit showed a significant red shift with enhanced intensity. Such glutathione-responsive fluorescence change allows for intracellular imaging and simultaneous monitoring of drug release in real time. On account of abundant positively charged amine groups on the supramolecular vesicle surface, siRNA (siPlK1) could be efficiently loaded on the vesicle. The gel retardation and fluorescence experiments proved that the siPlK1 was successfully bonded to the supramolecular vesicle. The vesicle with dendritic cyclodextrin ring exhibited negligible cytotoxicity even at high concentrations, avoiding the shortcoming of cytotoxicity from commonly used gene vectors. In vitro studies demonstrated that the loaded siRNA was transported into cancer cells to improve cancer therapeutic efficacy. Thus, we developed a prodrug-based supramolecular amphiphile via the host-guest interaction with better therapeutic performance than free camptothecin. The assembled system was utilized as a drug/gene vector to achieve combinational gene therapy and chemotherapy with a synergistic effect, providing an alternative strategy to deliver both prodrug and therapeutic gene.


Subject(s)
Prodrugs/chemistry , Camptothecin , Drug Liberation , RNA, Small Interfering , Theranostic Nanomedicine
8.
Small ; 13(29)2017 08.
Article in English | MEDLINE | ID: mdl-28544287

ABSTRACT

Inhomogeneous heating by photothermal therapy (PTT) during cancer treatment often results in the recurrence of tumors. Thus, integrating PTT with chemotherapy (CHT) may provide a complementary treatment for enhanced therapeutic efficiency. Herein, this study develops a hollow structured polymer-silica nanohybrid (HPSN) as a nanocarrier to simultaneously deliver the anticancer drug paclitaxel and photothermal agent palladium phthalocyanine to tumors through enhanced permeation and the retention effect. A combinational CHT/PTT therapy on mice bearing aggressive tumor grafts is conducted. The highly malignant tumor model, which recurs after sole treatment of PTT, can be eradicated by the combined CHT/PTT treatment. In addition, most of the off-targeted HPSN nanocarriers can be excreted through a hepatobiliary pathway in about 10 d. Serology results show that the fast-clearable HPSN can significantly reduce the side effect of the loaded paclitaxel drug. The present work provides an alternative approach for combinational cancer treatment with high therapeutic efficiency.


Subject(s)
Antineoplastic Agents/chemistry , Drug Carriers/chemistry , Nanoparticles/chemistry , Neoplasms/drug therapy , Neoplasms/therapy , Phototherapy/methods , Silicon Dioxide/chemistry , Animals , Combined Modality Therapy , Drug Therapy, Combination , Mice , Paclitaxel/chemistry , Paclitaxel/therapeutic use
9.
Chem Commun (Camb) ; 53(37): 5220-5223, 2017 May 04.
Article in English | MEDLINE | ID: mdl-28443883

ABSTRACT

Discriminative detection of glutathione (GSH) from cysteine/homocysteine (Cys/Hcy) is achieved through two emission channel analysis using a stable, highly sensitive, and selective near-infrared fluorescent probe that bears 7-nitrobenzo-2-oxa-1,3-diazole and aza-BODIPY units. The probe was successfully applied for simultaneous determination of GSH and Cys/Hcy in living cells.


Subject(s)
Aza Compounds/chemistry , Boron Compounds/chemistry , Cysteine/analogs & derivatives , Cysteine/analysis , Fluorescent Dyes/chemistry , Glutathione/analysis , Homocysteine/analysis , Cell Survival , Cysteine/chemistry , Fluorescent Dyes/analysis , Glutathione/chemistry , HeLa Cells , Homocysteine/chemistry , Humans , Infrared Rays , Nitrobenzenes/chemistry , Optical Imaging , Oxadiazoles/chemistry , Spectrometry, Fluorescence
10.
ACS Appl Mater Interfaces ; 8(37): 24319-24, 2016 Sep 21.
Article in English | MEDLINE | ID: mdl-27603417

ABSTRACT

Targeted drug delivery systems having controlled drug release property with an inherent fluorescence reporter have drawn a lot of attention in nanomedicine. However, only very few prodrugs can be directly used to construct such delivery systems. Herein, we report that an amphiphilic chlorambucil-based prodrug consisting of a fluorescence reporter and a d-mannose targeting ligand could directly self-assemble into glutathione-responsive nanovesicles for selective cancer therapy and intracellular imaging. These nanovesicles could be dissociated to release the chlorambucil drug with obviously red-shifted fluorescence when internalized by d-mannose receptor-overexpressed MCF-7 cancer cells. In addition, the nanovesicles displayed better selectivity and higher therapy efficiency than free chlorambucil drug.


Subject(s)
Prodrugs/chemistry , Drug Delivery Systems , Drug Liberation , Humans , MCF-7 Cells , Nanoparticles
11.
Small ; 12(38): 5239-5244, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27490362

ABSTRACT

Two near-infrared dyes featuring good dispersion and light-harvesting property present a remarkable nonlinear photoacoustic response in vitro and in vivo comparing with conventional gold nanorods. This study benefits the fabrication of drug delivery platforms with accurate targeting and control effect under photoacoustic image guidance.


Subject(s)
Fluorescent Dyes/chemistry , Imaging, Three-Dimensional , Infrared Rays , Nonlinear Dynamics , Organic Chemicals/chemistry , Photoacoustic Techniques/methods , Animals , Benzoates/chemistry , Indocyanine Green/analogs & derivatives , Indocyanine Green/chemistry , Indoles/chemistry , Nanotubes/chemistry , Nanotubes/ultrastructure , Rats
12.
Chem Commun (Camb) ; 52(57): 8854-7, 2016 Jul 07.
Article in English | MEDLINE | ID: mdl-27346609

ABSTRACT

Silylated zinc phthalocyanine (ZnPc) was anchored onto silica-coated gold nanorods (AuNR) with retained local surface plasmon resonance (LSPR). Independent LSPR and singlet oxygen production of anchored ZnPc enhance the photothermal and photodynamic efficacy of the obtained AuNR-Si-ZnPc under NIR light excitation. AuNR-Si-ZnPc was further grafted with hyaluronic acid (HA). Since HA has selective targeting capability to CD44 antigens, the final hybrid could target cancer cells directly for synergistic photothermal and photodynamic therapy.

13.
Small ; 12(24): 3302-8, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27174648

ABSTRACT

Vapochromic behavior is employed to selectively monitor the vapor changes in surrounding environment, particularly for toxic gas leaking and floating detection. Thus, sensitive trapping and accurate response to different toxic vapors are critical factors in vapochromic sensing. In this work, a self-assembled hybrid that consists of fluorescent organic octahedron encapsulated by metal-organic polyhedron (MOP) is reported. The fluorescent octahedron is used as a responsive sensor to probe various solvent vapors, while the MOP is employed as a protector to prevent the corrosion of solvents to the organic octahedron. The hybrid exhibits remarkable vapochromic behavior to different solvents, and shows the highest selectivity and sensitivity specifically to acetone. In addition, acetone vapor under different conditions is utilized for further studying the response mechanism of the hybrid. This work presents a promising vapochromic sensor with good stability, selectivity, and sensitivity. The study is expected to open up the applicability of MOP-based hybrids for specific molecular capture, interim storage, controlled release, and advanced sensing.


Subject(s)
Organic Chemicals/chemistry , Microscopy, Electron, Scanning , Microscopy, Electron, Transmission , Porosity , Solvents/chemistry
14.
Chem Commun (Camb) ; 52(22): 4128-31, 2016 Mar 18.
Article in English | MEDLINE | ID: mdl-26877025

ABSTRACT

Two porous covalent organic frameworks (COFs) with good biocompatibility were employed as drug nanocarriers, where three different drugs were loaded for subsequent drug release in vitro. The present work demonstrates that COFs are applicable in drug delivery for therapeutic applications.


Subject(s)
Drug Carriers , Nanotechnology , Organic Chemicals/chemistry , Biocompatible Materials , Microscopy, Electron, Scanning , Microscopy, Electron, Transmission
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