Huijun Phoebe Tham

Fast-Clearable Nanocarriers Conducting Chemo/Photothermal Combination Therapy to Inhibit Recurrence of Malignant Tumors

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.

Theranostic Prodrug Vesicles for Imaging Guided Codelivery of Camptothecin and siRNA in Synergetic Cancer Therapy

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.

Remarkable In Vivo Nonlinear Photoacoustic Imaging Based on Near-Infrared Organic Dyes.

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.

Responsive Prodrug Self-Assembled Vesicles for Targeted Chemotherapy in Combination with Intracellular Imaging

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.

Environment-Adaptive Coassembly/Self-Sorting and Stimulus-Responsiveness Transfer Based on Cholesterol Building Blocks

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.

Remarkable Vapochromic Behavior of Pure Organic Octahedron Embedded in Porous Frameworks.

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.

Cyclometalated Iridium(III)-Complex-Based Micelles for Glutathione-Responsive Targeted Chemotherapy and Photodynamic Therapy

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.

Cu2-xS Nanocrystals Cross-Linked with Chlorin e6-Functionalized Polyethylenimine for Synergistic Photodynamic and Photothermal Therapy of Cancer

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.