Aijun Zhu

Dual imaging-guided photothermal/photodynamic therapy using micelles

We report a type of photosensitizer (PS)-loaded micelles integrating cyanine dye as potential theranostic micelles for precise anatomical tumor localization via dual photoacoustic (PA)/near-infrared fluorescent (NIRF) imaging modalities, and simultaneously superior cancer therapy via sequential synergistic photothermal therapy (PTT)/photodynamic therapy (PDT). The micelles exhibit enhanced photostability, cell internalization and tumor accumulation. The dual NIRF/PA imaging modalities of the micelles cause the high imaging contrast and spatial resolution of tumors, which provide precise anatomical localization of the tumor and its inner vasculature for guiding PTT/PDT treatments. Moreover, the micelles can generate severe photothermal damage on cancer cells and destabilization of the lysosomes upon PTT photoirradiation, which subsequently facilitate synergistic photodynamic injury via PS under PDT treatment. The sequential treatments of PTT/PDT trigger the enhanced cytoplasmic delivery of PS, which contributes to the synergistic anticancer efficacy of PS. Our strategy provides a dual-modal cancer imaging with high imaging contrast and spatial resolution, and subsequent therapeutic synergy of PTT/PDT for potential multimodal theranostic application.

Smart Albumin‐Biomineralized Nanocomposites for Multimodal Imaging and Photothermal Tumor Ablation

Smart cyanine-grafted gadolinium oxide nanocrystals (Cy-GdNCs) obtained by albumin-based biomineralization are shown to be theranostic nanocomposites, with promising properties for trimodal near-infrared fluorescence/photoacoustics/magnetic-resonance imaging-guided photothermal tumor ablation.

Micelles assembled with carbocyanine dyes for theranostic near-infrared fluorescent cancer imaging and photothermal therapy.

It is an emerging focus to explore a theranostic nanocarrier for simultaneous cancer imaging and therapy. Herein, we demonstrate a theranostic micelle system for cancer near infrared fluorescent (NIRF) imaging with enhanced signal to noise ratio and superior photothermal therapy. The copolymers consisting of monomethoxy poly(ethylene glycol) and alkylamine-grafted poly(L-aspartic acid) are assembled with carbocyanine dyes into theranostic micelles, which exhibit small size, high loading capacity, good stability, sustained release behavior, and enhanced cellular uptake. The micelles achieve the preferable biodistribution and long-term retention of carbocyanine dyes at tumor, which result in enhanced NIRF imaging by generating stable retention of NIRF signals at both hypervascular and hypovascular tumors during a long-term imaging period of up to 8 day, accompanying with negligible noise at normal tissues. The photostability of carbocyanine dye (Cypate) plays an important role for long-term cancer imaging with enhanced SNR. Moreover, the micelles exhibit severe photothermal damage on cancer cells via the destabilization of subcellular organelles upon photoirradiation, causing superior photothermal tumor regress. The micelles act as a powerful theranostic nanocarrier for simultaneous cancer imaging with high contrast and superior photothermal therapy.

Dually pH/Reduction-Responsive Vesicles for Ultrahigh-Contrast Fluorescence Imaging and Thermo-Chemotherapy-Synergized Tumor Ablation

Smart nanocarriers are of particular interest as nanoscale vehicles of imaging and therapeutic agents in the field of theranostics. Herein, we report dually pH/reduction-responsive terpolymeric vesicles with monodispersive size distribution, which are constructed by assembling acetal- and disulfide-functionalized star terpolymer with near-infrared cyanine dye and anticancer drug. The vesicular nanostructure exhibits multiple theranostic features including on-demand drug releases responding to pH/reduction stimuli, enhanced photothermal conversion efficiency of cyanine dye, and efficient drug translocation from lysosomes to cytoplasma, as well as preferable cellular uptakes and biodistribution. These multiple theranostic features result in ultrahigh-contrast fluorescence imaging and thermo-chemotherapy-synergized tumor ablation. The dually stimuli-responsive vesicles represent a versatile theranostic approach for enhanced cancer imaging and therapy.

Highly Efficient Hierarchical Micelles Integrating Photothermal Therapy and Singlet Oxygen-Synergized Chemotherapy for Cancer Eradication

It is highly desirable to develop theranostic nanoparticles for achieving cancer imaging with enhanced contrast and simultaneously multimodal synergistic therapy. Herein, we report a theranostic micelle system hierarchically assembling cyanine dye (indocyanine green) and chemotherapeutic compound (doxorubicin) (I/D-Micelles) as a novel theranostic platform with high drug loading, good stability and enhanced cellular uptake via clathrin-mediated endocytosis. I/D-Micelles exhibit the multiple functionalities including near-infrared fluorescence (NIRF), hyperthermia and intracellular singlet oxygen from indocyanine green, and simultaneous cytotoxicity from doxorubicin. Upon photoirradiation, I/D-Micelles can induce NIRF imaging, acute photothermal therapy via hyperthermia and simultaneous synergistic chemotherapy via singlet oxygen-triggered disruption of lysosomal membranes, eventually leading to enhanced NIRF imaging and superior tumor eradication without any re-growth. Our results suggest that the hierarchical micelles can act as a superior theranostic platform for cancer imaging and multimodal synergistic therapy.

Rational Design of Multi-Stimuli-Responsive Nanoparticles for Precise Cancer Therapy.

Stimuli-responsive nanoparticles with target capacity are of great interest in drug delivery for cancer therapy. However, the challenge is to achieve highly smart release with precise spatiotemporal control for cancer therapy. Herein, we report the preparation and properties of multi-stimuli-responsive nanoparticles through the co-assembly of a 3-arm star quaterpolymer with a near-infrared (NIR) photothermal agent and chemotherapeutic compound. The nanoparticles can exhibit NIR light/pH/reduction-responsive drug release and intracellular drug translocation in cancer cells, which further integrate photoinduced hyperthermia for synergistic anticancer efficiency, thereby leading to tumor ablation without tumor regrowth. Thus, this rational design of nanoparticles with multiple responsiveness represents a versatile strategy to provide smart drug delivery paradigms for cancer therapy.

Multipronged Design of Light-Triggered Nanoparticles To Overcome Cisplatin Resistance for Efficient Ablation of Resistant Tumor

Chemotherapeutic drugs frequently encounter multiple drug resistance in the field of cancer therapy. The strategy has been explored with limited success for the ablation of drug-resistant tumor via intravenous administration. In this work, the rationally designed light-triggered nanoparticles with multipronged physicochemical and biological features are developed to overcome cisplatin resistance via the assembly of Pt(IV) prodrug and cyanine dye (Cypate) within the copolymer for efficient ablation of cisplatin-resistant tumor. The micelles exhibit good photostability, sustained release, preferable tumor accumulation, and enhanced cellular uptake with reduced efflux on both A549 cells and resistant A549R cells. Moreover, near-infrared light not only triggers the photothermal effect of the micelles for remarkable photothermal cytotoxicity, but also leads to the intracellular translocation of the micelles and reduction-activable Pt(IV) prodrug into cytoplasm through the lysosomal disruption, as well as the remarkable inhibition on the expression of a drug-efflux transporter, multidrug resistance-associated protein 1 (MRP1) for further reversal of drug resistance of A549R cells. Consequently, the multipronged effects of light-triggered micelles cause synergistic cytotoxicity against both A549 cells and A549R cells, and thus efficient ablation of cisplatin-resistant tumor without regrowth. The multipronged features of light-triggered micelles represent a versatile synergistic approach for the ablation of resistant tumor in the field of cancer therapy.

Photoconversion-Tunable Fluorophore Vesicles for Wavelength-Dependent Photoinduced Cancer Therapy

Photoconversion tunability of fluorophore dye is of great interest in cancer nanomedicine such as fluorescence imaging, photodynamic therapy (PDT), and photothermal therapy (PTT). Herein, this paper reports wavelength-dependent photoconversional polymeric vesicles of boron dipyrromethene (Bodipy) fluorophore for either PDT under 660 nm irradiation or PTT under 785 nm irradiation. After being assembled within polymeric vesicles at a high drug loading, Bodipy molecules aggregate in the conformations of both J-type and H-type, thereby causing red-shifted absorption into near-infrared region, ultralow radiative transition, and ideal resistance to photobleaching. Such vesicles further possess enhanced blood circulation, preferable tumor accumulation, as well as superior cell uptake as compared to free Bodipy. In particular, the vesicles mainly generate abundant intracellular singlet oxygen for PDT treatment under 660 nm irradiation, while they primarily produce a potent hyperthermia for PTT with tumor ablation through singlet oxygen-synergized photothermal necrosis under 785 nm irradiation. This approach provides a facile and general strategy to tune photoconversion characteristics of fluorophore dyes for wavelength-dependent photoinduced cancer therapy.

Cyanine-Anchored Silica Nanochannels for Light-Driven Synergistic Thermo-Chemotherapy.

Smart nanoparticles are increasingly important in a variety of applications such as cancer therapy. However, it is still a major challenge to develop light-responsive nanoparticles that can maximize the potency of synergistic thermo-chemotherapy under light irradiation. Here, spatially confined cyanine-anchored silica nanochannels loaded with chemotherapeutic doxorubicin (CS-DOX-NCs) for light-driven synergistic cancer therapy are introduced. CS-DOX-NCs possess a J-type aggregation conformation of cyanine dye within the nanochannels and encapsulate doxorubicin through the π-π interaction with cyanine dye. Under near-infrared light irradiation, CS-DOX-NCs produce the enhanced photothermal conversion efficiency through the maximized nonradiative transition of J-type Cypate aggregates, trigger the light-driven drug release through the destabilization of temperature-sensitive π-π interaction, and generate the effective intracellular translocation of doxorubicin from the lysosomes to cytoplasma through reactive oxygen species-mediated lysosomal disruption, thereby causing the potent in vivo hyperthermia and intracellular trafficking of drug into cytoplasma at tumors. Moreover, CS-DOX-NCs possess good resistance to photobleaching and preferable tumor accumulation, facilitating severe photoinduced cell damage, and subsequent synergy between photothermal and chemotherapeutic therapy with tumor ablation. These findings provide new insights of light-driven nanoparticles for synergistic cancer therapy.

N-Succinyl-chitosan nanoparticles coupled with low-density lipoprotein for targeted osthole-loaded delivery to low-density lipoprotein receptor-rich tumors

N-Succinyl-chitosan (NSC) was synthesized and NSC nanoparticles (NPs) with loaded osthole (Ost) (Ost/NSC-NPs) were prepared by emulsion solvent diffusion. Subsequently, low-density lipoprotein (LDL)-mediated NSC-NPs with loaded Ost (Ost/LDL-NSC-NPs) were obtained by coupling LDL with Ost/NSC-NPs through amide linkage. The average particle size of Ost/NSC-NPs was approximately 145 nm, the entrapment efficiency was 78.28%±2.06%, and the drug-loading amount was 18.09%±0.17%. The release of Ost from Ost/NSC-NPs in vitro showed a more evident sustained effect than the native material. The half maximal inhibitory concentration of Ost/LDL-NSC-NPs was only 16.23% that of the free Ost at 24 hours in HepG2 cells. Ost inhibited HepG2 cell proliferation by arresting cells in the synthesis phase of the cell cycle and by triggering apoptosis. Cellular uptake and subcellular localization in vitro and near-infrared fluorescence real-time imaging in vivo showed that Ost/LDL-NSC-NPs had high targeting efficacy. Therefore, LDL-NSC-NPs are a promising system for targeted Ost delivery to liver tumor.