Cuifang Zheng

Single-Step Assembly of DOX/ICG Loaded Lipid-Polymer Nanoparticles for Highly Effective Chemo-photothermal Combination Therapy

A combination of chemotherapy and photothermal therapy has emerged as a promising strategy for cancer therapy. To ensure the chemotherapeutic drug and photothermal agent could be simultaneously delivered to a tumor region to exert their synergistic effect, a safe and efficient delivery system is highly desirable. Herein, we fabricated doxorubicin (DOX) and indocyanine green (ICG) loaded poly(lactic-co-glycolic acid) (PLGA)-lecithin-polyethylene glycol (PEG) nanoparticles (DINPs) using a single-step sonication method. The DINPs exhibited good monodispersity, excellent fluorescence/size stability, and consistent spectra characteristics compared with free ICG or DOX. Moreover, the DINPs showed higher temperature response, faster DOX release under laser irradiation, and longer retention time in tumor. In the meantime, the fluorescence of DOX and ICG in DINPs was also visualized for the process of subcellular location in vitro and metabolic distribution in vivo. In comparison with chemo or photothermal treatment alone, the combined treatment of DINPs with laser irradiation synergistically induced the apoptosis and death of DOX-sensitive MCF-7 and DOX-resistant MCF-7/ADR cells, and suppressed MCF-7 and MCF-7/ADR tumor growth in vivo. Notably, no tumor recurrence was observed after only a single dose of DINPs with laser irradiation. Hence, the well-defined DINPs exhibited great potential in targeting cancer imaging and chemo-photothermal therapy.

Polypeptide cationic micelles mediated co-delivery of docetaxel and siRNA for synergistic tumor therapy

Combination of two or more therapeutic strategies with different mechanisms can cooperatively impede tumor growth. Co-delivery of chemotherapeutic drug and small interfering RNA (siRNA) within a single nanoparticle (NP) provides a rational strategy for combined cancer therapy. Here, we prepared polypeptide micelle nanoparticles (NPs) of a triblock copolymer poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu) to systemically codeliver docetaxel (DTX) and siRNA-Bcl-2 for an effective drug/gene vector. The hydrophobic PLLeu core entrapped with anticancer drugs, while the PLL polypeptide cationic backbone allowed for electrostatic interaction with the negatively charged siRNA. The resulting micelle NP exhibited very stable, good biocompatible and excellent passive targeted properties. The micelle complexes with siRNA-Bcl-2 effectively knocked down the expression of Bcl-2 mRNA and protein. Moreover, the co-delivery system of DTX and siRNA-Bcl-2 (DTX-siRNA-NPs) obviously down-regulation of the anti-apoptotic Bcl-2 gene and enhanced antitumor activity with a smaller dose of DTX, resulting the significantly inhibited tumor growth of MCF-7 xenograft murine model as compared to the individual siRNA and only DTX treatments. Our results demonstrated well-defined PEG-PLL-PLLeu polypeptide cationic micelles with the excellent synergistic effect of DTX and siRNA-Bcl-2 in combined cancer therapy.

Robust ICG Theranostic Nanoparticles for Folate Targeted Cancer Imaging and Highly Effective Photothermal Therapy

Folic acid (FA)-targeted indocyanine green (ICG)-loaded nanoparticles (NPs) (FA-INPs) were developed to a near-infrared (NIR) fluorescence theranostic nanoprobe for targeted imaging and photothermal therapy of cancer. The FA-INPs with good monodispersity exhibited excellent size and fluorescence stability, preferable temperature response under laser irradiation, and specific molecular targeting to MCF-7 cells with FA receptor overexpression, compared to free ICG. The FA-INPs enabled NIR fluorescence imaging to in situ monitor the tumor accumulation of the ICG. The cell survival rate assays in vitro and photothermal therapy treatments in vivo indicated that FA-INPs could efficiently targeted and suppressed MCF-7 cells and xenograft tumors. Hence, the FA-INPs are notable theranostic NPs for imaging-guided cancer therapy in clinical application.

Improving drug accumulation and photothermal efficacy in tumor depending on size of ICG loaded lipid-polymer nanoparticles

A key challenge to strengthen anti-tumor efficacy is to improve drug accumulation in tumors through size control. To explore the biodistribution and tumor accumulation of nanoparticles, we developed indocyanine green (ICG) loaded poly (lactic-co-glycolic acid) (PLGA) -lecithin-polyethylene glycol (PEG) core-shell nanoparticles (INPs) with 39 nm, 68 nm and 116 nm via single-step nanoprecipitation. These INPs exhibited good monodispersity, excellent fluorescence and size stability, and enhanced temperature response after laser irradiation. Through cell uptake and photothermal efficiency in vitro, we demonstrated that 39 nm INPs were more easily be absorbed by pancreatic carcinoma tumor cells (BxPC-3) and showed better photothermal damage than that of 68 nm and 116 nm size of INPs. Simultaneously, the fluorescence of INPs offered a real-time imaging monitor for subcellular locating and in vivo metabolic distribution. Near-infrared imaging in vivo and photothermal therapy illustrated that 68 nm INPs showed the strongest efficiency to suppress tumor growth due to abundant accumulation in BxPC-3 xenograft tumor model. The findings revealed that a nontoxic, size-dependent, theranostic INPs model was built for in vivo cancer imaging and photothermal therapy without adverse effect.

NIR-driven Smart Theranostic Nanomedicine for On-demand Drug Release and Synergistic Antitumour Therapy

Smart nanoparticles (NPs) that respond to external and internal stimulations have been developing to achieve optimal drug release in tumour. However, applying these smart NPs to attain high antitumour performance is hampered by limited drug carriers and inefficient spatiotemporal control. Here we report a noninvasive NIR-driven, temperature-sensitive DI-TSL (DOX/ICG-loaded temperature sensitive liposomes) co-encapsulating doxorubicin (DOX) and indocyanine green (ICG). This theranostic system applies thermo-responsive lipid to controllably release drug, utilizes the fluorescence (FL) of DOX/ICG to real-time trace the distribution of NPs, and employs DOX/ICG to treat cancer by chemo/photothermal therapy. DI-TSL exhibits uniform size distribution, excellent FL/size stability, enhanced response to NIR-laser, and 3 times increased drug release through laser irradiation. After endocytosis by MCF-7 breast adenocarcinoma cells, DI-TSL in cellular endosomes can cause hyperthermia through laser irradiation, then endosomes are disrupted and DI-TSL ‘opens’ to release DOX simultaneously for increased cytotoxicity. Furthermore, DI-TSL shows laser-controlled release of DOX in tumour, enhanced ICG and DOX retention by 7 times and 4 times compared with free drugs. Thermo-sensitive DI-TSL manifests high efficiency to promote cell apoptosis, and completely eradicate tumour without side-effect. DI-TSL may provide a smart strategy to release drugs on demand for combinatorial cancer therapy.

Self-Monitoring Artificial Red Cells with Sufficient Oxygen Supply for Enhanced Photodynamic Therapy.

Photodynamic therapy has been increasingly applied in clinical cancer treatments. However, native hypoxic tumoural microenvironment and lacking oxygen supply are the major barriers hindering photodynamic reactions. To solve this problem, we have developed biomimetic artificial red cells by loading complexes of oxygen-carrier (hemoglobin) and photosensitizer (indocyanine green) for boosted photodynamic strategy. Such nanosystem provides a coupling structure with stable self-oxygen supply and acting as an ideal fluorescent/photoacoustic imaging probe, dynamically monitoring the nanoparticle biodistribution and the treatment of PDT. Upon exposure to near-infrared laser, the remote-triggered photosensitizer generates massive cytotoxic reactive oxygen species (ROS) with sufficient oxygen supply. Importantly, hemoglobin is simultaneously oxidized into the more active and resident ferryl-hemoglobin leading to persistent cytotoxicity. ROS and ferryl-hemoglobin synergistically trigger the oxidative damage of xenograft tumour resulting in complete suppression. The artificial red cells with self-monitoring and boosted photodynamic efficacy could serve as a versatile theranostic platform.

Photosensitizer-conjugated redox-responsive dextran theranostic nanoparticles for near-infrared cancer imaging and photodynamic therapy

Photodynamic therapy (PDT) has emerged as an effective treatment for tumor with minimal nonspecific damage to adjacent healthy tissues. Herein, redox-responsive self-quenching polysaccharide-based theranostic nanoparticles (DEX-SS-Ce6 NPs) were developed for tumor imaging and photodynamic therapy. The dextran–chlorin e6 conjugates (DEX-SS-Ce6) could self-assemble into nanoparticles with uniform sphere shape in aqueous solution and exhibit cellular redox-responsive “OFF/ON” behavior of a fluorescence signal. In addition, the DEX-SS-Ce6 NPs demonstrated an effective cellular uptake property and high phototoxicity upon near-infrared (NIR) laser irradiation. More importantly, DEX-SS-Ce6 NP treated mice presented enhanced tumor targeting ability and improved photodynamic therapeutic efficiency in an in vivo study, compared with free Ce6 treated mice. These results suggest that the DEX-SS-Ce6 NP is a great potential system for tumor imaging and photodynamic therapy.

PEI protected aptamer molecular probes for contrast-enhanced in vivo cancer imaging

Aptamers have emerged as promising molecular probes for cancer diagnosis. However, their application for in vivo cancer imaging remains limitation due to the poor stability in blood and the degradation by nucleases. In the present study, we generated PEI/aptamer molecular complexes for cancer imaging in vivo by using deoxyribonuclease (DNase)-activatable fluorescence probes (DFProbes) to monitor DNA degradation. The results showed that the complexes with PEI at the N/P ratio from 3.8 to 15 effectively prevented the degradation of DFProbes both in vitro and in vivo. Moreover, PEI successfully protected TD05 aptamers from DNase degradation without affecting its specific recognition of Ramos cells. In tumor bearing mice, PEI/aptamer molecular complexes further demonstrated superior passive tumor targeting and extended circulation time as compared with free aptamer. Hence, the well-defined PEI/aptamer probe is a novel strategy to deliver targeted aptamer for tumor diagnosis and imaging in vivo.

PLGA–LECITHIN–PEG CORE-SHELL NANOPARTICLES FOR CANCER TARGETED THERAPY

We reported the development of multifunctional poly (lactic-co-glycolic acid) (PLGA)-lecithin-polyethylene glycol (PEG) core-shell nanoparticles (NPs) that combined the beneficial properties of liposome and polymeric NPs for chemotherapeutics delivery. The particle size, surface charge and surface functional groups were easily tunable in highly reproducible manner by various formulation parameters such as lipid/polymer, 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-PEG-COOH/lecithin, DSPE-PEG-COOH/DSPE-PEG-NH2 mass ratio and modification of terminal groups of DSPE-PEG. We encapsulated model chemotherapy drug, hydrophilic cisplatin (DDP) or hydrophobic DDP prodrug, in the NPs and showed high encapsulation efficiency, excellent stability, specific FA targeting recognition for MCF-7 cells with over FA receptors expression and pretty cytotoxicity. Such PLGA–lecithin–PEG core-shell nanoparticles (NPs) were proved to be a promising drug delivery nanocarrier for cancer-targeted therapy.

Application of Indocyanine Green Nanoparticles in Diagnosis and Treatment of Cancer

Indocyanine green(ICG) is a conventional near-infrared(NIR) dye that can be used in clinical fluorescence imaging, and it is also an effective light absorber for laser-mediated photothermal or photodynamic therapy. However, the ICG is still limited by its unstable properties in aqueous media and quick clearance from the body. The ICG-loaded nanoparticle has provided the versatile assembly tools for further development and application of the ICG. Herein, we review the application of ICG nanoparticles in NIR diagnosis and photothermal/photodynamic therapy of cancer.