Self-Assembled Metal-Organic Framework Stabilized Organic Cocrystals for Biological Phototherapy.

Organic self-assembled co-crystals have garnered considerable attention due to their facile synthesis and intriguing properties, but supramolecular interactions restrict their stability in aqueous solution, which is especially important for biological applications. Herein, we report on the first biological application of aqueous dispersible self-assembled organic co-crystals via the construction of metal-organic framework (MOF) -stabilized co-crystals. In particular, we built an electron-deficient MOF with naphthalene diimide (NDI) as the ligand and biocompatible Ca2+ as the metal nodes. An electron donor molecule, pyrene, was encapsulated to form the host-guest MOF self-assembled co-crystal. We observed that such MOF structure leads to uniquely high-density ordered arrangement and the close intermolecular distance (3.47 Å) of the charge transfer pairs. Hence, the concomitant superior charge transfer interaction between pyrene/NDI can be attained and the resultant photothermal conversion efficiency of Py@Ca-NDI in aqueous solution can thus reach up to 41.8 %, which, to the best of our knowledge, is the highest value among the reported organic co-crystal materials; it is also much higher than that of the FDA approved photothermal agent ICG as well as most of the reported MOFs. Based on this realization, as a proof of concept, we demonstrated that such a self-assembled organic co-crystal platform can be used in biological applications that are exemplified via highly effective long wavelength light photothermal therapy.

Simple D-A-D Structural Bisbithiophenyl Diketopyrrolopyrrole as Efficient Bioimaging and Photothermal Agents.

Design and synthesis of biocompatible and multifunctional photothermal agents is crucial for effective cancer phototherapy. In order to achieve this ambition, simple D-A-D structural bisbithiophenyl diketopyrrolopyrrole (TDPP) was fabricated. In this molecule, the donor, 2-thiophenylboric acid, was conjugated via Suzuki coupling reaction, which could expand the emission wavelength to the red region of the spectrum. TDPP could self-assemble into stable and uniform nanoparticles (TDPP NPs) in assistant of amphiphilic Pluronic F-127 polymer. Exposing TDPP NPs (100 µg/mL) aqueous dispersion to 638 nm (0.61 W/cm2) laser irradiation resulted in a temperature elevation of approximately 30 °C within 5 min, which is high enough for inducing the cytotoxicity and tumor inhibition. Because of the bathochromic shift absorption of TDPP NPs in water, TDPP NPs could also act as a contrast agent for near-infrared fluorescence imaging (NIRF) to visualize the drug distribution in vivo. Coupled with the infrared thermal imaging properties of the photothermal agent, TDPP NPs were proven to be a multifunctional theranostic agent for dual-modal imaging-guided phototherapy.

The Effect of Molecular Structure on Cytotoxicity and Antitumor Activity of PEGylated Nanomedicines.

Fundamental studies on the cellular uptake and drug release of PEGylated nanomedicines are beneficial to understand their fate in vivo and construct ideal nanoparticle formulations. In this work, the detailed metabolic process of PEGylated doxorubicin (Dox) nanomedicines were investigated via confocal laser scanning microscopy (CLSM), flow cytometry (FCM), cytotoxicity test, fluorescence imaging in vivo (FLIV) and liquid chromatography tandem mass spectrometry (LC-MS/MS). Among them, only LC-MS/MS could accurately determine the content of PEGylated Dox and Dox in vitro and in vivo. To the best of our knowledge, this was the first time the PEGylated Dox and released Dox were simultaneously quantified. The interplay of molecular structures, cellular uptake, drug release, and antitumor effect was well characterized. PEG with high molecular weight impeded the cellular uptake of nanoparticles, and the acid-labile hydrazone bond between Dox and PEG promoted Dox release significantly. Cellular uptake and drug release play decisive roles in cytotoxicity and antitumor effect, as evidenced by LC-MS/MS. We emphasized that LC-MS/MS would be a practicable method to quantify PEGylated drugs without complex tags, which could be more in-depth to understand the interaction between PEGylated nanomedicines and their antitumor efficacy.

Self-destructive PEG-BODIPY nanomaterials for photodynamic and photothermal therapy.

Photoactive nanoparticles are an important platform for multimodal imaging and phototherapy of tumors. Herein, amphiphilic photosensitizers were made from boron dipyrromethene (BODIPY) and poly(ethylene glycol) (PEG2k) by using a thioketal linker, which is reactive oxygen species-responsive. The photosensitizers could form stable nanoparticles in aqueous solution. The resulting nanoparticles could simultaneously produce heat and reactive oxygen species upon irradiation to achieve combined photothermal and photodynamic therapy. The produced singlet oxygen could destroy the thioketal linker, and accelerate the destruction of nanoparticles. In addition, the near-infrared fluorescence and photoacoustic imaging ability of nanoparticles can reflect the biodistribution and destiny of nanoparticles. This work highlights the application of integrated diagnostic and therapeutic photosensitizers in carriers.

Rational Design of BODIPY-Diketopyrrolopyrrole Conjugated Polymers for Photothermal Tumor Ablation.

Conjugated polymers (CPs) have drawn growing attention in cancer phototherapy and imaging due to their large extinction coefficients, robust photostability, and good biocompatibility. Herein, we propose a new type of photothermal therapy materials on the basis of BODIPY-diketopyrrolopyrrole CPs, where the number of methyl substituents at the ß and ß' positions on BODIPYs is variable, allowing us to investigate the interplay between the structure of the monomers and the related properties of CPs. Combining the experimental data with theoretical calculations, we concluded that with the decrease of the number of methyl moieties on the ß and ß' positions of BODIPY, the polymerization degree and the solubility of the obtained CPs improved and the polymeric spatial planarization and degrees of conjugation increased, inducing the bathochromic shift of absorption, which resulted in the absorption spectra getting closer to the near-infrared region and more conducive to the application of the conjugated polymers in vivo. Afterward, the CP nanoparticles were constructed and their photothermal activity in cancer therapy was validated by a series of in vitro and in vivo experiments. In this paper, we provide a new way to manipulate properties of CPs with great potential in photothermal therapy through structural engineering.

Amphiphilic redox-sensitive NIR BODIPY nanoparticles for dual-mode imaging and photothermal therapy.

Theranostics, integrating tumor treatment and diagnosis concurrently, has become an emerging and meaningful strategy in cancer therapy. In this work, an amphiphilic redox-sensitive near-infrared (NIR) BODIPY dye, which could be formed into nanoparticles (PEG-SS-BDP NPs) by self-assembly, was synthesized and possessed good capability of photothermal therapy (PTT), near-infrared fluorescence (NIRF) imaging, photoacoustic (PA) imaging and drug loading. The stable nanoparticles could be dissociated to turn on NIRF due to the rift of embedded disulfide bonds by glutathione (GSH). The enhanced fluorescence in vitro could be observed via confocal laser scanning microscopy (CLSM) after adding GSH, confirming the redox-sensitivity of disulfide bonds. NIRF and PA imaging demonstrated active accumulation in tumor and good imaging effect. At last, PEG-SS-BDP NPs could significantly suppress tumor growth in vivo upon irradiation. The amphiphilic redox-sensitive BODIPY nanoparticles provide a promising design strategy to formulate multifunctional stimuli-responsive theranostic nanoplatforms.

Tunable film degradation and sustained release of plasmid DNA from cleavable polycation/plasmid DNA multilayers under reductive conditions.

The controllable and sustained release of DNA from the surfaces of biomaterials or biomedical devices represents a new method for localized gene delivery. We report the synthesis of a novel polycation containing disulfide bonds in its backbone and the fabrication of polycation/plasmid DNA multilayered thin films by layer-by-layer assembly. The films are very stable during preparation and in storage, however, they gradually degrade and release the incorporated DNA when incubated in PBS buffer containing dithiothreitol (DTT), which results from the degradation of a disulfide-contained polymer under reductive conditions. The film degradation rate and DNA release rate can be tuned by the concentration of reducing agent. This approach will be useful in gene therapy and tissue engineering by controlled administration of therapeutic DNA deposited on the surface of implantable biomedical devices or tissue engineering scaffolds.

Rational Design of Polymeric Nanoparticles with Tailorable Biomedical Functions for Cancer Therapy.

Polymeric nanoparticles (NPs) play a key role in nanoscale formulations for bioimaging, cancer treatment, and theranostics. In this work, we designed and synthesized a series of hydrophobic polymers (P1-6) with different pendent groups via one-step multicomponent Passerini reaction. These polymers possessed similar molecular structures and various biomedical functions. Interestingly, they could self-assemble into stable NPs in aqueous media. All formed NPs were redox sensitive because of the existence of disulfide bonds in the backbone. The stability of NPs in aqueous media with or without glutathione was systematically evaluated and compared. The optical performance, including fluorescence resonance energy transfer, was characterized under different conditions for those polymers with fluorescent components. Importantly, all formed NPs showed good cytocompatibility toward HeLa cells and different biological functions, including drug loading and delivery, bioimaging with variable fluorescence, and photodynamic activity, as evidenced by experiments in vitro and in vivo. These results demonstrate the great potential of multicomponent reaction to customize versatile polymeric nanoparticles for biomedical applications.

Near-Infrared Polymeric Nanoparticles with High Content of Cyanine for Bimodal Imaging and Photothermal Therapy.

The discovery and synthesis of theranostic nanomedicines with high loading of imaging and therapeutic agents is challenging. In this work, a polymer assembling strategy was used to make nanoparticles with exceptionally high loading of theranostic agent. As an example, poly(heptamethine) was synthesized via multicomponent Passerini reaction, and then assembled into nanoparticles in the presence of poly(ethylene glycol)2k-block-poly(d,l-lactide)2k (PEG-PLA) with high heptamethine loading (>50%). The formed nanoparticles could be used for bimodal bioimaging and photothermal therapy. The bimodal bioimaging provided complementary message about biodistribution, and photothermal treatment inhibited the growth of cervical carcinoma upon laser irradiation. This assembly of polymers formed by imaging and therapeutic agents opens new possibilities for the construction of multifunctional nanomedicines.

Reduction-sensitive amphiphilic copolymers made via multi-component Passerini reaction for drug delivery.

One-step synthesis of amphiphilic polymers containing disulfide bond within the hydrophobic backbone was demonstrated via multi-component Passerini reaction. The obtained polymer was self-assembled into micelles in aqueous solution. Curcumin (CUR), an effective and safe anticancer agent, which was limited by its water insolubility and poor bioavailability, was loaded into the micelles as a model drug. The nanoscale polymeric micelles were confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Faster intracellular CUR release was observed by confocal laser scanning microscopy (CLSM) in the HeLa cells pretreated with GSH than in the unpretreated ones. Micelles also loaded with NH2-BODIPY which was almost non-fluorescent and gave strong enhanced fluorescence under acid conditions. The phenomenon of the stronger enhanced fluorescence in the pretreated HeLa cells showed further that the obtained polymer was reduction-sensitive. In vitro MTT assays showed that the micelles were biocompatible and CUR-loaded micelles had higher cellular proliferation inhibition in contrast to free CUR toward HeLa cells. These results highlight the potential of using multi-component Passerini reaction to make functional copolymers as smart nanocarriers for drug delivery.

The use of cisplatin-loaded mucoadhesive nanofibers for local chemotherapy of cervical cancers in mice.

Polymer-based local drug delivery system may be suitable for the treatment of cervix cancer. A pilot study was carried out to examine the efficacy of cisplatin-loaded poly(ethylene oxide)/polylactide composite electrospun nanofibers as a local chemotherapy system against cervical cancer in mice via vaginal implantation. The nanofibers were proven to have good mucoadhesive property by in vitro mucoadhesion test and in vivo vaginal retention evaluation. An orthotopic cervical/vaginal cancer model was established by injecting murine cervical cancer U14 cells into the vaginal submucosa nearby the cervix. By inserting the nanofibers mat into the vagina of mice, the cisplatin released from the fiber-mat showed a much more accumulation in the vagina/cervix region than in the peripheral organs such as kidneys, liver, or blood, in contrary to the case of intravenous (i.v) injection. The in vivo trials showed that a better balance between anti-tumor efficacy and systemic safety was achieved in nanofibers group than that in i.v injection group at the equal drug dose. Therefore, electrospun nanofibers present a promising approach to the local drug delivery via vagina against cervical cancer.