Antitumor Effect of Photodynamic Therapy/Sonodynamic Therapy/Sono-Photodynamic Therapy of Chlorin e6 and Other Applications.

Chlorin e6 (Ce6) has been extensively researched and developed as an antitumor therapy. Ce6 is a highly effective photosensitizer and sonosensitizer with promising future applications in photodynamic therapy, dynamic acoustic therapy, and combined acoustic and light therapy for tumors. Ce6 is also being studied for other applications in fluorescence navigation, antibacterials, and plant growth regulation. Here we review the role and research status of Ce6 in tumor therapy and the problems and challenges of its clinical application. Other biomedical effects of Ce6 are also briefly discussed. Despite the difficulties in clinical application, Ce6 has significant advantages in photodynamic therapy (PDT)/sonodynamic therapy (SDT) against cancer and offers several possibilities in clinical utility.

Preparation, Characterization, and In Vitro Release of Curcumin-Loaded IRMOF-10 Nanoparticles and Investigation of Their Pro-Apoptotic Effects on Human Hepatoma HepG2 Cells.

Curcumin (CUR) has a bright future in the treatment of cancer as a natural active ingredient with great potential. However, curcumin has a low solubility, which limits its clinical application. In this study, IRMOF-10 was created by the direct addition of triethylamine, CUR was loaded into IRMOF-10 using the solvent adsorption method, and the two were characterized using a scanning electron microscope (SEM), X-ray diffraction (XRD), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TG) methods, and Brunauer-Emmett-Teller (BET) analysis. We also used the MTT method, 4',6-diamidino-2-phenylindole (DAPI) staining, the annexin V/PI method, cellular uptake, reactive oxygen species (ROS), and the mitochondrial membrane potential (MMP) to perform a safety analysis and anticancer activity study of IRMOF-10 and CUR@IRMOF-10 on HepG2 cells. Our results showed that CUR@IRMOF-10 had a CUR load of 63.96%, with an obvious slow-release phenomenon. The CUR levels released under different conditions at 60 h were 33.58% (pH 7.4) and 31.86% (pH 5.5). Cell experiments proved that IRMOF-10 was biologically safe and could promote curcumin entering the nucleus, causing a series of reactions, such as an increase in reactive oxygen species and a decrease in the mitochondrial membrane potential, thereby leading to cell apoptosis. In summary, IRMOF-10 is an excellent drug carrier and CUR@IRMOF-10 is an effective anti-liver cancer sustained-release preparation.

Aloe-emodin: A review of its pharmacology, toxicity, and pharmacokinetics.

Aloe-emodin is a naturally anthraquinone derivative and an active ingredient of Chinese herbs, such as Cassia occidentalis, Rheum palmatum L., Aloe vera, and Polygonum multiflorum Thunb. Emerging evidence suggests that aloe-emodin exhibits many pharmacological effects, including anticancer, antivirus, anti-inflammatory, antibacterial, antiparasitic, neuroprotective, and hepatoprotective activities. These pharmacological properties lay the foundation for the treatment of various diseases, including influenza virus, inflammation, sepsis, Alzheimer's disease, glaucoma, malaria, liver fibrosis, psoriasis, Type 2 diabetes, growth disorders, and several types of cancers. However, an increasing number of published studies have reported adverse effects of aloe-emodin. The primary toxicity among these reports is hepatotoxicity and nephrotoxicity, which are of wide concern worldwide. Pharmacokinetic studies have demonstrated that aloe-emodin has a poor intestinal absorption, short elimination half-life, and low bioavailability. This review aims to provide a comprehensive summary of the pharmacology, toxicity, and pharmacokinetics of aloe-emodin reported to date with an emphasis on its biological properties and mechanisms of action.

Underlying mechanisms of apoptosis in HepG2 cells induced by polyphyllin I through Fas death and mitochondrial pathways.

Aims: Polyphyllin I, a steroidal saponin in Rhizoma paridis, which possess broad application prospects in cancer prevention and treatment. The purpose of this study was to determine the potential cytotoxicity and mechanism of Polyphyllin I in HepG2 cells.Main methods: In this study, we used MTT to evaluate cell survival. Cell apoptosis rate, cell cycle distribution, mitochondrial membrane potential and ros levels were measured by flow cytometry, and the expression of apoptosis-related proteins was determined by Western blot analysis.Key findings: Polyphyllin I significantly reduced cell viability and induced HepG2 cell apoptosis in a dose and time-dependent manner. Compared with the control group, it could induce reactive oxygen species (ROS) generation and depolarization of matrix metalloproteinases in liver cells. Polyphyllin I dose-dependent increased the release of mitochondrial cytochrome c, and levels of Fas, p53, p21, and Bax/Bcl-2 ratios, as well as the activation of cleaved caspase-3, -8, -9, and subsequent cleavage of the poly (ADP-ribose) polymerase (PARP). The G2/M phase cell cycle arrest was induced by increasing the expression of p21 and cyclin E1, and significantly reducing the expression of cyclin A2 and CDK2.Significance: Our results suggested that Polyphylin I inhibited cell proliferation and growth by triggering G2/M cell cycle arrest, and induced apoptosis through intracellular and extracellular apoptosis pathways to cause cell death by generating reactive oxygen species.

Pharmacology, toxicity and pharmacokinetics of acetylshikonin: a review.

CONTEXT: Acetylshikonin, a naphthoquinone derivative, is mainly extracted from some species of the family Boraginaceae, such as Lithospermum erythrorhizon Sieb. et Zucc., Arnebia euchroma (Royle) Johnst., and Arnebia guttata Bunge. As a bioactive compound, acetylshikonin has attracted much attention because of its broad pharmacological properties. OBJECTIVE: This review provides a comprehensive summary of the pharmacology, toxicity, and pharmacokinetics of acetylshikonin focussing on its mechanisms on the basis of currently available literature. METHODS: The information of acetylshikonin from 1977 to 2020 was collected using major databases including Elsevier, Scholar, PubMed, Springer, Web of Science, and CNKI. Acetylshikonin, pharmacology, toxicity, pharmacokinetics, and naphthoquinone derivative were used as key words. RESULTS: According to emerging evidence, acetylshikonin exerts a wide spectrum of pharmacological effects such as anticancer, anti-inflammatory, lipid-regulatory, antidiabetic, antibacterial, antifungal, antioxidative, neuroprotective, and antiviral properties. However, only a few studies have reported the adverse effects of acetylshikonin, with respect to reproductive toxicity and genotoxicity. Pharmacokinetic studies demonstrate that acetylshikonin is associated with a wide distribution and poor absorption. CONCLUSIONS: Although experimental data supports the beneficial effects of this compound, acetylshikonin cannot be considered as a therapy drug without further investigations, especially, on the toxicity and pharmacokinetics.

Apoptosis in HepaRG and HL-7702 cells inducted by polyphyllin II through caspases activation and cell-cycle arrest.

Rhizoma Paridis, a traditional Chinese medicine, has shown promise in cancer prevention and therapy. Polyphyllin II is one of the most significant saponins in Rhizoma Paridis and it has toxic effects on kinds of cancer cells. However, our results in this study proved that the polyphyllin II has hepatotoxicity in vitro through caspases activation and cell-cycle arrest. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide results indicated polyphyllin II inhibited proliferation, induced apoptosis in HepaRG cells and HL-7702 cells and showed a concentration and time-dependent. Then, we selected the innovative cell model-HepaRG cells to explore the mechanism of hepatotoxicity. Our data showed the reactive oxygen species (ROS) increased and the mitochondrial membrane potential decreased in HepaRG cells after administration of polyphyllin II. Besides, with the increase of concentration, the release of lactate dehydrogenase increased and the S phase of the cell cycle was arrested. Nevertheless, when pretreatment with antioxidant N-acetylcysteine, apoptotic cells decreased significantly, inhibited the production of ROS and improved the decrease of membrane potential in HepaRG cells. Moreover, polyphyllin II treatment increased levels of Fas, Bax, cytochrome c, activated caspase-3, -8, -9, cleaved poly(ADP-ribose) polymerase and decreased Bcl-2 expression levels. Finally, we identified two signal pathways of apoptosis induced by polyphyllin II including the death receptor pathway and the mitochondria pathway. This study confirmed the hepatotoxicity of the polyphyllin II in vitro, which has never been discovered and gave a wake-up call for the clinical application of Rhizoma Paridis.

In Vitro Toxicity Study of a Porous Iron(III) Metal‒Organic Framework.

A MIL series metal‒organic framework (MOF), MIL-100(Fe), was successfully synthesized at the nanoscale and fully characterized by TEM, TGA, XRD, FTIR, DLS, and BET. A toxicological assessment was performed using two different cell lines: human normal liver cells (HL-7702) and hepatocellular carcinoma (HepG2). In vitro cytotoxicity of MIL-100(Fe) was evaluated by the MTT assay, LDH releasing rate assay, DAPI staining, and annexin V/PI double staining assay. The safe dose of MIL-100(Fe) was 80 µg/mL. It exhibited good biocompatibility, low cytotoxicity, and high cell survival rate (HL-7702 cells' viability >85.97%, HepG2 cells' viability >91.20%). Therefore, MIL-100(Fe) has a potential application as a drug carrier.

A Novel Gel-Forming Solution Based on PEG-DSPE/Solutol HS 15 Mixed Micelles and Gellan Gum for Ophthalmic Delivery of Curcumin.

Curcumin (Cur) is a naturally hydrophobic polyphenol with potential pharmacological properties. However, the poor aqueous solubility and low bioavailability of curcumin limits its ocular administration. Thus, the aim of this study was to prepare a mixed micelle in situ gelling system of curcumin (Cur-MM-ISG) for ophthalmic drug delivery. The curcumin mixed micelles (Cur-MMs) were prepared via the solvent evaporation method, after which they were incorporated into gellan gum gels. Characterization tests showed that Cur-MMs were small in size and spherical in shape, with a low critical micelle concentration. Compared with free curcumin, Cur-MMs improved the solubility and stability of curcumin significantly. The ex vivo penetration study revealed that Cur-MMs could penetrate the rabbit cornea more efficiently than the free curcumin. After dispersing the micelles in the gellan gum solution at a ratio of 1:1 (v/v), a transparent Cur-MM-ISG with the characteristics of a pseudoplastic fluid was formed. No obvious irritations were observed in the rabbit eyes after ocular instillation of Cur-MM-ISG. Moreover, Cur-MM-ISG showed a longer retention time on the corneal surface when compared to Cur-MMs using the fluorescein sodium labeling method. These findings indicate that biocompatible Cur-MM-ISG has great potential in ophthalmic drug therapy.

Investigation of Metal-Organic Framework-5 (MOF-5) as an Antitumor Drug Oridonin Sustained Release Carrier.

Oridonin (ORI) is a natural active ingredient with strong anticancer activity. But its clinical use is restricted due to its poor water solubility, short half-life, and low bioavailability. The aim of this study is to utilize the metal organic framework material MOF-5 to load ORI in order to improve its release characteristics and bioavailability. Herein, MOF-5 was synthesized by the solvothermal method and direct addition method, and characterized by Scanning Electron Microscopy (SEM), X-Ray Diffraction (XRD), Fourier Transform Infrared Spectrometer (FTIR), Thermogravimetric Analysis (TG), Brunauer-Emmett-Teller (BET), and Dynamic Light Scattering (DLS), respectively. MOF-5 prepared by the optimal synthesis method was selected for drug-loading and in vitro release experiments. HepG2 cells were model cells. MTT assay, 4',6-diamidino-2-phenylindole (DAPI) staining and Annexin V/PI assay were used to detect the biological safety of blank carriers and the anticancer activity of drug-loaded materials. The results showed that nano-MOF-5 prepared by the direct addition method had complete structure, uniform size and good biocompatibility, and was suitable as an ORI carrier. The drug loading of ORI@MOF-5 was 52.86% ± 0.59%. The sustained release effect was reliable, and the cumulative release rate was about 87% in 60 h. ORI@MOF-5 had significant cytotoxicity (IC50:22.99 µg/mL) and apoptosis effect on HepG2 cells. ORI@MOF-5 is hopeful to become a new anticancer sustained release preparation. MOF-5 has significant potential as a drug carrier material.

Simultaneous determination and pharmacokinetic study of giraldoid a, giraldoid B in rat plasma after oral administration of Daphne giraldii Nitsche extracts by LC-MS/MS.

A simple sensitive LC-MS/MS method has been developed for the simultaneous determination of giraldoid A and giraldoid B in rat plasma. The method was applied to pharmacokinetics studies of the two compounds from Daphne giraldii Nitsche. Chromatographic separation was accomplished on an Acquity UPLC™ BEH C18 column (100 × 2.1 mm, 1.7 mm) by gradient elution with a flow rate of 0.2 mL min-1. The method was linear over the concentration range of 1.0-1000 ng mL-1 , and the lower limits of quantification were 1.04 ± 0.10 and 1.04 ± 0.09 ng mL-1 , respectively. The intra- and inter-day precisions (RSD) were <10.14 and 9.96%. The extraction recovery of the analytes was acceptable. Stability studies demonstrated that the two compounds were stable in the preparation and analytical process. The maximum plasma concentration was 687.78 ± 243.62 ng mL-1 for giraldoid A and 952.38 ± 131.99 ng mL-1 for giraldoid B. The time to reach the maximum plasma concentration was 0.50 ± 0.37 h for giraldoid A and 0.50 ± 0.66 h for giraldoid B. The validated method was successfully applied to investigate the concentration-time profiles of giraldoid A and giraldoid B.

Rhein Induces Cell Death in HepaRG Cells through Cell Cycle Arrest and Apoptotic Pathway.

Rhein, a naturally occurring active anthraquinone found abundantly in various medicinal and nutritional herbs, possesses a wide spectrum of pharmacological effects. Furthermore, previous studies have reported that rhein could induce hepatotoxicity in rats. However, its cytotoxicity and potential molecular mechanisms remain unclear. Therefore, the present study aimed to investigate the cytotoxicity of rhein on HepaRG cells and the underlying mechanisms of its cytotoxicity. Our results demonstrate, by 3-(4,5-dimethyl thiazol-2-yl-)-2,5-diphenyl tetrazolium bromide (MTT) and Annexin V-fluoresce isothiocyanate (FITC)/propidium iodide (PI) double-staining assays, that rhein significantly inhibited cell viability and induced apoptosis in HepaRG cells. Moreover, rhein treatment resulted in the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP), and S phase cell cycle arrest. The results of Western blotting showed that rhein treatment resulted in a significant increase in the protein levels of Fas, p53, p21, Bax, cleaved caspases-3, -8, -9, and poly(ADP-ribose)polymerase (PARP). The protein expression of Bcl-2, cyclin A, and cyclin-dependent kinase 2 (CDK 2) was decreased. In conclusion, these results suggest that rhein treatment could inhibit cell viability of HepaRG cells and induce cell death through cell cycle arrest in the S phase and activation of Fas- and mitochondrial-mediated pathways of apoptosis. These findings emphasize the need to assess the risk of exposure for humans to rhein.

Biocompatible Fe-Based Micropore Metal-Organic Frameworks as Sustained-Release Anticancer Drug Carriers.

Sustained-release preparation is a hot spot in antitumor drug research, where the first task is to select suitable drug carriers. Research has revealed that carboxylic acid iron metal⁻organic frameworks (MOFs), constructed from iron (Fe) ions and terephthalic acid, are nontoxic and biocompatible. Due to the breathing effect, the skeleton of this mesoporous material is flexible and can reversibly adapt its pore size through drug adsorption. Therefore, we chose one kind of Fe-MOF, MIL-53(Fe), as a carrier for the anticancer drug oridonin (Ori). In this work, we report the design and synthesis of MIL-53(Fe) and explore its ability as a transport vehicle to deliver Ori. MIL-53(Fe) is characterized by scanning electron microscopy and X-ray powder diffraction. A loading capacity of 56.25 wt % was measured by high performance liquid chromatography. This carrier was safe and nontoxic (cell viability > 95.27%), depending on the results of 3-(4,5-dimethylthiazol-2-yl)--2,5-diphenyltetrazolium bromide assays, lactate dehydrogenase assays, and Annexin V-fluoresce isothiocyanate/propidium iodide double-staining assays. After loading the drug, the structure of the MIL-53(Fe) was not destroyed, and Ori was amorphous in MIL-53(Fe). Based on an analysis of the Ori release profile, results suggest that it lasts for more than seven days in vitro. The cumulative release rate of Ori at the seventh day was about 82.23% and 91.75% in phosphate buffer saline solution at 37 °C under pH 7.2 and pH 5.5, respectively. HepG2 cells were chosen to study the cytotoxicity of Ori@MIL-53(Fe), and the results show that the anticancer ratio of Ori@MIL-53(Fe) system reaches 90.62%. Thus, MIL-53 can be used as a carrier for anticancer drugs and Ori@MIL-53(Fe) is a promising sustained-release drug delivery system for the cancer therapy.

A new polymorph of isoimperatorin.

Isoimperatorin is a naturally occurring furocoumarin and is being considered as a potential chemoprevention. Only one crystal form of isoimperatorin (Form I) was reported during previous research so that an investigation of polymorphism of isoimperatorin was successfully undertaken. A new polymorph of isoimperatorin was discovered through comprehensive polymorph screening experiments. Their structures were elucidated by single-crystal structure analysis and extensively characterized by XRPD, DSC, FT-IR, and SEM. The results showed that the crystal structure and thermal properties of the new polymorph (Form II) were significantly different from those of Form I. Thermodynamic stability and phase transformation were also discussed in detail.

Induction of Apoptosis in HepaRG Cell Line by Aloe-Emodin through Generation of Reactive Oxygen Species and the Mitochondrial Pathway.

BACKGROUND/AIMS: Aloe-emodin (1,8-dihydroxy-3-hydroxymethyl-anthraquinone), an anthraquinone active compounds, is isolated from some traditional medicinal plants such as Rheum palmatum L. and Cassia occidentalis, which induce hepatotoxicity in rats. The aim of this study was to determine potential cytotoxic effects of aloe-emodin on HepaRG cells and to define the underlying mechanism. METHODS: MTT was used to evaluate cell viability. Apoptotic cell death was analyzed via Annexin V-FITC/PI double staining. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were determined by flow cytometry, while the expression of apoptosis-related proteins was determined by Western blot analysis. RESULTS: Treatment with aloe-emodin significantly reduced cell viability and induced apoptosis in HepaRG cells in a dose- and time-dependent manner. It provoked ROS generation and depolarization of MMP in HepaRG cells when compared with controls. Aloe-emodin dose-dependently increased release of mitochondrial cytochrome c, and levels of Fas, p53, p21, Bax/Bcl-2 ratio, as well as activation of caspase-3, caspase-8, caspase-9, and subsequent cleavage of poly(ADP-ribose)polymerase (PARP). It also induced S-phase cell cycle arrest by increasing the expression of p21 and cyclin E proteins while significantly decreasing the expression of cyclin A and CDK2. CONCLUSION: These results suggest that aloe-emodin inhibits cell proliferation and induces apoptosis in HepaRG cells, most probably through a mechanism involving both Fas death pathway and the mitochondrial pathway by generation of ROS. These findings underscore the need for risk assessment of human exposure to aloe-emodin.

Aloe-emodin Induces Apoptosis in Human Liver HL-7702 Cells through Fas Death Pathway and the Mitochondrial Pathway by Generating Reactive Oxygen Species.

Aloe-emodin (1,8-dihydroxy-3-hydroxymethyl-anthraquinone) is one of the primary active compounds in total rhubarb anthraquinones isolated from some traditional medicinal plants such as Rheum palmatum L. and Cassia occidentalis, which induce hepatotoxicity in rats. Thus, the aim of this study was to determine the potential cytotoxic effects and the underlying mechanism of aloe-emodin on human normal liver HL-7702 cells. The CCK-8 assays demonstrated that aloe-emodin decreased the viability of HL-7702 cells in a dose-dependent and time-dependent manner. Aloe-emodin induced S and G2/M phase cell cycle arrest in HL-7702 cells. This apoptosis was further investigated by flow cytometry and nuclear morphological changes by DAPI staining, respectively. Moreover, aloe-emodin provoked the production of intracellular reactive oxygen species and the depolarization of mitochondrial membrane potential (MMP). Further studies by western blot indicated that aloe-emodin dose-dependently up-regulated the levels of Fas, p53, p21, Bax/Bcl-2 ratio, and cleaved caspase-3, -8, -9, and subsequent cleavage of poly(ADP-ribose)polymerase (PARP). Taken together, these results suggest that aloe-emodin inhibits cell proliferation of HL-7702 cells and induces cell cycle arrest and caspase-dependent apoptosis via both Fas death pathway and the mitochondrial pathway by generating reactive oxygen species, indicating that aloe-emodin should be taken into account in the risk assessment for human exposure. Copyright © 2017 John Wiley & Sons, Ltd.

Emodin: A Review of its Pharmacology, Toxicity and Pharmacokinetics.

Emodin is a natural anthraquinone derivative that occurs in many widely used Chinese medicinal herbs, such as Rheum palmatum, Polygonum cuspidatum and Polygonum multiflorum. Emodin has been used as a traditional Chinese medicine for over 2000 years and is still present in various herbal preparations. Emerging evidence indicates that emodin possesses a wide spectrum of pharmacological properties, including anticancer, hepatoprotective, antiinflammatory, antioxidant and antimicrobial activities. However, emodin could also lead to hepatotoxicity, kidney toxicity and reproductive toxicity, particularly in high doses and with long-term use. Pharmacokinetic studies have demonstrated that emodin has poor oral bioavailability in rats because of its extensive glucuronidation. This review aims to comprehensively summarize the pharmacology, toxicity and pharmacokinetics of emodin reported to date with an emphasis on its biological properties and mechanisms of action. Copyright © 2016 John Wiley & Sons, Ltd.

Isoliquiritigenin attenuates emodin-induced hepatotoxicity in vivo and in vitro through Nrf2 pathway.

Emodin (EMO), the main bioactive component of Polygonum multiflorum, Rheum palmatum, Aloe vera and Cassia acutifolia, can cause severe hepatotoxicity. Isoliquiritigenin (ISL), a flavonoid compound from the Glycyrrhiza, has been reported to be the most potent antioxidant response element (ARE)-luciferase inducer among the main components of licorice. But the protective effect and underlying mechanism of ISL on liver injury induced by EMO has not been reported. This study aims to explore the role of nuclear transcription factor 2 (Nrf2) in EMO-induced hepatotoxicity and the protective effect of ISL. EMO treatment caused cytotoxicity in L-02 cells. Combined treatment of EMO with ISL effectively reversed changes in cell viability, reduced reactive oxygen species (ROS) generation and malondialdehyde (MDA) generation, enhanced the levels of glutathione (GSH) and super oxide dismutase (SOD) induced by EMO in L-02 cells. Furthermore, ISL could also phosphorylate mitogen-activated protein kinases (MAPKs) and up-regulate Kelth-like ECH-associated protein (Keap1). The pathways of MAPKs and Keap1 lead to the separation of Keap1 and Nrf2. Free Nrf2 transferred to the nucleus and enhanced the expression of phase II detoxification enzymes. In conclusion, our results are the first to highlight the beneficial role and relevant mechanisms of ISL in EMO-induced liver injury and provide novel insight into its application.

Design of an L-Valine-Modified Nanomicelle-Based Drug Delivery System for Overcoming Ocular Surface Barriers.

The incidence of ocular surface disease (OSD) is increasing, with a trend towards younger ages. However, it is difficult for drugs to reach the deep layers of the cornea due to ocular surface barriers, and bioavailability is less than 5%. In this study, DSPE-PEG2000 was modified with L-valine (L-Val), and an HS15/DSPE-PEG2000-L-Val nanomicelle delivery system containing baicalin (BC) (BC@HS15/DSPE-PEG2000-L-Val) was constructed using thin-film hydration, with a high encapsulation rate, small particle size and no irritation to the ocular surface. Retention experiments on the ocular surface of rabbits and an in vivo corneal permeation test showed that, compared with the control, nanomicelles not only prolonged retention time but also enhanced the ability to deliver drugs to the deep layers of the cornea. The results of a protein inhibition and protein expression assay showed that nanomicelles could increase uptake in human corneal epithelial cells (HCEC) through energy-dependent endocytosis mediated by clathrin, caveolin and the carrier pathway mediated by PepT1 by inhibiting the overexpression of claudin-1 and ZO-1 and suppressing the expression of PepT1-induced by drug stimulation. These results indicate that BC@HS15/DSPE-PEG2000-L-Val is suitable for drug delivery to the deep layers of the ocular surface, providing a potential approach for the development of ocular drug delivery systems.

Aperture Modulation of Isoreticular Metal Organic Frameworks for Targeted Antitumor Drug Delivery.

The introduction of different pore diameters in metal organic frameworks (MOFs) could adjust their drug delivery performance. MOFs with customized structures have potential application value in targeted drug delivery. However, no research on this topic has been found so far. In this report, isoreticular metal organic frameworks (IRMOFs) have been taken as a typical case of tailor-made MOFs, the pore size of which is enlarged (average BJH pore sizes of about 2.43, 3.06, 5.47, and 6.50 nm were determined for IRMOF-1, IRMOF-8, IRMOF-10, and IRMOF-16, respectively), emphasizing the relationship between pore size and model drugs (Oridonin, ORI) and clarifying its potential working mechanism. IRMOF-1, whose pore size matches the size of ORI, has an outstanding drug loading capacity (57.93% by wt) and release profile (about 90% in 24 h at pH 7.4). IRMOF-1 was further coated with polyethylene glycol (PEG) modified with a cell penetrating peptide (CPP44) bound to M160 (CD163L1) protein for targeting of hepatic tumor lines. This nanoplatform (CPP44-PEG@ORI@IRMOF-1) exhibited acid-responsive drug release behavior (37.86% in 10 h at pH 7.4 and 66.66% in 10 h at pH 5.5) and significantly enhanced antitumor effects. The results of cell targeting and in vivo animal imaging indicated that CPP44-PEG@ORI@IRMOF-1 may serve as a tumor-selective drug delivery nanoplatform. Toxicity assessment confirmed that PEGylated IRMOF-1 did not cause organ or systemic toxicity. Furthermore, it is encouraging that the IRMOF-based targeted drug delivery system with pore size modulation showed rapid clearance (most administered NPs are metabolized from urine and feces within 1 week) and avoided accumulation in the body, indicating their promise for biomedical applications. This MOF-based aperture modulation combined with a targeted modification strategy might find broad applications in cancer theranostics. Thus, it is convenient to customize personalized MOFs according to the size of drug molecules in future research.

Phototherapeutic effect of transformable peptides containing pheophorbide a on colorectal cancer.

Photodynamic therapy (PDT) and photothermal therapy (PTT) have attracted research interest for their noninvasive nature and selective treatment of tumor tissues. They are effective through the generation of reactive oxygen species (ROS) or heat. Nevertheless, several problems, including low bioavailability and long-lasting cutaneous photosensitivity, have limited their clinical application. In this study, we reported an in situ self-assembly strategy that could improve various biological properties of the photosensitizer in vivo. A photosensitizer connected to a receptor-mediated smart peptide can self-assemble into nanoparticles (NPs) under the force of hydrophobic interaction and then transform into a nanofibrillar network after attaching to the tumor cell surface with the help of the ß-sheet-forming peptide KLVFF. The supramolecular structural changes deeply affected the PDT and PTT properties of the photosensitizer on tumors. After being aggregated into the nanostructure, the water solubility and targeting ability of the photosensitizer was ameliorated. Moreover, the improvement of the photothermal conversion efficiency, ROS generation, and tumor retention followed the formation of nanofibrils (NFs). This self-assembly strategy showed the ability of supramolecular nanofibrils to improve the bioavailability of photosensitizers, which provides a new potential treatment avenue for various cancer therapies.