Ginsenoside as a new stabilizer enhances the transfection efficiency and biocompatibility of cationic liposome.

Nucleic acid drugs have emerged as important therapeutics but their clinical application has been greatly limited by their large molecular weight, high polarity, negative charge and short half-life. Cationic liposomes (CLs) have gained wide attention as non-viral vectors for nucleic acid delivery. However, the absolute transfection efficiency of CLs can still be enhanced while their cytotoxicity should be decreased simultaneously. Ginsenosides, obtained from natural plants, possess a similar steroid structure to cholesterol and might be an alternative to cholesterol for acting as a membrane stabilizer of CLs. Herein, seven kinds of ginsenoside-based compounds were utilized to prepare CLs (GCLs) and their efficacy in siRNA delivery was investigated. The particle sizes of the GCLs were 90-300 nm and the siRNA delivery efficiencies were in the range of 23.6%-78.4%. Rg5-based CLs (Rg5-CLs) exhibited the highest transfection efficiency of 81% and the lowest toxicity, with 82% cell viability obtained even at high concentrations. Ginsenosides are shown as promising biomaterials as membrane stabilizers of CLs. Rg5-CLs have been demonstrated as efficient non-viral vectors with high transfection efficiency and good biocompatibility for gene delivery, possessing great potential for gene therapy.

Mechanical stretching of cells and lipid nanoparticles for nucleic acid delivery.

Gene therapy has gained popularity in the treatment of incurable diseases. However, cell components, such as surface membrane, cytoskeleton protein, and nuclear envelope, retard the transport of nucleic acids, lowering the transfection efficiency. We developed a physical-chemical hybrid platform (S-RCLs) involving cationic lipid nanoparticles (RCLs) exposed to cyclic stretch. The transfection efficiency and delivery mechanisms of S-RCLs for siRNAs and pDNAs (plasmid DNAs encoding luciferase) were investigated. S-RCLs effectively delivered both siRNAs and pDNAs by overcoming the cell barriers. Mechanistically, S-RCLs promote the cellular uptake mediated by CD44, EH-domain containing 2 (EHD2), and caveolin-1 (CAV-1); intracellular transport via MAP6 Domain Containing 1 (Map6d1) and F-actin; and DNA transcription regulated by LSM3 and Hist1h3e in the nucleus. Thus, S-RCLs are a promising hybrid platform with excellent efficiency and biocompatibility for gene delivery both in vitro and in vivo.

Outer membrane vesicles derived from E. coli as novel vehicles for transdermal and tumor targeting delivery.

Transdermal drug delivery is favored in clinical therapy because of its ability to overcome the shortcomings of the first pass elimination of the liver caused by traditional oral administration and the irreversibility of the injection. However, skin stratum corneum (SC) forms a big barrier that precludes most of the biomacromolecules. Herein, we propose the engineering of transformed Escherichia coli (E. coli) derived outer membrane vesicles, detoxified by lysozymes (named TEVs) as the carrier for transdermal drug delivery. TEVs were derived from transgenic E. coli and then modified by an integrin alpha(v)beta(3) (αvß3) targeting peptide and co-loaded with indocyanine green (ICG) (P-TEVs-G). TEVs were shown to have excellence in penetrating through intact SC without any additional enhancement, followed by targeting of melanoma cells. TEVs are promising nanoplatforms for transdermal and tumor targeting drug delivery with high efficacy and biosafety, possessing great potential in the treatment of superficial tumors.

Engineering bacterial outer membrane vesicles as transdermal nanoplatforms for photo-TRAIL-programmed therapy against melanoma.

Melanoma is an aggressive cancer with rapid progression, relapse, and metastasis. Systemic therapies for melanoma exhibit limited anticancer potential and high toxicity. Here, we developed the outer membrane vesicles derived from transgenic Escherichia coli, modified with αvß3 integrin peptide targeting ligand and indocyanine green (named as I-P-OMVs), to induce the transdermal photo-TRAIL-programmed treatment in skin melanoma.-OMVs, which are outer membrane vesicles derived from transgenic Escherichia coli, modified with αvß3 integrin targeting ligand and indocyanine green (named as I-P-OMVs), to induce the transdermal photo-TRAIL-programmed treatment in skin melanoma. I-P-OMVs exhibited excellent stratum corneum penetration and specificity to melanoma. Upon near-infrared irritation, I-P-OMVs not only induced photothermal-photodynamic responses against primary melanoma spheroids but also activated TRAIL-induced apoptosis in disseminated tumor cells, resulting in a complete eradication of melanoma. I-P-OMVs are the first nanoplatforms to induce transdermal photo-TRAIL-programmed therapy in melanoma with enhanced antitumor performance and high safety, having great potential in cancer therapy.

Transdermal siRNA delivery by pH-switchable micelles with targeting effect suppress skin melanoma progression.

Melanoma is an aggressive disease with rapid progression and fast relapse, representing one of the formidable challenges in clinic. Current systemic therapies for melanoma exhibit limited anticancer potential due to the lack of specificity and limited efficacy. Herein, we design a cationic polymer (SCP-HA-PAE) by conjugating skin/cell penetrating peptide (SCP) and hyaluronic acid (HA) to the amphipathic polymer (poly ß-amino esters, PAE), then fabricate the nanocarriers (SHP) composed by SCP-HA-PAE for delivering siRNA to skin melanoma by transdermal application. SHP not only manifests the excellent ability in penetrating through skin stratum corneum (SC), targeting melanoma and being sensitive to pH, but also expresses the advantages in compacting the vector/siRNAs nanocomplexes and stimulating their endosome escape inside cells, which ensure the enhanced siRNA delivery efficiency. SHP/siRNA induce the strong efficacy in retarding the progression and relapse of skin melanoma through the enhanced apoptosis effect both in vitro & in vivo. This study provides a proof-of-concept design of pH-switchable cationic micelles as transdermal gene delivery nanoplatforms with targeting effect for melanoma therapy, which may be adapted widely in the treatment of various superficial tumors and skin genetic diseases.

Synthesis of crocetin derivatives and their potent inhibition in multiple tumor cells proliferation and inflammatory property of macrophage.

BACKGROUND: Crocetin is a major active component of saffron, which has a wide range of pharmacological effects. However, due to its low solubility, the pharmacological effects of crocetin cannot be better utilized. METHODS: In this study, we modified the chemical structure of crocetin by conjugating with ethylamine and 4-Fluorbenzylamine to enhance its solubility and biological activities. The solubility and the influence of synthesized derivatives on the proliferation of tumor cells and the inflammatory effect of macrophage were investigated. RESULTS: It was shown that, compared with the crocetin, the synthesized derivatives have much higher solubility. Moreover, the inhibitory effect of the derivatives on varieties of tumor cells, including human ovarian carcinoma cell line, human lung cancer cell line, rat melanoma cell line was enhanced after the modification. Besides that, the derivatives were improved for the anti-inflammatory efficacy with the cytotoxicity decreased. CONCLUSIONS: The synthesized derivatives were shown for their good solubility and the great potential in tumor and inflammation treatment.

The crude ethanol extract of Periplaneta americana L. stimulates wound healing in vitro & in vivo.

Periplaneta americana L. is a Traditional Chinese Medicine that has been used in clinic treatment of various diseases for a long history. However, the therapeutic potential and the underlying mechanism of Periplaneta americana L. in the skin wound therapy was not investigated comprehensively yet. This study aims to investigate the influence of the crude ethanol extract of PAL in the different wound stages including: (1) the migration and chemotaxis to skin cells in the first stage; (2) proliferation and cells cycle of skin cells in the second stage; (3) remodeling effect and secretion of growth factors, collagens in the third stage; (4) as well as the influence in the blood vessels regeneration in the late stage. The crude ethanol extract of PAL was shown to (1) promote the keratinocytes proliferation and regulate the cells cycle of fibroblasts significantly; (2) stimulate the migration of keratinocytes and fibroblasts obviously; (3) enhance the EGF and VEGF secretion both in vitro & in vivo; (4) accelerate the wound healing, collagen synthesis and angiogenesis. The crude ethanol extract of KFX was shown a promising therapeutic agent for the wound therapy with great efficacy to accelerate the wound healing with improved quality.

Construction of a biomimetic chemokine reservoir stimulates rapid in situ wound repair and regeneration.

Skin is the first protection of human body. It is always challenged by a range of external factors, resulting in the wounds of skin. Hydrogel, as a dressing with multiple advantages, causes increasing interests or the applications in wound treatment. However, the function and importance of micro-environment of wound region are frequently neglected. In this study, we successfully developed a chemokine loaded biomimetic hydrogel as a functional reservoir to stimulate the rapid in situ recruitment of BMSCs for fast wound repair and regeneration. The biomimetic hydrogel was fabricated by using the Polyvinyl alcohol (PVA) combined with chitosan (CS) as the hybrid materials. The fabricated hydrogel possesses many features such as the porous structure, high swelling rate and moisture retention property. More importantly, the incorporated chemokine could be released with a sustained manner from the hydrogel and recruited the bone marrow mesenchymal stem cells (BMSCs) significantly both in vitro & in vivo. Moreover, the hydrogel was demonstrated to be highly biocompatible to the skin tissue without any side effect or irritation observed. Topical delivery of chemokine by the biomimetic PVA/CS hybrid material based hydrogel is demonstrated as a promising carrier to accelerate wound repair and regeneration without inducing scar formation and any other negative complications. The PVA/CS/SDF-1 hydrogel was shown a novel therapeutic system for wound therapy.

Synthesis, characterization and inhibitory effects of crocetin derivative compounds in cancer and inflammation.

Crocetin is a natural product possessing extraordinary therapeutic effects for various diseases. However, its extremely low solubility limits its application greatly. Conjugation of organic compounds containing heteroatoms such as N to poor soluble molecules can help the synthesized derivative to form stable hydrogen bonds by lowering the salvation energy, which will improve the solubility of the synthesized compounds. Herein, crocetin was modified by conjugating with piperidyl, diethylin and benzylamine to improve their solubility and bioactivities. In the present study, the conjugation of crocetin with piperidyl, diethylin and benzylamine and their influence on the solubility and the pharmacological effects of crocetin were investigated. With the described strategy, crocetin derivatives were synthesized and their structures were elucidated by 1H NMR, 13C NMR and UPLC-MS spectroscopic analysis. The solubility of crocetin and its derivatives were identified. Upon that, the pharmacological effects of the crocetin derivatives on the tumor and inflammation treatment were investigated. It was shown that, in contrast to crocetin, of which, the solubility and pharmacological effects were low and limited, the synthesized compounds have significantly higher solubility and possess broad spectrum of anticancer effects in multiple tumor cell lines, including B16F10, MCF-7, A549 and SKOV3, as well as enhanced anti-inflammation efficacy in macrophage (RAW264.7) without causing cells damage. Conjugation of piperidyl, diethylin and benzylamine with the crocetin was demonstrated to be a highly efficient strategy to improve the solubility of crocetin. The synthesized crocetin derivatives were shown the promising therapeutics for the tumor and inflammation treatment with high safety.