Cyclodextrins as eminent constituents in nanoarchitectonics for drug delivery systems.

Cyclodextrins have been widely employed for drug delivery systems (DDSs) in which drugs are selectively delivered to a target site in the body. Recent interest has been focused on the construction of cyclodextrin-based nanoarchitectures that show sophisticated DDS functions. These nanoarchitectures are precisely fabricated based on three important features of cyclodextrins, namely (1) the preorganized three-dimensional molecular structure of nanometer size, (2) the easy chemical modification to introduce functional groups, and (3) the formation of dynamic inclusion complexes with various guests in water. With the use of photoirradiation, drugs are released from cyclodextrin-based nanoarchitectures at designated timing. Alternatively, therapeutic nucleic acids are stably protected in the nanoarchitectures and delivered to the target site. The efficient delivery of the CRISPR-Cas9 system for gene editing was also successful. Even more complicated nanoarchitectures can be designed for sophisticated DDSs. Cyclodextrin-based nanoarchitectures are highly promising for future applications in medicine, pharmaceutics, and other relevant fields.

Hypericin: A natural anthraquinone as promising therapeutic agent.

BACKGROUND: Hypericin is a prominent secondary metabolite mainly existing in genus Hypericum. It has become a research focus for a quiet long time owing to its extensively pharmacological activities especially the anti-cancer, anti-bacterial, anti-viral and neuroprotective effects. This review concentrated on summarizing and analyzing the existing studies of hypericin in a comprehensive perspective. METHODS: The literature with desired information about hypericin published after 2010 was gained from electronic databases including PubMed, SciFinder, Science Direct, Web of Science, China National Knowledge Infrastructure databases and Wan Fang DATA. RESULTS: According to extensive preclinical and clinical studies conducted on the hypericin, an organized and comprehensive summary of the natural and artificial sources, strategies for improving the bioactivities, pharmacological activities, drug combination of hypericin was presented to explore the future therapeutic potential of this active compound. CONCLUSIONS: Overall, this review offered a theoretical guidance for the follow-up research of hypericin. However, the pharmacological mechanisms, pharmacokinetics and structure activity relationship of hypericin should be further studied in future research.

Sorafenib-loaded silica-containing redox nanoparticles for oral anti-liver fibrosis therapy.

Liver fibrosis is a chronic disease resulting from repetitive or prolonged liver injury with limited treatment options. Sorafenib has been reported to be a potential antifibrotic agent; however, its therapeutic effect is restricted because of its low bioavailability and severe adverse effects in the gastrointestinal (GI) tract. In this study, we developed sorafenib-loaded silica-containing redox nanoparticles (sora@siRNP) as an oral nanomedicine to treat liver fibrosis. The designed siRNP were prepared by self-assembly of amphiphilic block copolymers, which possess antioxidant nitroxide radicals as a side chain of the hydrophobic segment and porous silica particles in the nanoparticle core. The silica moieties in the core formed a crosslink between the self-assembling block copolymers to afford stable drug absorption, which could be useful in harsh GI conditions after oral drug administration. Based on in vitro evaluation, sora@siRNP exerted antiproliferative and antifibrotic effects against hepatic stellate cells (HSCs) and low toxicity against normal endothelial cells. A pharmacokinetic study showed that siRNP significantly improved the bioavailability and distribution of sorafenib in the liver. In an in vivo study using a mouse model of CCl4-induced liver fibrosis, oral administration of sora@siRNP significantly suppressed the fibrotic area in comparison to free sorafenib administration. In mice with CCl4-induced fibrosis, free sorafenib administration did not suppress the expression of α-smooth muscle actin; however, mice treated with sora@siRNP showed significantly suppressed expression of α-smooth muscle actin, indicating the inhibition of HSC activation, which was confirmed by in vitro experiments. Moreover, oral administration of free sorafenib induced severe intestinal damage and increased leakage into the gut, which can be attributed to the generation of reactive oxygen species (ROS). Our antioxidant nanocarriers, siRNP, reduced the adverse effects of local ROS scavenging in the GI tract. Our results suggest that sora@siRNP could serve as a promising oral nanomedicine for liver fibrosis.

DNA-RNA Heteroduplex Oligonucleotide for Highly Efficient Gene Silencing.

Heteroduplex oligonucleotides (HDOs) were a novel type of nucleic acid drugs based on an antisense oligonucleotide (ASO) strand and its complementary RNA (cRNA ) strand. HDOs were originally designed to improve the properties of RNase H-dependent ASOs and we reported in our first paper that HDOs conjugated with an α-tocopherol ligand (Toc-HDO ) based on a gapmer ASO showed 20 times higher silencing effect to liver apolipoprotein B (apoB) mRNA in vivo than the parent ASO. Thereafter the HDO strategy was found to be also effective for improving the properties of ASOs modulating blood-brain barrier function and ASO antimiRs which are RNase H-independent ASOs. Therefore, the HDO strategy has been shown to be versatile technology platform to develop effective nucleic acid drugs.

Development of a nanogel-based nasal vaccine as a novel antigen delivery system.

INTRODUCTION: Nasal vaccination is one of the most effective immunization methods because it can induce effective antigen-specific immune responses not only at the mucosal site of administration but also at distant mucosal surfaces, as well as in the systemic compartment. Based on this advantage, many nasal vaccines are being developed and some have been licensed and marketed for clinical use. However, some have been withdrawn because of unacceptable adverse events such as inactivated influenza vaccine administrated with a heat-labile enterotoxin of Escherichia coli as an adjuvant. Thus, it is important to consider both the efficacy and safety of nasal vaccines. Areas covered: This review describes the benefits of cholesteryl group-bearing pullulan (CHP) nanogels for nasal vaccine delivery and vaccine development identified on Pubmed database with the term 'Nanogel-based nasal vaccine'. Expert commentary: CHP nanogels have been developed as novel drug delivery system, and a cationic CHP nanogels have been demonstrated to induce effective immunity as a nasal vaccine antigen carrier. Since vaccine antigens incorporated into CHP nanogels have exhibited no brain deposition after nasal administration in mice and nonhuman primates, the vaccine seems safe, and could be a promising new delivery system.

Advanced Chemoembolization by Anti-angiogenic Calcium-Phosphate Ceramic Microspheres Targeting the Vascular Heterogeneity of Cancer Xenografts.

The purpose of the present study was to develop an advanced method of anti-angiogenic chemoembolization to target morphological vascular heterogeneity in tumors and further the therapeutic efficacy of cancer treatment. This new chemoembolization approach was designed using resorbable calcium-phosphate ceramic microspheres (CPMs), in a mixture of three different sizes, which were loaded with an anti-angiogenic agent to target the tumor vasculature in highly angiogenic solid tumors in humans in vivo. The human uterine carcinosarcoma cell line, FU-MMT-3, was used in this study because the tumor is highly aggressive and exhibits a poor response to radiotherapy and chemotherapeutic agents that are in current use. CPMs loaded with TNP-470, an anti-angiogenic agent, were injected into FU-MMT-3 xenografts in nude mice three times per week for 8 weeks. The treatment with TNP-470-loaded CPMs of three different diameters achieved a greater suppression of tumor growth in comparison to treatment with single-size TNP-470-loaded CPMs alone, and the control. Severe loss of body weight was not observed in any mice treated with any size of TNP-470-loaded CPMs. These results suggest that treatment with a mixture of differently-sized anti-angiogenic CPMs might be more effective than treatment with CPMs of a single size. This advanced chemoembolization method, which incorporated an anti-angiogenic agent to target the morphological vascular heterogeneity of tumors may contribute to effective treatment of locally advanced or recurrent solid tumors.