Smart delivery of lethal poly-peptide composite for effective cancer therapy

In the past decade, multifunctional peptides have attracted increasing attention in the biomedical field. Peptides possess many impressive advantages, such as high penetration ability, low cost, and etc. However, the short half-life and instability of peptides limit their application. In this study, a poly-peptide drug loading system (called HKMA composite) was designed based on the different functionalities of four peptides. The peptide compositions of HKMA composite from N-terminal to C-terminal were HCBP1, KLA, MMP-2-cleavable peptide and ABD. The targeting and lethality of HKMA to NSCLC cell line H460 sphere cells and the half-life of the system were measured in vivo. The results showed that the HKMA composite had a long half-life and specific killing effect on H460 sphere cells in vitro and in vivo. Our result proposed smart peptide drug loading system and provided a potential methodology for effective cancer treatment.

Permeability of the Composite Magnetic Microcapsules Triggered by a Non-Heating Low-Frequency Magnetic Field

Nanosystems for targeted delivery and remote-controlled release of therapeutic agents has become a top priority in pharmaceutical science and drug development in recent decades. Application of a low frequency magnetic field (LFMF) as an external stimulus opens up opportunities to trigger release of the encapsulated bioactive substances with high locality and penetration ability without heating of biological tissue in vivo. Therefore, the development of novel microencapsulated drug formulations sensitive to LFMF is of paramount importance. Here, we report the result of LFMF-triggered release of the fluorescently labeled dextran from polyelectrolyte microcapsules modified with magnetic iron oxide nanoparticles. Polyelectrolyte microcapsules were obtained by a method of sequential deposition of oppositely charged poly(allylamine hydrochloride) (PAH) and poly(sodium 4-styrenesulfonate) (PSS) on the surface of colloidal vaterite particles. The synthesized single domain maghemite nanoparticles integrated into the polymer multilayers serve as magneto-mechanical actuators. We report the first systematic study of the effect of magnetic field with different frequencies on the permeability of the microcapsules. The in situ measurements of the optical density curves upon the 100 mT LFMF treatment were carried out for a range of frequencies from 30 to 150 Hz. Such fields do not cause any considerable heating of the magnetic nanoparticles but promote their rotating-oscillating mechanical motion that produces mechanical forces and deformations of the adjacent materials. We observed the changes in release of the encapsulated TRITC-dextran molecules from the PAH/PSS microcapsules upon application of the 50 Hz alternating magnetic field. The obtained results open new horizons for the design of polymer systems for triggered drug release without dangerous heating and overheating of tissues.

A Nanogel with Effective Blood-Brain Barrier Penetration Ability through Passive and Active Dual-Targeting Function

Clinically, surgery assisted by chemotherapy is the most effective treatment of cancer. But from our clinical observation, the median survival of patients with glioblastoma is still not so good with only 15-16 months. The low therapeutic index is mainly due to the blood-brain barrier (BBB) which significantly hindered the chemotherapeutic drug accumulation in tumor tissue. One main composition of the BBB is astrocyte, which contains a lipophilic cell membrane, which prevents more than 98% of small-molecule drugs from entering the brain. Previously, we found that the nanogel with passive targeting function can increase the BBB penetration ability, which indicates that it could be used to overcome the above mentioned in vivo obstacles which promoted drug accumulation in the tumor. In this study, thermosensitive targeted nanogel delivery systems (DPPC) with cell-penetrating peptides (CPP) are introduced onto the particle surface for active astrocyte breaking. The hydrodynamic radius of DPPC is around 300 nm, the potential is about 0-5 mV, and the TEM and DLS studies further confirm its well spherical morphology and uniform distribution. The DPPC is verified as the biocompatible carriers for further application by cell viability tests. The in vitro-constructed BBB model successfully proves that DPPC can efficiently penetrate the BBB, which is attributed to both the temperature-sensitive passive targeting and the active CPP penetration. Consequently, the intracellular doxorubicin (DOX) promotes such functional DPPC at the relatively high temperature inside tumor microenvironment (TME) (~42°C), which obviously improves intratumor drug accumulation and tumor cell-killing effects. The dual-targeted nanogel delivery systems designed in this study provides a more effective strategy for the treatment of glioma.

Gelatin/Polycaprolactone Electrospun Nanofibrous Membranes: The Effect of Composition and Physicochemical Properties on Postoperative Cardiac Adhesion

Cardiovascular diseases have become a major threat to human health. The adhesion formation is an inevitable pathophysiological event after cardiac surgery. We have previously shown that gelatin/polycaprolactone (GT/PCL, mass ratio 50:50) electrospun nanofibrous membranes have high potential in preventing postoperative cardiac adhesion, but the effect of GT:PCL composition on anti-adhesion efficacy was not investigated. Herein, nanofibrous membranes with different GT:PCL mass ratios of 0:100, 30:70, 50:50, and 70:30 were prepared via electrospinning. The 70:30 membrane failed to prevent postoperative cardiac adhesion, overly high GT contents significantly deteriorated the mechanical properties, which complicated the suturing during surgery and hardly maintained the structural integrity after implantation. Unexpectedly, the 0:100 membrane (no gelatin contained) could not effectively prevent either, since its large pore size allowed the penetration of numerous inflammatory cells to elicit a severe inflammatory response. Only the GT:PCL 50:50 membrane exhibited excellent mechanical properties, good biocompatibility and effective anti-cell penetration ability, which could serve as a physical barrier to prevent postoperative cardiac adhesion and might be suitable for other biomedical applications such as wound healing, guided tissue or bone regeneration.

Multifunctional exosome-mimetics for targeted anti-glioblastoma therapy by manipulating protein corona

Targeted drug delivery to the glioblastoma (GBM) overcoming blood–brain barrier (BBB) has been challenging. Exosomes are promising vehicles for brain tumor drug delivery, but the production and purification hinder its application for nanomedicine. Besides, the formation of protein corona (PC) may affect the behaviour of nanocarriers. Here, multifunctional exosomes-mimetics (EM) are developed and decorated with angiopep-2 (Ang) for enhancing GBM drug delivery by manipulating PC. Docetaxel (DTX)-loaded EM with Ang modification (DTX@Ang-EM) show less absorption of serum proteins and phagocytosis by macrophages. Ang-EM show enhanced BBB penetration ability and targeting ability to the GBM. Ang-EM-mediated delivery increase the concentration of DTX in the tumor area. The multifunctional DTX@Ang-EM exhibits significant inhibition effects on orthotopic GBM growth with reduced side effects of the chemotherapeutic. Findings from this study indicate that the developed DTX@Ang-EM provide a new strategy for targeted brain drug delivery and GBM therapy. Graphical abstract

Penetration and Tensile Strength of Various Impression Materials of Vinylsiloxanether, Polyether, and Polyvinylsiloxane Impression Materials

Objectives The aim of this study was to evaluate and compare penetration ability and tensile strength among vinylsiloxanether (VSE), polyether (PE), and polyvinylsiloxane (PVS) elastomeric dental impression materials. Materials and Methods The models were constructed for penetration ability test by simulated gingival sulcus width and moist environment. The 0.05, 0.1, and 0.2 mm of simulated gingival sulcus widths were used. Each simulated gingival sulcus width was impressed 10 repeats per one elastomeric impression material. All extension of elastomeric dental impression materials was scaled by Measuring Microscope (MM-11; Nikon, Tokyo, Japan). On the issue of the tensile strength study, the models were constructed following type 1 of the ISO 37:2017 specifications and/or type C of ASTM.D412 specifications. The two-way analysis of variance (ANOVA) and Tukey's honest significant difference test were performed in the penetration ability test. The one-way ANOVA and Dunnett's T3 test were performed in the tensile strength test. The significance level was set at 0.05. Results PE showed the best extension into all widths of simulated sulcus followed by VSE and PVS, respectively. PVS was significantly higher in tensile strength than VSE and PE, while VSE was significantly higher than PE. Conclusion Penetration ability of elastomeric dental impression materials was depended on gingival sulcus width. The wider the sulcular width, the better the penetration ability of elastomeric dental impression materials. PE presented the best penetration ability, while the novel PVS showed highest tensile strength.

Xanthine: Synthetic Strategy And Biological Activity

Xanthine and its derivatives belong to the class of purine alkaloids. They are natural bases holding nitrogen atoms within the molecular structure, and they have an effective pharmacological alteration in both animals and human beings. Substituted xanthine, theophylline/caffeine being prototype, is one of the derivatives which have shown prominent binding to adenosine receptors as agonist or antagonist. Various mechanistic approaches are involved in exerting bronchospasmolytic, neuroprotective, hypoglycemic, MAO modulatory, along cardiac effects. Mostly, xanthine derivatives reduce inflammation and bronchospasm in asthmatic conditions. Other therapeutics effects are in the management of cancer, Alzheimer's disease, vasoconstriction, and also possess excellent central nervous system-penetration ability; thus, they can also be used as stimulants and anti-depressants. Their actions are relatively very weak, but their pharmacological effects are also associated with snarl-up adenosine-mediated functions. An assortment of the biological profile of the xanthine scaffold attracted many research groups over the years to explore this nucleus vividly. The present review is aimed to cover every aspect of the xanthine moiety reported in the earlier years. This review covers all the major biological roles and various synthetic strategies adopted to synthesize xanthine moiety and its derivatives.

Recent Progress on the Synergistic Antitumor Effect of a Borneol-Modified Nanocarrier Drug Delivery System

Borneol, a traditional Chinese medicine, can enhance therapeutic efficacy by guiding the active ingredients to the target site. Reportedly, borneol improves the penetration capacity of the nasal, cornea, transdermal, intestinal, and blood-brain barriers. Although nanotechnology dramatically changed the face of oncology by targeting tumor sites, the efficiency of nanoparticles delivered to tumor sites is very low, with only 0.7% of the total particles delivered. Thus, based on the penetration ability and the inhibition drug efflux of borneol, it was expected to increase the targeting and detention efficacy of drugs into tumor sites in nanocarriers with borneol modification. Borneol modified nanocarriers used to improve drug-targeting has become a research focus in recent years, but few studies in this area, especially in the antitumor application. Hence, this review summarizes the recent development of nanocarriers with borneol modification. We focus on the updated works of improving therapeutic efficacy, reducing toxicity, inhibiting tumor metastasis, reversing multidrug resistance, and enhancing brain targeting to expand their application and provide a reference for further exploration of targeting drug delivery systems for solid tumor treatment.