Multicompartment Nanoparticles by Crystallization-Driven Self-Assembly of Star Polymers: Combining High Stability and Loading Capacity.

Herein novel multicompartment nanoparticles (MCNs) that combine high stability and cargo loading capacity are developed. The MCNs are fabricated by crystallization-driven self-assembly (CDSA) of a tailor-made 21 arm star polymer, poly(L-lactide)[poly(tert-butyl acrylate)-block-poly(ethylene glycol)]20 [PLLA(PtBA-b-PEG)20 ]. Platelet-like or spherical MCNs containing a crystalline PLLA core and hydrophobic PtBA subdomains are formed and stabilized by PEG. Hydrophobic cargos, such as Nile Red and chemotherapeutic drug doxorubicin, can be successfully encapsulated into the collapsed PtBA subdomains with loading capacity two orders of magnitude higher than traditional CDSA nanoparticles. Depolarized fluorescence measurements of the Nile Red loaded MCNs suggest that the free volume of the hydrophobic chains in the nanoparticles may be the key for regulating their drug loading capacity. In vitro study of the MCNs suggests excellent cytocompatibility of the blank nanoparticles as well as a dose-dependent cellular uptake and cytotoxicity of the drug-loaded MCNs.

Sequential acid/reduction response of triblock copolymeric nanomicelles to release camptothecin and toll-like receptor 7/8 agonist for orchestrated chemoimmunotherapy.

BACKGROUND: Immunosuppressive tumor immune microenvironment (TIME) lowers immunotherapy effectiveness. Additionally, low penetration efficiency and unpredictable drug release in tumor areas restrict tumor therapy. METHODS: A triblock copolymeric micelle (NanoPCPT+PIMDQ) was developed to carry the chemotherapeutic drug camptothecin (CPT) and the TLR7/8 agonist 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c] quinoline-4-amine (IMDQ) to achieve deep tumor penetration and on-demand drug release by responding to acid and reduction stimuli sequentially. The synergistic antitumour efficacy of NanoPCPT+PIMDQ was assessed both in vitro and in vivo. RESULTS: NanoPCPT+PIMDQ is composed of a hydrophilic PEG(polyethylene glycol) outer layer, an acid-sensitive EPEMA middle layer, and a drug inner core. Upon intratumoral injection, (i) NanoPCPT+PIMDQ first responds to the acidic tumor microenvironment and disintegrates to PIMDQ and PCPT, penetrating deep regions of the tumor; (ii) tumor cells are killed by the released CPT; (iii) DCs are activated by PIMDQ to increase the infiltration of cytotoxic T lymphocyte (CTL); and (iv) both downregulated Foxp3+ Tregs by CPT and repolarized M2 macrophages by PIMDQ can relieve the TIME. CONCLUSION: This pH/GSH-responsive triblock polymer-drug conjugate reduces immunosuppression and enhances the infiltration of CTLs by codelivering CPT and IMDQ in a controllable manner, providing a promising platform for synergistic tumor chemoimmunotherapy.

Prevalence of Enamel Markings on Third Molars.

The purpose of this study was to measure the prevalence of enamel markings in routinely extracted third molars. One hundred donated third molars were examined. All had some marking(s). Caries was almost universal; white snowcapping of cusps and ridges was extremely common; pit and valley defects were very common; spots and bands were very common, most were white; horizontal grooves were common; linear enamel hypoplasia, considered to be a true developmental defect, was rare.

Optimization of direct currents to enhance dentine bonding of simplified one-step adhesive.

The aim of this study was to investigate the effects of different direct current intensities on dentine bonding effectiveness of Clearfil S(3) Bond and on cell viability of human dental pulp cells (HDPCs). Thirty-five-third molars were sectioned and ground to provide flat surfaces. Clearfil S(3) Bond was applied under different current conditions for 30 s and then resin composite was built up. Specimens were processed for microtensile bond strength (µTBS) testing and for nanoleakage investigation using scanning electron microscopy. Primary HDPCs isolated from premolars were stimulated with different intensities of electric current for 30 s. Then, cell viability was tested using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Specimens bonded with application of electrical current intensities of 50, 60, 70, and 90 µA exhibited a significant increase in immediate µTBS compared with all other groups. Bonded interfaces prepared using electrically assisted current application showed reduced interfacial nanoleakage upon scanning electron microscopy. Electric current application, from 20 to 70 µA, had no effect on the viability of HDPCs. This study provides further evidence for its future clinical use.

An Intelligent Nanovehicle Armed with Multifunctional Navigation for Precise Delivery of Toll-Like Receptor 7/8 Agonist and Immunogenic Cell Death Amplifiers to Eliminate Solid Tumors and Trigger Durable Antitumor Immunity.

Cancer immunotherapy is revolutionary in oncology and hematology. However, a low response rate restricts the clinical benefits of this therapy owing to inadequate T lymphocyte infiltration and low delivery efficiency of immunotherapeutic drugs. Herein, an intelligent nanovehicle (folic acid (FA)/1-(4-(aminomethyl) benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (IMDQ)-oxaliplatin (F/IMO)@CuS) armed with multifunctional navigation is designed for the accurate delivery of cargoes to tumor cells and dendritic cells (DCs), respectively. The nanovehicle is based on a near infrared-responsive inorganic CuS nanoparticles, acting as a photosensitizer and carrier of the chemotherapeutic agent oxaliplatin, and enters tumor cells owing to the presence of folic acid on the surface of CuS upon intratumoral injection. Furthermore, a toll-like receptor (TLR) 7/8 agonist-conjugated polymer, anchored on the surface of CuS, is modified with mannose to bind with DCs in the tumor microenvironment. Upon exposure to laser irradiation, nanovehicles disassemble, releasing oxaliplatin, to ablate tumor cells and amplify immunogenic cell death in combination with photothermal therapy. Mannose-modified polymer-TLR7/8 agonist conjugates are subsequently exposed, leading to the activation of DCs and proliferation of T cells. Collectively, these intelligent nanovehicles reduce tumor burden, exert a robust antitumor immune response, and generate long-term immune protection to prevent tumor recurrence.

Nanoleakage evaluation at adhesive-dentin interfaces by different observation methods.

The purpose of this study was to evaluate the capability and characteristics of different nanoleakage observation methods, including light microscope (LM), field-emission scanning electron microscope (FESEM), transmission electron microscope (TEM), and confocal laser scanning microscope (CLSM). Dentin specimens were bonded with either an etch-and-rinse adhesive (SBMP) or a self-etch adhesive (GB), and prepared for nanoleakge evaluation according to different observation methods. LM, FESEM and CLSM results demonstrated that the SBMP group showed more interfacial nanoleakage than the GB group (p<0.05); by contrast, no significant difference was found in TEM results (p>0.05), however, TEM illustrated concrete nanoleakage forms or patterns. The results suggested that different observation methods might exhibit distinct images and a certain degree of variations in nanoleakage statistical results. Researchers should carefully design and calculate the optimum assembly in combination with qualitative and quantitative approaches to obtain objective and accurate nanoleakage evaluation.