[Full-zirconia single-tooth molar implant-supported restorations with angulated screw channel abutments: evaluation of short-term outcomes].

PURPOSE: To evaluate the effect of full-zirconia single-tooth molar implant-supported restorations with angulated screw channel abutments. METHODS: Seventy-six patients with a single missing tooth in the posterior region of the maxilla and mandible underwent dental implants from March 2016 to March 2018 were enrolled. After 3 months, each patient received a full-contour screw-retained zirconia restoration with angulated screw channel abutment. Modified sulcus bleeding index (MSBI), modified plaque index (mPLI), periodontal probing depth (PD), marginal bone levels (MBLs) and mid-buccal mucosal levels (MBMLs) were recorded at the implantation moment (T0), four weeks (T1), one year (T2) and two years (T3) after treatment. During the follow-up period, the incidence of implant defects, survival rate and porcelain fracture were recorded. The data were processed using SPSS 23.0 software package. RESULTS: Of the 76 patients, 9 did not have a complete follow-up record (two of the implants failed before restoration, two patients had bilateral first molars missing, and five were lost to follow-up), and the remaining 67 patients with a total of 67 implants had a complete follow-up record. The success rate of implant was 97.01%(65/67) during one-year follow-up, and the initial success rate was 100% at an interval of three months. Compared with indexes at T0, mSBI and mPLI were significantly reduced at T1, T2 and T3 (P<0.05). There was no significant difference in PD level at T0, T1, T2 and T3(P>0.05), and the effective depth averaged 1.75 mm. Compared with indexes at T0, MBLs and MBMLs were significantly increased at T1(P<0.05). A total of 4 cases had implant reconstruction at T1 due to concerns about framework fracture, veneering fracture and aesthetics. At T2 and T3, there was no implant problems and loosening of restoration. There were 2 cases of peri-implant inflammation, one case of implant loss and one case of abutment pain, which were all improved after corresponding treatments. Two cases of porcelain fracture occurred in 67 zirconia restorations (2.63%), and the implant survival rate was 100%. CONCLUSIONS: Full-zirconia single-tooth molar implant-supported restorations with angulated screw channel abutments can effectively improve the implant stability in early phase, with high success rate, good short-term effect and few complications.

Restoring anti-tumor functions of T cells via nanoparticle-mediated immune checkpoint modulation.

The core purpose of cancer immunotherapy is the sustained activation and expansion of the tumor specific T cells, especially tumor-infiltrating cytotoxic T lymphocytes (CTLs). Currently, one of the main foci of immunotherapy involving nano-sized carriers is on cancer vaccines and the role of professional antigen presenting cells, such as dendritic cells (DCs) and other phagocytic immune cells. Besides the idea that cancer vaccines promote T cell immune responses, targeting immune inhibitory pathways with nanoparticle delivered regulatory agents such as small interfering RNA (siRNA) to the difficultly-transfected tumor-infiltrating T cells may provide more information on the utility of nanoparticle-mediated cancer immunotherapy. In this study, we constructed nanoparticles to deliver cytotoxic T lymphocyte-associated molecule-4 (CTLA-4)-siRNA (NPsiCTLA-4) and showed the ability of this siRNA delivery system to enter T cells both in vitro and in vivo. Furthermore, T cell activation and proliferation were enhanced after NPsiCTLA-4 treatment in vitro. The ability of direct regulation of T cells of this CTLA-4 delivery system was assessed in a mouse model bearing B16 melanoma. Our results demonstrated that this nanoparticle delivery system was able to deliver CTLA-4-siRNA into both CD4(+) and CD8(+) T cell subsets at tumor sites and significantly increased the percentage of anti-tumor CD8(+) T cells, while it decreased the ratio of inhibitory T regulatory cells (Tregs) among tumor infiltrating lymphocytes (TILs), resulting in augmented activation and anti-tumor immune responses of the tumor-infiltrating T cells. These data support the use of potent nanoparticle-based cancer immunotherapy for melanoma.

Nanomedicine-mediated cancer stem cell therapy.

Circumstantial evidence suggests that most tumours are heterogeneous and contain a small population of cancer stem cells (CSCs) that exhibit distinctive self-renewal, proliferation and differentiation capabilities, which are believed to play a crucial role in tumour progression, drug resistance, recurrence and metastasis in multiple malignancies. Given that the existence of CSCs is a primary obstacle to cancer therapy, a tremendous amount of effort has been put into the development of anti-CSC strategies, and several potential approaches to kill therapeutically-resistant CSCs have been explored, including inhibiting ATP-binding cassette transporters, blocking essential signalling pathways involved in self-renewal and survival of CSCs, targeting CSCs surface markers and destroying the tumour microenvironment. Meanwhile, an increasing number of therapeutic agents (e.g. small molecule drugs, nucleic acids and antibodies) to selectively target CSCs have been screened or proposed in recent years. Drug delivery technology-based approaches hold great potential for tackling the limitations impeding clinical applications of CSC-specific agents, such as poor water solubility, short circulation time and inconsistent stability. Properly designed nanocarrier-based therapeutic agents (or nanomedicines) offer new possibilities of penetrating CSC niches and significantly increasing therapeutic drug accumulation in CSCs, which are difficult for free drug counterparts. In addition, intelligent nanomedicine holds great promise to overcome pump-mediated multidrug resistance which is driven by ATP and to decrease detrimental effects on normal somatic stem cells. In this review, we summarise the distinctive biological processes related to CSCs to highlight strategies against inherently drug-resistant CSCs. We then focus on some representative examples that give a glimpse into state-of-the-art nanomedicine approaches developed for CSCs elimination. A perspective on innovative therapeutic strategies and the potential direction of nanomedicine-based CSC therapy in the near future is also presented.

Tumor Acidity-Sensitive Polymeric Vector for Active Targeted siRNA Delivery.

Although surface PEGylation of siRNA vectors is effective for preventing protein adsorption and thereby helps these vectors to evade the reticuloendothelial system (RES) in vivo, it also suppresses the cellular uptake of these vectors by target cells. This dilemma could be overcome by employing stimuli-responsive shell-detachable nanovectors to achieve enhanced cellular internalization while maintaining prolonged blood circulation. Among the possible stimuli, dysregulated pH in tumor (pHe) is the most universal and practical. However, the design of pHe-sensitive system is problematic because of the subtle differences between the pHe and pH in other tissues. Here, a simple acid-sensitive bridged copolymer is developed and used for tumor-targeted systemic delivery of siRNA. After forming the micelleplex delivery system, the corresponding nanoparticles (Dm-NP) might undergo several modifications as follows: (i) a poly(ethylene glycol) (PEG) corona, which is stable in the circulatory system and protects nanovectors from RES clearance; (ii) a pHe responsive linkage breakage, which induces PEG detachment at tumor sites and thereby facilitates cell targeting; and (iii) a cell-penetration peptide, which is exposed upon the removal of PEG and further enhances cellular uptake. Thus, Dm-NP achieved both prolonged circulation and effective accumulation in tumor cells and resulted in the safe and enhanced inhibition of non-small cell lung cancer growth.

Co-delivery of platinum drug and siNotch1 with micelleplex for enhanced hepatocellular carcinoma therapy.

As part of HCC tumor cellularity, cancer stem cells (CSCs) are considered a major obstacle to eradicate hepatocellular carcinoma (HCC), which is the third most common cause of cancer-related death worldwide, and the accumulation of chemotherapeutic drug-resistant CSCs invariably accounts for poor prognosis and HCC relapse. In the present study, we explored the efficacy of co-delivery of platinum drug and siRNA targeting Notch1 to treat CSCs-harboring HCC. To overcome the challenging obstacles of platinum drug and siRNA in the systemic administration, we developed a micellar nanoparticle (MNP) to deliver platinum(IV) prodrug and siNotch1, hereafter referred to as (Pt(IV))MNP/siNotch1. We demonstrated that (Pt(IV))MNP/siNotch1 was able to efficiently deliver two drugs into both non-CSCs and CSCs of SMMC7721, a HCC cell line. We further found that siRNA-mediated inhibition of Notch1 suppression can increase the sensitivity of HCC cells to platinum drugs and decrease the percentage of HCC CSCs, and consequently resulting in enhanced proliferation inhibition and apoptosis induction in HCC cells in vitro. Moreover, our results indicated that the combined drug delivery system can remarkably augment drug enrichment in tumor tissues, substantially suppressing the tumor growth while avoiding the accumulation of CSCs in a synergistic manner in the SMMC7721 xenograft model.