Self-Assembled PD-L1 Downregulator to Boost Photodynamic Activated Tumor Immunotherapy Through CDK5 Inhibition.

The immunosuppressive characteristics and acquired immune resistance can restrain the therapy-initiated anti-tumor immunity. In this work, an antibody free programmed death receptor ligand 1 (PD-L1) downregulator (designated as CeSe) is fabricated to boost photodynamic activated immunotherapy through cyclin-dependent kinase 5 (CDK5) inhibition. Among which, FDA approved photosensitizer of chlorin e6 (Ce6) and preclinical available CDK5 inhibitor of seliciclib (Se) are utilized to prepare the nanomedicine of CeSe through self-assembly technique without drug excipient. Nanoscale CeSe exhibits an increased stability and drug delivery efficiency, contributing to intracellular production of reactive oxygen species (ROS) for robust photodynamic therapy (PDT). The PDT of CeSe can not only suppress the primary tumor growth, but also induce the immunogenic cell death (ICD) to release tumor associated antigens. More importantly, the CDK5 inhibition by CeSe can downregulate PD-L1 to re-activate the systemic anti-tumor immunity by decreasing the tumor immune escape and therapy-induced acquired immune resistance. This work provides an antibody free strategy to activate systemic immune response for metastatic tumor treatment, which may accelerate the development of translational nanomedicine with sophisticated mechanism.

Tumor Homing Chimeric Peptide Rhomboids to Improve Photodynamic Performance by Inhibiting Therapy-Upregulated Cyclooxygenase-2.

Negative therapeutic feedback of inflammation would extensively attenuate the antitumor effect of photodynamic therapy (PDT). In this work, tumor homing chimeric peptide rhomboids (designated as NP-Mel) are fabricated to improve photodynamic performance by inhibiting PDT-upregulated cyclooxygenase-2 (COX-2). The hydrophobic photosensitizer of protoporphyrin IX (PpIX) and palmitic acid are conjugated onto the neuropilin receptors (NRPs) targeting peptide motif (CGNKRTR) to obtain tumor homing chimeric peptide (Palmitic-K(PpIX)CGNKRTR), which can encapsulate the COX-2 inhibitor of meloxicam. The well dispersed NP-Mel not only improves the drug stability and reactive oxygen species (ROS) production ability, but also increase the breast cancer targeted drug delivery to intensify the PDT effect. In vitro and in vivo studies verify that NP-Mel will decrease the secretion of prostaglandin E2 (PGE2) after PDT treatment, inducing the downregulation of IL-6 and TNF-α expressions to suppress PDT induced inflammation. Ultimately, an improved PDT performance of NP-Mel is achieved without inducing obvious systemic toxicity, which might inspire the development of sophisticated nanomedicine in consideration of the feedback induced therapeutic resistance.

Chimeric Peptide-Engineered Self-Delivery Nanomedicine for Photodynamic-Triggered Breast Cancer Immunotherapy by Macrophage Polarization.

A systemic treatment strategy is urgently demanded to suppress the rapid growth and easy metastasis characteristics of breast cancer. In this work, a chimeric peptide-engineered self-delivery nanomedicine (designated as ChiP-CeR) for photodynamic-triggered breast cancer immunotherapy by macrophage polarization. Among these, ChiP-CeR is composed of the photosensitizer of chlorine e6 (Ce6) and the TLR7/8 agonist of lmiquimod (R837), which is further modified with tumor matrix targeting peptide (Fmoc-K(Fmoc)-PEG8 -CREKA. ChiP-CeR is preferred to actively accumulate at the tumor site via specific recognition of fibronectin, which can eradicate primary tumor growth through photodynamic therapy (PDT). Meanwhile, the destruction of primary tumors would trigger immunogenic cell death (ICD) effects to release high-mobility group box-1(HMGB1) and expose calreticulin (CRT). Moreover, ChiP-CeR can also polarize M2-type tumor-associated macrophages (TAMs) into M1-type TAMs, which can activate T cell antitumor immunity in combination with ICD. Overall, ChiP-CeR possesses superior antitumor effects against primary and lung metastatic tumors, which provide an applicable nanomedicine and a feasible strategy for the systemic management of metastatic breast cancer.

Chimeric Peptide Engineered Bioregulator for Metastatic Tumor Immunotherapy through Macrophage Polarization and Phagocytosis Restoration.

Tumor-associated macrophages (TAMs) are the most abundant immune cells in solid tumor tissues, which restrict antitumor immunity by releasing tumor-supporting cytokines and attenuating phagocytosis behaviors. In this work, a chimeric peptide engineered bioregulator (ChiP-RS) is constructed for tumor immunotherapy through macrophage polarization and phagocytosis restoration. ChiP-RS is fabricated by utilizing macrophage-targeting chimeric peptide (ChiP) to load Toll-like receptor agonists (R848) and Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP-2) inhibitor (SHP099). Among which, ChiP-RS prefers to be internalized by TAMs, repolarizing M2 macrophages into M1 macrophages to reverse the immunosuppressive microenvironment. In addition, SHP-2 can be downregulated to promote phagocytotic elimination behaviors of M1 macrophages, which will also activate T cell-based antitumor immunity for metastatic tumor therapy. In vitro and in vivo findings demonstrate a superior suppression effect of ChiP-RS against metastatic tumors without systemic side effects. Such a simple but effective nanoplatform provides sophisticated synergism for immunotherapy, which may facilitate the development of translational nanomedicine for metastatic tumor treatment.

A carrier free photodynamic oxidizer for enhanced tumor therapy by redox homeostasis disruption.

Abnormal tumor microenvironments play important roles in cancer progression. In general, tumor cells are capable of upregulating glutathione (GSH) levels to maintain aberrant redox homeostasis and cause resistance to oxidative damage. Herein, we develop a photodynamic oxidizer to disrupt the redox homeostasis of tumor cells for enhanced photodynamic tumor therapy. Based on pyropheophorbide-a (Pyro) and naphthazarin (Nap), a carrier free photodynamic oxidizer (named PyroNap) is prepared by the self-assembly technique through hydrophobic interactions. It is confirmed that nanosized PyroNap has high drug contents as well as favorable dispersity and stability. Besides, the photodynamic property of Pyro has obviously improved after self-assembly into the nanomedicine of PyroNap, which facilitates the production of reactive oxygen species (ROS) for robust photodynamic therapy (PDT). More importantly, the Nap induced GSH decrease could disrupt the redox homeostasis of tumor cells to further improve the PDT efficacy on tumor suppression. Consequently, after intravenous administration, PyroNap was able to significantly inhibit tumor growth and cause minimal side effects. This study might shed light on developing translational nanomedicine for tumor precision therapy.

Self-delivery nanomedicine to overcome drug resistance for synergistic chemotherapy.

Multidrug resistance (MDR) is one of the prime reasons for the failure of cancer chemotherapy, which continues to be a great challenge to be solved. In this work, α-tocopherol succinate (α-TOS) and doxorubicin (DOX)-based self-delivery nanomedicine (designated as α-TD) is prepared to combat drug resistance for cancer synergistic chemotherapy. Carrier-free α-TD possesses a fairly high drug loading rate and improves the cellular uptake via the endocytosis pathway. More importantly, the apoptotic inducer α-TOS could elevate the reactive oxygen species (ROS) generation, disrupt mitochondrial function and reduce adenosine 5'-triphosphate (ATP) production, which facilitate the intracellular drug retention while decreasing its efflux. As a result, α-TD achieves a considerable synergistic chemotherapeutic effect against drug resistant cancer cells. Moreover, it also exhibits a preferable inhibitory effect on tumor growth with a low system toxicity in vivo. This synergistic drug self-delivery strategy would open a new window for developing carrier-free nanomedicine for overcoming drug resistance in cancer therapy.

Self-Delivery Photo-Immune Stimulators for Photodynamic Sensitized Tumor Immunotherapy.

Self-delivery of photosensitizer and immune modulator to tumor site is highly recommendable to improve the photodynamic immunotherapy yet remains challenging. Herein, self-delivery photoimmune stimulators (designated as iPSs) are developed for photodynamic sensitized tumor immunotherapy. Carrier-free iPSs are constructed by optimizing the noncovalent interactions between the pure drugs of chlorine e6 (Ce6) and NLG919, which avoid the excipients-raised toxicity and immunogenicity. Intravenously administrated iPSs prefer to passively accumulate on tumor tissues for a robust photodynamic therapy (PDT) with the induction of immunogenetic cell death (ICD) cascade to activate cytotoxic T lymphocytes (CTLs) and initiate antitumor immune response. Meanwhile, the concomitant delivery of NLG919 inhibits the activation of indoleamine 2,3-dioxygenase 1 (IDO-1) to reverse the immunosuppressive tumor microenvironment. Ultimately, the photodynamic sensitized immunotherapy with iPSs efficiently inhibit the primary and distant tumor growth with a low system toxicity, which would shed light on the development of self-delivery nanomedicine for clinical transformation in tumor precision therapy.

Treatment planning of implants when 3 mandibular posterior teeth are missing: a 3-dimensional finite element analysis.

PURPOSE: To analyze the biomechanics of 3 designs of implant treatment for 3 teeth missing in posterior low arch quadrants. MATERIAL AND METHODS: A posterior portion of the human mandible missing 44, 45, 46 and three 4.1 × 10 mm threaded ITI implants with crowns were used to construct the finite element model. According to 3 implants being single, splinted or 2 implants support fixed partial denture (FPD) fixed in bone segments. Three implant support conditions were prepared with ANSYS 10.0. A load of 100 N was applied at the central fossa of the occlusal surfaces of the crowns at 45 degrees buccolingually along the triangular ridge of the buccal cusp. The von Mises stress and strain distributions in periimplant bone were observed. RESULTS: The results demonstrated that the von Mises stress in the supporting bone of the 2-implant supported FPD significantly increased compared with that in the 3-implant replacement. Meanwhile, when 3 implants were splinted, only the median implant had a decreased and more homogenous stress distribution, and the other implants did not exhibit significant differences when splinted. CONCLUSION: This study suggests that when space and cost permit, a 2-implant supported FPD should not be used, and 1 implant for each missing tooth being single is recommended.

Influence of masticatory fatigue on the fracture resistance of the pulpless teeth restored with quartz-fiber post-core and crown.

To investigate whether masticatory fatigue affects the fracture resistance and pattern of lower premolars restored with quartz-fiber post-core and full crown, 44 single rooted lower premolars recently extracted from orthodontic patients were divided into two groups of 22 each. The crowns of all teeth were removed and endodontically treated and then restored with quartz-fiber post-core and full crown. Twenty-two teeth in one group were selected randomly and circularly loaded at 45° to the long axis of the teeth of 127.4 N at a 6 Hz frequency, and the other group was not delivered to cyclic loading and considered as control. Subsequently, all teeth in two groups were continually loaded to fail at 45° to the long axis of the teeth at a crosshead speed of 1 mm⋅min(-1). The mean destructive force values were (733.88±254.99) and (869.14±280.26) N for the experimental and the control group, respectively, and no statistically significant differences were found between two groups (P>0.05). Bevel fracture and horizontal fracture in the neck of root were the major fracture mode of the specimens. Under the circumstances of this study, it seems that cyclic loading does not affect the fracture strength and pattern of the quartz-fiber post-core-crown complex.

[Influence of bone quality on the stress distribution for three-posterior immediately loaded implants: a three-dimensional finite element analysis].

OBJECTIVE: To assess and compare the peri-implant stress distribution of three posterior implants under immediate loading with 4 different bone qualities using three dimensional (3D) finite element (FE) analysis. METHODS: A 3D finite element model representing three implants in a portion of mandible at the 654 region was developed, and three implants received a crown each. Four types of bone qualities (B1, B2, B3 and B4) were designed for the model. Load of 100 N was applied on the occlusal surfaces of the crowns at a 45° angle to the vertical axis of the implants. RESULTS: Von Mises stresses in the peri-implant bone of 4 in bone quality from B1 to B4 were (13.17 ± 9.32), (12.95 ± 9.14), (15.00 ± 9.44), and (16.81 ± 10.74) MPa, and those of 5 were (15.51 ± 10.32), (14.73 ± 8.96), (16.79 ± 8.40), and (18.34 ± 8.45) MPa. Stress in bone quality B4 showed the highest value, followed by B3 bone, the lowest stress were found in B1 and B2 bone. It was significantly different (P < 0.05). However, von Mises stresses in different quality of bone around 6 [(42.45 ± 25.71), (41.66 ± 25.29), (42.70 ± 23.24), (42.06 ± 23.66) MPa] were close to each other, and were as twice or three times as those of 4 and 5, irrespective of different bone qualities. CONCLUSIONS: The stress distribution around implant under immediate loading was not only affected by different bone qualities, but also by the direction of loading, and the latter may have a greater impact when a severe load delivered.

Experimental research of accurate reduction of zygomatic-orbitomaxillary complex fractures with individual templates.

PURPOSE: To develop a feasible intraoperative guiding device using computer-aided design and computer-aided manufacturing of individual templates to permit anatomic fracture reduction of zygomatic-orbitomaxillary complex (ZOMC) comminuted fractures. The simplicity and accessibility of this method should allow its widespread clinical application. MATERIALS AND METHODS: Under an institutional review board-approved protocol, diverse ZOMC fracture types were created in 6 cadaver heads with a hammer and a saw, and preoperative multislice spiral computerized tomography scan and 3-dimensional reconstruction were performed. Three individual templates were made by computer-aided design and computer-aided manufacturing, and the fractures were repaired under the guidance of individual templates. A clinical case was carried out with this method. After surgery, the outcome evaluation was completed by superimposing the postoperative computed tomographic model onto the planned model. RESULTS: Successful planning and repositioning of the 6 cadavers and a clinical patient were achieved using this method. Computer-aided design and computer-aided manufacturing of individual templates were successfully used in all cases at the time of surgery. Postoperative computed tomographic scans confirmed anatomic repair in all cases. CONCLUSIONS: A feasible intraoperative ZOMC fracture monitoring and reduction guidance device has been developed. This technique is a simple, economical, and readily accessible method of comminuted ZOMC fracture reduction that can be learned and used rapidly.

Accuracy of intraoral vertical ramus osteotomy with a stereolithographic template.

Various modifications have been described to improve the accuracy in intraoral vertical ramus osteotomy (IVRO), but there was not a measurable facility to determine the osteotomy line. The purpose of this study was to evaluate the accuracy of the computer tomography (CT)-based osteotomy template on cadaver mandibles and to assess the outcome after IVRO correcting mandibular prognathism. Four human wet cadaver heads were subjected to a high-resolution multislice spiral CT scan. After the virtual osteotomies in the planning program, the individual osteotomy templates were produced by stereolithography. A stable and secure fit of the stereolithographic templates was achieved via the individual CT-based osteotomy template. The osteotomy lines were performed exactly as planned in the virtual osteotomies planning program. Similar sound outcome was also observed in the clinic. Use of the CT-based osteotomy templates is a safe method for osteotomy. It is rather convenient for vertical osteotomy in IVRO increasing the intraoperative accuracy and efficiency.