Precisely Programmable Degradation and Drug Release Profiles in Triblock Copolyether Hydrogels with Cleavable Acetal Pendants.

Hydrogels hold significant promise as drug delivery systems due to their distinct advantage of sustained localized drug release. However, the challenge of regulating the initial burst release while achieving precise control over degradation and drug-release kinetics persists. Herein, we present an ABA-type triblock copolymer-based hydrogel system with precisely programmable degradation and release kinetics. The resulting hydrogels were designed with a hydrophilic poly(ethylene oxide) midblock and a hydrophobic end-block composed of polyethers with varying ratios of ethoxyethyl glycidyl ether and tetrahydropyranyl glycidyl ether acetal pendant possessing different hydrolysis kinetics. This unique side-chain strategy enabled us to achieve a broad spectrum of precise degradation and drug-release profiles under mildly acidic conditions while maintaining the cross-linking density and viscoelastic modulus, which is unlike the conventional polyester-based backbone degradation system. Furthermore, programmable degradation of the hydrogels and release of active therapeutic agent paclitaxel loaded therein are demonstrated in an in vivo mouse model by suppressing tumor recurrence following surgical resection. Tuning of the fraction of two acetal pendants in the end-block provided delicate tailoring of hydrogel degradation and the drug release capability to achieve the desired therapeutic efficacy. This study not only affords a facile means to design hydrogels with precisely programmable degradation and release profiles but also highlights the critical importance of aligning the drug release profile with the target disease.

H2O2-Activatable Antioxidant Polymeric Prodrug Nanoparticles for the Prevention of Renal Ischemia/Reperfusion Injury.

Renal ischemia-reperfusion (IR) injury is an inevitable complication in various clinical settings including kidney transplantation and major vascular surgeries. Renal IR injury is a major risk factor for acute kidney injury, which still remains a major clinical challenge without effective therapy. The main cause of renal IR injury is the massive production of reactive oxygen species (ROS) including hydrogen peroxide (H2O2) that initiate inflammatory signaling pathways, leading to renal cell death. In this study, we developed fucoidan-coated polymeric prodrug (Fu-PVU73) nanoparticles as renal IR-targeting nanotherapeutics that can rapidly eliminate H2O2 and exert anti-inflammatory and antiapoptotic effects. Fu-PVU73 nanoparticles were composed of H2O2-activatable antioxidant and anti-inflammatory polymeric prodrug (PVU73) that incorporated H2O2-responsive peroxalate linkages, ursodeoxycholic acid (UDCA), and vanillyl alcohol (VA) in its backbone. Fu-PVU73 nanoparticles rapidly scavenged H2O2 and released UDCA and VA during H2O2-triggered degradation. In the study of renal IR injury mouse models, Fu-PVU73 nanoparticles preferentially accumulated in the IR injury-induced kidney and markedly protected the kidney from IR injury by suppressing the generation of ROS and the expression of proinflammatory cytokines. We anticipate that Fu-PVU73 nanoparticles have tremendous therapeutic potential for not only renal IR injury but also various ROS-associated inflammatory diseases.

pH-Responsive Amphiphilic Polyether Micelles with Superior Stability for Smart Drug Delivery.

Despite widespread interest in the amphiphilic polymeric micelles for drug delivery systems, it is highly desirable to achieve high loading capacity and high efficiency to reduce the side effects of therapeutic agents while maximizing their efficacy. Here, we present a novel hydrophobic epoxide monomer, cyclohexyloxy ethyl glycidyl ether (CHGE), containing an acetal group as a pH-responsive cleavable linkage. A series of its homopolymers, poly(cyclohexyloxy ethyl glycidyl ether)s (PCHGEs), and block copolymers, poly(ethylene glycol)-block-poly(cyclohexyloxy ethyl glycidyl ether)s (mPEG-b-PCHGE), were synthesized via anionic ring-opening polymerization in a controlled manner. Subsequently, the self-assembled polymeric micelles of mPEG-b-PCHGE demonstrated high loading capacity, excellent stability in biological media, tunable release efficiency, and high cell viability. Importantly, quantum mechanical calculations performed by considering prolonged hydrolysis of the acetal group in CHGE indicated that the CHGE monomer had higher hydrophobicity than three other functional epoxide monomer analogues developed. Furthermore, the preferential cellular uptake and in vivo therapeutic efficacy confirmed the enhanced stability and the pH-responsive degradation of the amphiphilic block copolymer micelles. This study provides a new platform for the development of versatile smart polymeric drug delivery systems with high loading efficiency and tailorable release profiles.

Targeting of intragraft reactive oxygen species by APP-103, a novel polymer product, mitigates ischemia/reperfusion injury and promotes the survival of renal transplants.

Inflammatory responses associated with ischemia/reperfusion injury (IRI) play a central role in alloimmunity and transplant outcomes. A key event driving these inflammatory responses is the burst of reactive oxygen species (ROS), with hydrogen peroxide (H2 O2 ) as the most abundant form that occurs as a result of surgical implantation of the donor organ. Here, we used a syngeneic rat renal transplant and IRI model to evaluate the therapeutic properties of APP-103, a polyoxalate-based copolymer molecule containing vanillyl alcohol (VA) that exhibits high sensitivity and specificity toward the production of H2 O2 . We show that APP-103 is safe, and that it effectively promotes kidney function following IRI and survival of renal transplants. APP-103 reduces tissue injury and IRI-associated inflammatory responses in models of both warm ischemia (kidney clamping) and prolonged cold ischemia (syngeneic renal transplant). Mechanistically, we demonstrate that APP-103 exerts protective effects by specifically targeting the production of ROS. Our data introduce APP-103 as a novel, nontoxic, and site-activating therapeutic approach that effectively ameliorates the consequences of IRI in solid organ transplantation.

Engineered Polymeric Micelles for Combinational Oxidation Anticancer Therapy through Concurrent HO-1 Inhibition and ROS Generation.

Cancer cells have a large amount of ROS (reactive oxygen species) because of disturbed ROS homeostasis. Cancer cells therefore undertake redox adaptation to drive proliferation in tumor environments and even survive during anticancer treatment by upregulating endogenous antioxidants. As one of antioxidant defense systems, heme oxygenase-1 (HO-1) acts as an essential role in tumor development by offering antioxidant bilirubin to protect cancer cells under stress conditions. It can be therefore reasoned that the combination of ROS generation and HO-1 inhibition would exert synergistic anticancer effects through the amplification of oxidative stress and provide a new opportunity for targeted anticancer therapy. To establish targeted anticancer therapy based on amplified oxidative stress, we developed molecularly engineered polymer, termed CZP, which incorporates ROS generating CA (cinnamaldehyde) and HO-1 inhibiting ZnPP (zinc protoporphyrin) in its backbone and could form stable micelles in aqueous solutions. CZP micelles not only elevated oxidative stress but also suppressed the expression of antioxidant HO-1, leading to apoptotic cell death. CZP micelles could also significantly suppress the tumor growth without body weight loss, tumor recurrence, and noticeable toxicity in organs. This study demonstrates that a combination of ROS generation and HO-1inhibition synergistically magnifies oxidative stress to kill cancer cells and oxidative stress amplifying CZP micelles may provide a promising strategy in anticancer treatment.

Hydrogen peroxide-activatable polymeric prodrug of curcumin for ultrasound imaging and therapy of acute liver failure.

Curcumin is a major active phenolic component of turmeric and has gained great attention in pharmaceutics due to its potent antioxidant, anti-inflammatory and anticancer activity. Here, we developed poly(oxalate-co-curcumin) (POC) as a hydrogen peroxide (H2O2)-activatable polymeric prodrug of curcumin by incorporating curcumin in the backbone of H2O2-responsive polyoxalate. POC particles effectively scavenged H2O2 and released curcumin in a H2O2-triggered manner. POC particles exhibited excellent antioxidant and anti-inflammatory activity in activated cells. POC particles intravenously administrated into acetaminophen-intoxicated mice remarkably suppressed the level of alanine transaminase and inhibited apoptotic cell death in liver. Interestingly, POC particles could also enhance the ultrasound contrast in the intoxicated liver due to CO2 bubble generation through H2O2-triggered oxidation of peroxalate esters. Given their H2O2-responsiveness and highly potent antioxidant activity, POC particles hold great translational potential as theranostic agents for H2O2-associated diseases.

Reactive Oxygen Species Responsive Naturally Occurring Phenolic-Based Polymeric Prodrug.

Reactive Oxygen Species (ROS) play a vital role in the biological system. Exaggerated, ROS have devastating effects on the human body leading to the pathophysiological condition including the transformation of a normal cell into a cancer phenotype. Nature has blessed us with various biomolecules that we use along with our dietary supplements. Using such therapeutic small molecules covalently incorporated into biodegradable polyoxalate polymer backbone with a responsive group forms an efficient drug delivery vehicle. This chapter "Reactive oxygen species responsive naturally occurring phenolic-based polymeric prodrug" will be focusing on redox-responsive polymers incorporated with naturally occurring phenolics and clinical application.

Effect of Ratio of Residual Alveolar Bone to Graft Material in Contact With Fixture Surface on Marginal Bone Loss of Implants in Augmented Maxillary Sinuses: A 1-Year Retrospective Study.

PURPOSE: The purpose of this retrospective study was to evaluate the influences of height or area ratio of residual alveolar bone to graft material on marginal bone loss around implants in the augmented maxillary sinuses with delayed implant placement. MATERIALS AND METHODS: In this study, 42 patients with Astra implants in sinuses that had been augmented with alloplasts and allografts or xenografts (alveolar bone height ≤ 5 mm) were selected. Marginal bone level surrounding 1 implant per sinus was assessed by radiographic imaging at the time of final restoration delivery and 12 months after functional loading. To evaluate the marginal bone level alterations using clinical and radiographic data, Pearson's correlation analysis and Mann-Whitney test were performed. RESULTS: Forty-six implants were included in this study. The residual bone/implant length ratio and the residual bone/implant area ratio were not associated with marginal bone loss at 1 year after functional loading (P > 0.05). And, marginal bone loss did not differ significantly between 2 types of graft materials during the observation period (P > 0.05). CONCLUSION: The residual bone/implant length ratio and residual bone/implant area ratio were not associated with marginal bone loss around implants placed in augmented sinuses during 1 year of functional loading.

Effects of thread size in the implant neck area on peri-implant hard and soft tissues: an animal study.

OBJECTIVES: The aim of this animal study was to examine the effects of thread size in the implant neck area on peri-implant tissues in terms of BIC and hard- and soft-tissue dimensions. MATERIALS AND METHODS: Six Beagle dogs received experimental implants in the mandible 3 month after the removal of premolars and first molars (P2, P3, P4, and M1). Two different types of implants were installed in each animal: Anyone microthread(®) as Group 1 and Anyone(®) as Group 2. Resonance frequency test, intraoral radiography, micro-CT, and histomorphometry were used to evaluate peri-implant tissue after implantation periods of 4 and 8 weeks. RESULTS: No remarkable complication was observed during the healing period in either group. Resonance frequency testing revealed no significant difference between groups. In radiographic evaluation, Group 2 showed more bone loss than Group 1. However, this difference was not statistically significant. In the micro-CT analysis, BIC and BIV values and soft-tissue height were not significant in both groups. Histological analysis revealed no significant difference in BIC ratio, bone density, or bone loss between groups. However, soft-tissue height was significantly greater in Group 2 than in Group 1 (P = 0.0004). CONCLUSION: No difference in peri-implant hard or soft tissues was observed according to thread size in the implant neck area.

Structural insights into the dual nucleotide exchange and GDI displacement activity of SidM/DrrA.

GDP-bound prenylated Rabs, sequestered by GDI (GDP dissociation inhibitor) in the cytosol, are delivered to destined sub-cellular compartment and subsequently activated by GEFs (guanine nucleotide exchange factors) catalysing GDP-to-GTP exchange. The dissociation of GDI from Rabs is believed to require a GDF (GDI displacement factor). Only two RabGDFs, human PRA-1 and Legionella pneumophila SidM/DrrA, have been identified so far and the molecular mechanism of GDF is elusive. Here, we present the structure of a SidM/DrrA fragment possessing dual GEF and GDF activity in complex with Rab1. SidM/DrrA reconfigures the Switch regions of the GTPase domain of Rab1, as eukaryotic GEFs do toward cognate Rabs. Structure-based mutational analyses show that the surface of SidM/DrrA, catalysing nucleotide exchange, is involved in GDI1 displacement from prenylated Rab1:GDP. In comparison with an eukaryotic GEF TRAPP I, this bacterial GEF/GDF exhibits high binding affinity for Rab1 with GDP retained at the active site, which appears as the key feature for the GDF activity of the protein.

Macrophage depletion ameliorates glycerol-induced acute kidney injury in mice.

BACKGROUND: This study was conducted to elucidate the role of renal macrophages in the development of acute kidney injury (AKI) in a glycerol (Gly)-induced rhabdomyolysis mouse model. METHODS: The experimental model of rhabdomyolysis requires injecting 50% Gly (10 ml/kg) intramuscularly into mice. Control mice were injected into the tail vein with the liposomal vehicle. Liposome-encapsulated clodronate (LEC)-only mice were injected with LEC. Gly-only mice were injected with Gly into a hind limb. LEC+Gly-treated mice were injected intravenously with 100 µl of LEC 24 h prior to Gly injection. Mice were sacrificed 24 h after Gly injection. RESULTS: Gly injection increased the serum creatinine level, and induced tubular damage. Renal CD45(+)CD11b(+)Ly6c(+) or CD45(+)CD11b(+)Ly6c(+)F4/80(+) macrophages were decreased by pretreatment with LEC in both normal and injured kidneys. Macrophage depletion prevented Gly-induced apoptotic death of tubular epithelial cells by decreasing caspase-9, ERK and p53, while increasing Bcl-2 expression. Expression of the inflammatory mediators NF-κB, MCP-1, ICAM-1, iNOS and COX-2 were also decreased with LEC pretreatment of mice injected with Gly. CONCLUSION: These results support the hypothesis that depletion of macrophages prevents renal dysfunction by abrogating apoptosis and attenuating inflammation during AKI.

The effects of off-axial loading on periimplant marginal bone loss in a single implant.

STATEMENT OF PROBLEM: A discrepancy between crown width and implant width may contribute to potential bending overload. PURPOSE: The purpose of this study was to evaluate the influence of the crown width-fixture width ratio on crestal bone loss around single dental implants placed in the first molar area. MATERIAL AND METHODS: Seventy-six participants (37 men and 39 women; age range, 25-83 years; mean age [standard deviation], 56.3 ±10.6 years) were selected from individuals who were treated with single tooth implants between May 2004 and December 2009 at the Department of Periodontology, Gangnam Severance Dental Hospital. The marginal bone-level change and gingival parameters (modified plaque index and modified sulcus bleeding index) of the periimplant soft tissue were assessed 1 year after functional loading. The perpendicular distances from the vertical axis of each fixture to the most distal aspect of the crown and most mesial aspect of the crown were measured in the periapical radiographic view. RESULTS: No statistically significant relationship was found between crown width-fixture width ratio and the 1-year bone-level change (Pearson correlation, P=.06; Spearman rank test, P=.14). No statistically significant differences in marginal bone-level change were found between axial and nonaxial loading implants (2 independent samples t test; P=.19). The bone-level change for the surface adjacent and distant to the cantilever was not statistically significant (paired t test; P=.10). CONCLUSION: From this study, it may be concluded that off-axial loading that results from a high crown width-fixture width ratio does not increase the risk for periimplant marginal bone loss after 1-year functional loading.

Change in masticatory ability with the implant restoration of second molars.

STATEMENT OF PROBLEM: Controversy exists as to whether missing second molars should be replaced to restore masticatory ability. PURPOSE: The purpose of this study was to analyze the alteration in masticatory ability associated with the implant restoration of the second molar; the subjective effect of implant treatment on the participant was also assessed. MATERIAL AND METHODS: Twenty-one individuals (13 men and 8 women) participated. Masticatory ability was recorded before the cementation of implant-supported single crowns, immediately after cementation, and 1 month after cementation. The occlusal load (Pa), the load-bearing contact area (mm(2)), and the maximum occlusal force (N) were calculated. A subjective evaluation of masticatory ability was conducted before treatment and 1 month after treatment through the use of a questionnaire to evaluate chewing difficulties and global satisfaction with treatment. The Wilcoxon signed rank test was used to analyze the difference in scores. RESULTS: The load-bearing contact area, maximum occlusal force, and participant satisfaction were found to increase significantly 1 month after the cementation of implant-supported single crowns. The restoration of the second molar with an implant increased both objective masticatory ability and subjective satisfaction 1 month after cementation of the implant-supported single crowns. CONCLUSIONS: Patients presenting with a missing second molar may benefit from replacement with implant-supported crowns. Longer study periods and larger sample populations are needed to obtain more definitive results.

Tumor-targeted and stimulus-responsive polymeric prodrug nanoparticles to enhance the anticancer therapeutic efficacy of doxorubicin.

Polymeric prodrug nanoparticles have gained increasing attention in the field of anticancer drug delivery because of their dual functions as a drug carrier and a therapeutic agent. Doxorubicin (DOX) is a highly effective chemotherapeutic agent for various cancers but causes cardiotoxicity. In this work, we developed polymeric prodrug (pHU) nanoparticles that serve as both a drug carrier of DOX and a therapeutic agent. The composition of pHU includes antiangiogenic hydroxybenzyl alcohol (HBA) and ursodeoxycholic acid (UDCA), covalently incorporated through hydrogen peroxide (H2O2)-responsive peroxalate. To enhance cancer cell specificity, pHU nanoparticles were surface decorated with taurodeoxycholic acid (TUDCA) to facilitate p-selectin-mediated cancer targeting. TUDCA-coated and DOX-loaded pHU nanoparticles (t-pHUDs) exhibited controlled release of DOX triggered by H2O2, characteristic of the tumor microenvironment. t-pHUDs also effectively suppressed cancer cell migration and vascular endothelial growth factor (VEGF) expression in response to H2O2. In animal studies, t-pHUDs exhibited highly potent anticancer activity. Notably, t-pHUDs, with their ability to accumulate preferentially in tumors due to the p-selectin targeting, surpassed the therapeutic efficacy of equivalent DOX and pHU nanoparticles alone. What is more, t-pHUDs significantly suppressed VEGF expression in tumors and mitigated hepato- and cardiotoxicity of DOX. Given their cancer targeting ability, enhanced therapeutic efficacy and minimized off-target toxicity, t-pHUDs present an innovative and targeted approach with great translational potential as an anticancer therapeutic agent.

Inflammation-responsive antioxidant nanoparticles based on a polymeric prodrug of vanillin.

Oxidative stress is induced by accumulation of hydrogen peroxide (H2O2), and therefore, H2O2 could serve as a potential biomarker of various oxidative stress-associated inflammatory diseases. Vanillin is one of the major components of natural vanilla and has potent antioxidant and anti-inflammatory activities. In this work, we developed a novel inflammation-responsive antioxidant polymeric prodrug of vanillin, termed poly(vanillin oxalate) (PVO). In design, PVO incorporates H2O2-reacting peroxalate ester bonds and bioactive vanillin via acid-responsive acetal linkages in its backbone. Therefore, in cells undergoing damages by oxidative stress, PVO readily degrades into three nontoxic components, one of which is antioxidant and anti-inflammatory vanillin. PVO nanoparticles exhibit potent antioxidant activities by scavenging H2O2 and inhibiting the generation of ROS (reactive oxygen species) and also reduce the expression of pro-inflammatory cytokines in activated macrophages in vitro and in vivo. We, therefore, anticipate that PVO nanoparticles have great potential as novel antioxidant therapeutics and drug delivery systems for ROS-associated inflammatory diseases.

Endoscopic resection of upper neck masses via retroauricular approach is feasible with excellent cosmetic outcomes.

PURPOSE: In this study, the authors introduce and evaluate the feasibility of endoscopic resection using the retroauricular approach for various benign lesions of the upper neck. PATIENTS AND METHODS: A retrospective comparative analysis was performed on the clinical outcomes of patients who underwent surgery for upper neck masses as endoscopic resection using the retroauricular approach or conventional transcervical resection at the authors' center from January 2010 through August 2011. The primary outcome was the cosmetic satisfaction of the patients in each group. In addition, the feasibility of the procedure was evaluated by comparing the operation time; hospital stay; amount and duration of drainage; complications such as marginal mandibular nerve, lingual, or hypoglossal nerve palsy; paresthesia of the ear lobe; and wound problems such as hematoma and skin necrosis. Statistical analysis was performed by independent-samples t test and the Fisher exact test, and a P value less than .05 was considered statistically significant. RESULTS: Thirty-six patients underwent endoscopic resection (endo group; 15 men, 21 women; mean age, 38.8 ± 15.0 years) and 40 patients underwent conventional transcervical resection (conventional group; 18 men, 22 women; mean age, 45.1 ± 14.1 years). The operating time in the endo group was longer than in the conventional group (P = .003). No significant difference was observed in the overall perioperative complications between the 2 groups. Cosmetic satisfaction evaluated with a graded scale showed much better results in the endo group (P < .001). CONCLUSIONS: Endoscopic resection using the retroauricular approach is feasible for various benign upper neck masses when conducted by an experienced endoscopic surgeon, with excellent cosmetic results.

Autotransplantation combined with orthodontic treatment to restore an adult's posttraumatic dentition.

This case report describes the successful treatment of an adult with a skeletal Class II Division 2 posttraumatic dentition with consequential restorations. The extracted maxillary premolar was autotransplanted to replace the hopeless mandibular first molar. The endodontically treated maxillary right canine was extracted instead of the premolar. A multidisciplinary approach including autotransplantation and orthodontic treatment provided a satisfactory outcome.

Nanoassemblies of Self-Immolative Boronate-Bridged Retinoic Acid Dimeric Prodrug as a Clot-Targeted Self-Deliverable Antithrombotic Nanomedicine.

All trans-retinoic acid (atRA) has potent anti-inflammatory and antiplatelet activity, but its clinical translation as an antithrombotic drug has been hampered by its low therapeutic efficacy. Here, we describe a facile and elegant strategy that converts atRA into systemically injectable antithrombotic nanoparticles. The strategy involves the dimerization of two atRA molecules using a self-immolative boronate linker that is cleaved specifically by hydrogen peroxide (H2O2) to release anti-inflammatory hydroxybenzyl alcohol (HBA), followed by dimerization-induced self-assembly to generate colloidally stable nanoparticles. The boronated atRA dimeric prodrug (BRDP) could form injectable nanoparticles in the presence of fucoidan that serves as an emulsifier and a targeting ligand to P-selectin overexpressed on the damaged endothelium. In response to H2O2, fucoidan-decorated BRDP (f-BRDP) nanoassemblies dissociate to release both atRA and HBA, while scavenging H2O2. In a mouse model of ferric chloride (FeCl3)-induced carotid arterial thrombosis, f-BRDP nanoassemblies target the thrombosed vessel and significantly inhibit thrombus formation. The results demonstrate that dimerization of atRA molecules via a boronate linker enables the formation of stable nanoassemblies with several benefits: high drug loading, drug self-delivery, on-demand multiple antithrombotic actions, and simple fabrication of nanoparticles. Overall, this strategy provides a promising expedient and practical route for the development of translational self-deliverable antithrombotic nanomedicine.

Evaluation of the clinical and radiographic effectiveness of treating peri-implant bone defects with a new biphasic calcium phosphate bone graft: a prospective, multicenter randomized controlled trial.

PURPOSE: Biphasic calcium phosphate (BCP), a widely used biomaterial for bone regeneration, contains synthetic hydroxyapatite (HA) and ß-tricalcium phosphate (ß-TCP), the ratio of which can be adjusted to modulate the rate of degradation. The aim of this study was to evaluate the clinical and radiographic benefits of reconstructing peri-implant bone defects with a newly developed BCP consisting of 40% ß-TCP and 60% HA compared to demineralized bovine bone mineral (DBBM). METHODS: This prospective, multicenter, parallel, single-blind randomized controlled trial was conducted at the periodontology departments of 3 different dental hospitals. Changes in clinical (defect width and height) and radiographic (augmented horizontal bone thickness) parameters were measured between implant surgery with guided bone regeneration (GBR) and re-entry surgery. Postoperative discomfort (severity and duration of pain and swelling) and early soft-tissue wound healing (dehiscence and inflammation) were also assessed. Data were compared between the BCP (test) and DBBM (control) groups using the independent t-test and the χ² test. RESULTS: Of the 53 cases included, 27 were in the test group and 26 were in the control group. After a healing period of 18 weeks, the full and mean resolution of buccal dehiscence defects were 59.3% (n=16) and 71.3% in the test group and 42.3% (n=11) and 57.9% in the control group, respectively. There were no significant differences between the groups in terms of the change in mean horizontal bone augmentation (test group: -0.50±0.66 mm vs. control groups: -0.66±0.83 mm, P=0.133), postoperative discomfort, or early wound healing. No adverse or fatal complications occurred in either group. CONCLUSION: The GBR procedure with the newly developed BCP showed favorable clinical, radiographic, postoperative discomfort-related, and early wound healing outcomes for peri-implant dehiscence defects that were similar to those for DBBM. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0006428.

Acid-sensitive stable polymeric micelle-based oxidative stress nanoamplifier as immunostimulating anticancer nanomedicine.

Oxidative stress amplifying compounds could elicit selective killing of cancer cells with minimal toxicity to normal cells and also induce immunogenic cell death (ICD). However, compared to conventional anticancer drugs, oxidative stress amplifying compounds have inferior therapeutic efficacy. It can be postulated that the anticancer therapeutic efficacy and immunostimulating activity of oxidative stress amplifying hybrid prodrug (OSamp) could be fully maximized by employing ultrastable polymeric micelles as drug carriers. In this work, we developed tumour-targeted oxidative stress nanoamplifiers, composed of OSamp, amphiphilic poly(ethylene glycol) methyl ether-block-poly(cyclohexyloxy ethyl glycidyl ether)s (mPEG-PCHGE) and a lipopeptide containing Arg-Gly-Asp (RGD). Tumour targeted OSamp-loaded mPEG-PCHGE (T-POS) micelles exhibited excellent colloidal stability and significant cytotoxicity to cancer cells with the expression of DAMPs (damage-associated molecular patterns). In the syngeneic mouse tumour model, T-POS micelles induced significant apoptotic cell death to inhibit tumour growth without noticeable body weight changes. T-POS micelles also induced ICD and activated adaptive immune responses by increasing the populations of cytotoxic CD4+ and CD8+ T cells. Therefore, these results suggest that T-POS micelles hold great translational potential as immunostimulating anticancer nanomedicine.