Development of Novel Tamsulosin Pellet-Loaded Oral Disintegrating Tablet Bioequivalent to Commercial Capsule in Beagle Dogs Using Microcrystalline Cellulose and Mannitol.

In this study, we developed a tamsulosin pellet-loaded orally disintegrating tablet (ODT) that is bioequivalent to commercially available products and has improved patient compliance using microcrystalline cellulose (MCC) and mannitol. Utilizing the fluid bed technique, the drug, sustained release (SR) layer, and enteric layer were sequentially prepared by coating MCC pellets with the drug, HPMC, Kollicoat, and a mixture of Eudragit L and Eudragit NE, respectively, resulting in the production of tamsulosin pellets. The tamsulosin pellet, composed of the MCC pellet, drug layer, SR layer, and enteric layer at a weight ratio of 20:0.8:4.95:6.41, was selected because its dissolution was equivalent to that of the commercial capsule. Tamsulosin pellet-loaded ODTs were prepared using tamsulosin pellets and various co-processed excipients. The tamsulosin pellet-loaded ODT composed of tamsulosin pellets, mannitol-MCC mixture, silicon dioxide, and magnesium stearate at a weight ratio of 32.16:161.84:4.0:2.0 gave the best protective effect on the coating process and a dissolution profile similar to that of the commercial capsule. Finally, no significant differences in beagle dogs were observed in pharmacokinetic parameters, suggesting that they were bioequivalent. In conclusion, tamsulosin pellet-loaded ODTs could be a potential alternative to commercial capsules, improving patient compliance.

Psychometric properties of the Barriers Self-Efficacy Scale for Physical Activity-Korean.

This study examined the psychometric properties of the Barriers Self-Efficacy Scale-Physical Activity for Korean-speaking adults with osteoarthritis at risk for metabolic syndrome (N = 150). Factor analysis identified three dimensions of the Korean Barriers scale, explaining 65.9 % of the total variance. Confirmatory factor analysis indicated that the structural validity adequately fits the data. Construct validity confirmed significant associations between the amount of physical activity and psychological variables. The test-retest reliability was 0.87; the alpha was 0.90. The standardized response mean (0.497) indicated responsiveness to medium-magnitude change. The Korean Barriers scale can assess self-efficacy to engage in regular physical activity in clinical settings.

Comparable clinical and radiological outcomes between anatomical and high femoral tunnels in posterior cruciate ligament reconstruction.

PURPOSE: To compare clinical and radiological outcomes and failure rates between anatomical and high femoral tunnels in remnant-preserving single-bundle posterior cruciate ligament (PCL) reconstruction. METHODS: 63 patients who underwent remnant-preserving single-bundle PCL reconstruction between 2011 and 2018 with a minimum 2-year follow-up were retrospectively reviewed. Patients were divided into two groups according to the femoral tunnel position: group A (33 patients with anatomical femoral tunnel) and group H (30 patients with high femoral tunnels). The femoral tunnel was positioned at the center (group A) or upper margin (group H) of the remnant anterolateral bundle. The position of the femoral tunnel was evaluated using the grid method on three-dimensional computed tomography. Clinical and radiological outcomes and failure rates were compared between the groups at the 2-year follow-up. RESULTS: The position of the femoral tunnel was significantly high in group H than in group A (87.4% ± 4.2% versus 76.1% ± 3.7%, p < 0.001). Clinical outcomes were not significantly different between the two groups in terms of the clinical scores (International Knee Documentation Committee subjective, Lysholm, and Tegner activity scores), range of motion, and posterior drawer test. Radiological outcomes also showed no intergroup differences in the side-to-side differences of posterior tibial translation and osteoarthritis progression. Side-to-side difference on the Telos stress radiograph was 5.2 ± 2.9 mm in group A and 5.2 ± 2.7 mm in group H (n.s.). There were four failures in group A (12.1%) and one in group H (3.3%). The differences between the groups were not statistically significant. CONCLUSION: The clinical and radiological outcomes and failure rates of the high femoral tunnels were comparable with those of the anatomical femoral tunnels at the 2-year follow-up after remnant-preserving single-bundle PCL reconstruction. The findings of this study suggest that high femoral tunnels can be considered an alternative in remnant-preserving single-bundle PCL reconstruction. LEVEL OF EVIDENCE: III.

Delayed Ocular Motility Restriction After Endoscopic Sinus Surgery in a Patient With Chronic Rhinosinusitis and an Old Medial Orbital Wall Fracture.

The orbital complications of endoscopic sinus surgery, including diplopia and ocular motility restriction, are mainly caused by direct injury to the orbital structures. These complications are rare, but can have catastrophic consequences. Symptoms occur immediately after surgery in most cases. The authors encountered an unusual case of delayed ocular motility restriction after endoscopic sinus surgery in a patient with old medial wall fracture, without direct orbital injury during the procedure. A 77-year-old man with an old medial wall fracture of the right orbit underwent endoscopic sinus surgery for chronic pansinusitis. He complained mild diplopia on right lateral gaze after 2 weeks, which gradually worsened. After 2 months, he exhibited severe lateral gaze movement impairment in the right eye and finally underwent surgical exploration. His symptoms improved after adhesiolysis of the overgrown ethmoid sinus mucosa and periorbital tissue. The authors reported this unusual case and discussed the possible mechanism underlying ocular motility restriction.

Revaprazan-loaded surface-modified solid dispersion: physicochemical characterization and in vivo evaluation.

The purpose of this research was to develop a novel revaprazan-loaded surface-modified solid dispersion (SMSD) with improved drug solubility and oral bioavailability. The impact of carriers on aqueous solubility of revaprazan was investigated. HPMC and Cremophor A25 were selected as an appropriate polymer and surfactant, respectively, due to their high drug solubility. Numerous SMSDs were prepared with various concentrations of carriers, using distilled water, and the drug solubility of each was assessed. Moreover, the physicochemical properties, dissolution and pharmacokinetics of selected SMSD in rats were assessed in comparison to revaprazan powder. Of the SMSDs assessed, the SMSD composed of revaprazan/HPMC/Cremophor A25 at the weight ratio of 1:0.28:1.12 had the most enhanced drug solubility (∼6000-fold). It was characterized by particles with a relatively rough surface, suggesting that the carriers were attached onto the surface of the unchanged crystalline revaprazan powder. It had a significantly higher dissolution rate, AUC and Cmax, and a faster Tmax value in comparison to revaprazan powder, with a 5.3-fold improvement in oral bioavailability of revaprazan. Therefore, from an environmental perspective, this SMSD system prepared with water, and without organic solvents, should be recommended as a revaprazan-loaded oral pharmaceutical alternative.

The Influence of Segond Fracture on Outcomes After Anterior Cruciate Ligament Reconstruction.

PURPOSE: To determine the prevalence of Segond fractures using computed tomography (CT) and to investigate the effects of Segond fractures on the outcomes of primary anterior cruciate ligament (ACL) reconstruction for isolated ACL injuries. METHODS: Between January 2010 and July 2015, we retrospectively evaluated 383 patients who underwent primary ACL reconstruction, who underwent CT scans immediately after surgery, and who were available at 2 years of follow-up. The absence or presence of a Segond fracture was confirmed using CT. The following parameters were evaluated in all patients at the 2-year follow-up visit: clinical scores (International Knee Documentation Committee subjective score, Lysholm score, and Tegner activity score) and knee joint stability (anterior drawer test, Lachman test, pivot-shift test, and side-to-side difference in anterior tibial translation on Telos stress radiographs). RESULTS: Among 383 patients with primary ACL tears, a Segond fracture was confirmed in 8.9% (n = 34) using 3-dimensional CT. We placed 349 patients into the group with ACL tears without Segond fractures (group A) and the other 34 into the group with ACL tears with Segond fractures (group B). Between the 2 groups, there were no significant differences in the postoperative International Knee Documentation Committee subjective score (P = .97), Lysholm score (P = .17), or Tegner activity score (P = .95). No significant differences in the anterior drawer test (P = .28), Lachman test (P = .45), pivot-shift test (P = .14), and side-to-side difference in anterior tibial translation on Telos stress radiographs (P = .93) between the 2 groups were found preoperatively and postoperatively. CONCLUSIONS: The presence of a Segond fracture did not affect knee joint stability in patients with ACL tears. Moreover, the 2 groups did not show significant differences in clinical scores or knee joint stability after undergoing ACL reconstruction. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Novel revaprazan-loaded gelatin microsphere with enhanced drug solubility and oral bioavailability.

To develop a novel revaprazan-loaded gelatine microsphere with enhanced solubility and oral bioavailability, numerous gelatine microspheres were prepared using a spray-drying technique. The impact of gelatine amount on drug solubility in the gelatine microspheres was investigated. The physicochemical properties of the selected gelatine microsphere, such as shape, particle size and crystallinity, were evaluated. Moreover, its dissolution and pharmacokinetics in rats were assessed in comparison with revaprazan powder. Amongst the gelatine microspheres tested, the gelatine microsphere consisting of revaprazan and gelatine (1:2, w/w), which gave about 150-fold increased solubility, had the most enhanced drug solubility. It provided a spherical shape, amorphous drug and reduced particle size. Furthermore, it gave a higher dissolution rate and plasma concentration than did revaprazan powder. Particularly, it gave about 2.3-fold improved oral bioavailability in comparison with revaprazan powder. Therefore, this novel gelatine microsphere system is recommended as an oral pharmaceutical product of poorly water-soluble revaprazan.

Multifunctional Self-Adhesive Fibrous Layered Matrix (FiLM) for Tissue Glues and Therapeutic Carriers.

Tissue adhesives, which inherently serve as wound sealants or as hemostatic agents, can be further augmented to acquire crucial functions as scaffolds, thereby accelerating wound healing or elevating the efficacy of tissue regeneration. Herein, multifunctional adherent fibrous matrices, acting as self-adhesive scaffolds capable of cell/gene delivery, were devised by coaxially electrospinning poly(caprolactone) (PCL) and poly(vinylpyrrolidone) (PVP). Wrapping the building block PCL fibers with the adherent PVP layers formed film-like fibrous matrices that could rapidly adhere to wet biological surfaces, referred to as fibrous layered matrix (FiLM) adhesives. The inclusion of ionic salts (i.e., dopamine hydrochloride) in the sheath layers generated spontaneously multilayered fibrous adhesives, whose partial layers could be manually peeled off, termed derivative FiLM (d-FiLM). In the context of scaffolds/tissue adhesives, both FiLM and d-FiLM demonstrated almost identical characteristics (i.e., sticky, mechanical, and performances as cell/gene carriers). Importantly, the single FiLM-process can yield multiple sets of d-FiLM by investing the same processing time, materials, and labor required to form a single conventional adhesive fibrous mat, thereby highlighting the economic aspects of the process. The FiLM/d-FiLM offer highly impacting contributions to many biomedical applications, especially in fields that require urgent aids (e.g., endoscopic surgeries, implantation in wet environments, severe wounds).

Effect of malocclusion severity on oral health-related quality of life and food intake ability in a Korean population.

INTRODUCTION: The aim of this study was to evaluate the effect of malocclusion severity on oral health-related quality of life and food intake ability in adult patients, controlling for sex, age, and the type of dental clinic visited. METHODS: The sample consisted of 472 Korean patients (156 male, 316 female) with a mean age of 21.1 (SD, 8.6) years in a dental hospital and a private clinic. The correlations between the Korean version of the Oral Health Impact Profile-14 (OHIP-14K), subjective food intake ability (FIA) for 5 key foods, and Index of Orthodontic Treatment Need-Dental Health Component (IOTN-DHC) were investigated. RESULTS: The mean IOTN-DHC and OHIP-14K scores were significantly higher for the dental hospital patients than for the private clinic patients (IOTN-DHC, P <0.001; OHIP-14K, P <0.05). Malocclusion severity was significantly higher in male than in female subjects (P <0.001). Older patients perceived their oral health-related quality of life more negatively than did the teens (P <0.001). As the severity of the malocclusion increased, oral health-related quality of life and masticatory function worsened (OHIP-14K, P <0.001; FIA, P <0.05). CONCLUSIONS: As the severity of the malocclusion and the age of the patients increased, oral health-related quality of life and masticatory function relatively deteriorated. This finding provides evidence that severe malocclusions are associated with lower quality of life and less masticatory efficiency in older patients.

The change of whole lumbar segmental motion according to the mobility of degenerated disc in the lower lumbar spine: a kinetic MRI study.

PURPOSE: To analyze the effects of mobility of degenerated disc in the lower lumbar discs (L4-5 and L5-S1) on both whole lumbar motion and adjacent segment ROM. METHODS: The kMRIs with disc degeneration at L4-5 or L5-S1 were classified into three groups: the normal group, the motion-preserved (MP) group and the motion-lost (ML) group based on range of motion (ROM) of 5° in the degenerated segment. Each segmental ROM, whole lumbar motion, and the contribution % of the upper lumbar spine (ULS: L1-2-3) and the lower lumbar spine (LLS: L4-5-S1) motion to whole lumbar motion were measured and compared with each of the other groups. RESULTS: There were 94, 99 and 66 patients in the normal group, MP group and ML group, respectively. The normal group showed no significant difference compared to the MP group in all ROM parameters. The ML group showed significantly less whole lumbar motion, more contribution % in the ULS and less in the LLS than the normal and the MP groups. The ROM in the superior adjacent segment in the ML group was not significantly different between that in the normal and MP group. CONCLUSIONS: Degenerated lumbar discs did not show hypermobility within functional ROM. Loss of segmental ROM from advanced disc degeneration did not cause an increase in the ROM of the superior adjacent segment in vivo. When the LLS had motion-lost, advanced disc degeneration, whole lumbar motion was significantly decreased and compensatory increase in ROM was accomplished by the ULS.

Do the radiographic findings of symptomatic discoid lateral meniscus in children differ from normal control subjects?

PURPOSE: The aim of this study was to quantitatively compare radiographic findings of symptomatic discoid lateral meniscus in children with those of matched controls. METHODS: Seventy-eight consecutive children (91 knees) who underwent arthroscopic surgery for a symptomatic discoid lateral meniscus (discoid group) were included. Another 91 age- and sex-matched controls with normal medial and lateral menisci on the basis of magnetic resonance imaging findings were included in this study (control group). Each plain radiograph was evaluated from the anteroposterior view for the following variables: height of the lateral tibial spine, lateral joint space distance, height of the fibular head, squaring of the lateral femoral condyle, obliquity of the lateral tibial plateau and cupping of the lateral tibial plateau. Lateral femoral condylar notch was evaluated in lateral view. Statistical analyses were used to determine the differences between the two groups. RESULTS: A significant difference in the mean height of the lateral tibial spine, lateral joint space distance, height of the fibular head, and obliquity of the lateral tibial plateau distinguished the two groups (p < 0.0001). However, there was no statistical difference in the condylar off sign, squaring of the lateral femoral condyle, cupping of the lateral tibial plateau and lateral femoral condylar notch between groups (n.s.). The cut-off values for the height of the lateral tibial spine (6 mm), lateral joint space distance (8 mm), height of the fibular head (14.9 mm) and obliquity of the lateral tibial plateau (17.6°) were determined. With these cut-off values in diagnosing discoid lateral meniscus, the sensitivity and accuracy of height of the fibular head were 78 and 70 %, respectively. CONCLUSIONS: Several plain radiographic findings in symptomatic discoid lateral meniscus in children were significantly different from those in normal control. These findings would be helpful in screening tool of discoid lateral meniscus for children. LEVEL OF EVIDENCE: II.

Arthroscopic anatomic study of posteromedial joint capsule in knee joint associated with popliteal cyst.

PURPOSE: The purpose of this study was to examine the arthroscopic anatomy of posteromedial capsule and magnetic resonance imaging (MRI) findings in internal derangement of the knee joint and to analyze the relationship between popliteal cysts and the posteromedial capsule. METHODS: From 2011 to 2012, a prospective study included 194 knees of consecutive arthroscopic surgeries for assorted knee problems. The anatomy of the posteromedial joint capsule was evaluated arthroscopically and divided into three types by the presence of capsular fold and opening: no capsular fold and no opening (type I), capsular fold without opening (type II), capsular fold with opening (type III). The presence and size of popliteal cyst were documented by MRI. RESULTS: Type I was observed in 160 knees (82.5 %), type II in 10 (5.1 %) and type III in 24 (12.4 %). Popliteal cysts were found in 25 knees (12.9 %) by MRI. Of these cases, symptomatic popliteal cysts were identified in 12 knees (6.9 %). On 160 knees demonstrated to be type I, only 3 knees (1.9 %) had popliteal cysts in MRI, 6 knees (60 %) in 10 knees of type II and 16 knees (66.7 %) in 24 knees of type III. Therefore, there was a statistically significant relationship between the type of anatomy in the posteromedial capsule and the popliteal cyst (p < 0.001). CONCLUSION: An association between popliteal cyst and arthroscopic anatomy of posteromedial capsule was demonstrated. Comprehensive understanding and knowledge of the arthroscopic anatomy of posteromedial capsule would contribute to the arthroscopic approach in understanding the pathogenesis of popliteal cyst. STUDY DESIGN: Development of diagnostic criteria on basis of consecutive patients. LEVEL OF EVIDENCE: 2.

Novel rivaroxaban-loaded microsphere systems with different surface microstructure for enhanced oral bioavailability.

This study compares rivaroxaban-loaded polymeric microsphere systems with three types of surface microstructure. Three types of polymeric microspheres loaded with rivaroxaban were fabricated using a spray-drying technique: solvent-evaporated, surface-attached, and solvent-wet microspheres, depending on whether the drug and additives used are soluble in the solvent. The solvent-evaporated and surface-attached microspheres had a rivaroxaban/polyvinylpyrrolidone/sodium lauryl sulfate (SLS) weight ratio of 1/0.25/2.2, and the solvent-wetted microspheres contained rivaroxaban/polyvinyl alcohol/SLS in equal weight ratio (1/0.25/2). The physicochemical properties of the microspheres were evaluated using scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and particle size distribution analysis. The aqueous solubility and dissolution rate of rivaroxaban in the three types of microspheres were compared to those of the drug powder. The solvent-evaporated, surface-attached, and solvent-wetted microspheres were approximately 208, 140, and 172 times as soluble as the drug powder, and the final dissolution rate (120 min) was approximately 5, 2, and 4 times that of the drug powder, respectively. In addition, the oral bioavailability increased by approximately 2, 1.3, and 1.6 times compared to that of the drug powder (area under drug concentration-time curve: 2101.3 ± 314.8, 1325.2 ± 333.3, and 1664.0 ± 102.6 h·ng/mL, respectively). Finally, the solvent-evaporated microspheres showed the greatest improvement (solvent evaporating microspheres > solvent wetted microspheres > surface-attached microspheres ≥ drug powder). Therefore, the solvent-evaporated microspheres may represent a novel oral dosage form that improves the oral bioavailability of rivaroxaban, a poorly soluble drug.

Injectable dual thermoreversible hydrogel for sustained intramuscular drug delivery.

Herein, we reported novel docetaxel-decorated solid lipid nanoparticle (DCT-SLN)-loaded dual thermoreversible system (DCT-DRTS) for intramuscular administration with reduced burst effect, sustained release and improved antitumor efficacy. The optimized DCT-DRTs was subjected to in-vitro and in-vivo analyses. Antitumor evaluation of the DCT-DRTS was executed and compared with DCT-hydrogel, and DCT-suspension trailed by the histopathological and immune-histochemical analyses. The DCT-SLN gave a mean particle size of 157 nm and entrapment efficiency of 93 %. It was a solid at room temperature, and changed to liquid at physiological temperature due to its melting point of about 32 °C. Unlikely, poloxamer mixture remained liquefied at 25-27 °C, however converted to gel at physiological temperature. This behavior demonstrated opposed reversible property of the DCT-SLN and poloxamer hydrogel in DCT-DRTS system, making it ideal for intramuscular administration and quick gelation inside the body. The DCT-DRTS sustained the drugs release and unlike DCT-hydrogel, the preliminary plasma concentration of DCT-DRTS was significantly reduced, overcoming the burst release. A meaningfully enhanced antitumor efficacy and improved survival rate was observed from DCT-DRTS in tumor cell xenograft athymic nude mice. Additionally, increased apoptotic and reduced proliferation markers were observed in DCT-DRTS treated tumor masses. It was concluded that DCT-DRTS may be a suitable choice for intramuscular administration of DCT with sustained release, improved bioavailability, reduced toxicity and enhanced antitumor effects.

Establishment of nanoparticle screening technique: A pivotal role of sodium carboxymethylcellulose in enhancing oral bioavailability of poorly water-soluble aceclofenac.

A novel nanoparticle screening technique was established to mostly enhance the aqueous solubility and oral bioavailability of aceclofenac using nanoparticle systems. Among the polymers investigated, sodium carboxymethylcellulose (Na-CMC) showed the greatest increase in drug solubility. Utilizing spray-drying technique, the solvent-evaporated solid dispersion (SESD), surface-attached solid dispersion (SASD), and solvent-wetted solid dispersion (SWSD) were prepared using aceclofenac and Na-CMC at a weight ratio of 1:1 in 50 % ethanol, distilled water, and ethanol, respectively. Using Na-CMC as a solid carrier, an aceclofenac-loaded liquid self-emulsifying drug delivery system was spray-dried and fluid-bed granulated together with microcrystalline cellulose, producing a solid self-nanoemulsifying drug delivery system (SNEDDS) and solid self-nanoemulsifying granule system (SNEGS), respectively. Their physicochemical properties and preclinical assessments in rats were performed. All nanoparticles exhibited very different properties, including morphology, crystallinity, and size. As a result, they significantly enhanced the solubility, dissolution, and oral bioavailability in the following order: SNEDDS ≥ SNEGS > SESD ≥ SASD ≥ SWSD. Based on our screening technique, the SNEDDS was selected as the optimal nanoparticle with the highest bioavailability of aceclofenac. Thus, our nanoparticle screening technique should be an excellent guideline for solubilization research to improve the solubility and bioavailability of many poorly water-soluble bioactive materials.

Comparison of two self-nanoemulsifying drug delivery systems using different solidification techniques for enhanced solubility and oral bioavailability of poorly water-soluble celecoxib.

In this study, we aimed to develop a solid self-nanoemulsifying drug delivery system (S-SNEDDS) and a solid self-nanoemulsifying granule system (S-SNEGS) to enhance the solubility and oral bioavailability of celecoxib. This process involved the preparation of a liquid SNEDDS (L-SNEDDS) and its subsequent solidification into a S-SNEDDS and a S-SNEGS. The L-SNEDDS consisted of celecoxib (drug), Captex® 355 (Captex; oil), Tween® 80 (Tween 80; surfactant) and D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS; cosurfactant) in a weight ratio of 3.5:25:60:15 to produce the smallest nanoemulsion droplet size. The S-SNEDDS and S-SNEGS were prepared with L-SNEDDS/Ca-silicate/Avicel PH 101 in a weight ratio of 103.5:50:0 using a spray dryer and 103.5:50:100 using a fluid bed granulator, respectively. We compared the two novel developed systems and celecoxib powder based on their solubility, dissolution rate, physicochemical properties, flow properties and oral bioavailability in rats. S-SNEGS showed a significant improvement in solubility and dissolution rate compared to S-SNEDDS and celecoxib powder. Both systems had been converted from crystalline drug to amorphous form. Furthermore, S-SNEGS exhibited a significantly reduced angle of repose, compressibility index and Hausner ratio than S-SNEDDS, suggesting that S-SNEGS was significantly superior in flow properties. Compared to S-SNEDDS and celecoxib powder, S-SNEGS increased the oral bioavailability (AUC value) in rats by 1.3 and 4.5-fold, respectively. Therefore, S-SNEGS wolud be recommended as a solid self-nanoemulsifying system suitable for poorly water-soluble celecoxib.

Integration of adeno-associated virus-derived peptides into nonviral vectors to synergistically enhance cellular transfection.

This study describes a simple, versatile approach for developing a nonviral gene carrier by adopting the highly efficient gene delivery properties of the adeno-associated virus (AAV). Specific viral peptides (r3.45_hepBD) extracted from AAV r3.45, which directly evolved to improve gene delivery capabilities in many cell types, were conjugated onto branched polyethylenimine (PEI) to form hybrid gene carriers. AAV r3.45 carries a sequence insertion (LATQVGQKTA; r3.45) within the heparin-binding domain (LQRGNRQA; hepBD), which ultimately comprises a novel sequence (LQRGNLATQVGQKTARQA; r3.45_hepBD) on the capsid. This sequence is hypothesized to be a crucial cue to enhance gene delivery efficiency. Consequently, the intimate interactions of the conjugated r3.45_hepBD with the glycosaminoglycans, including chondroitin sulfate, resulted in significantly enhanced cellular transfection of DNA/PEI-r3.45_hepBD complexes. The successful establishment of a nonviral system that is built with novel peptides will provide a powerful means for developing a substantial number of gene therapy applications.

Lysyl oxidase-responsive anchoring nanoparticles for modulation of the tumor immune microenvironment.

In the tumor microenvironment, lysyl oxidase (LOX) is known to play a key role in stabilizing the tumor extracellular matrix. Here, we designed LOX-responsive nanoparticles to interact with the collagen matrix of the tumor microenvironment. Collagen-coated and imiquimod-loaded polydopamine nanoparticles (CPN/IQ) could form crosslinked structures with the collagen matrix via LOX. In vitro, anchoring of CPN/IQ nanoparticles was observed with LOX-secreting CT26 cells, but this was blocked by a LOX inhibitor. In CT26 tumor-bearing mice, co-administration of nanoparticles plus the LOX inhibitor did not significantly alter the antitumor efficacy among nanoparticles. In the absence of the LOX inhibitor, however, a single administration of CPN/IQ could provide sustained responsiveness to near-infrared irradiation and ablation of primary tumors. In the primary tumor microenvironment, CPN/IQ lowered the Treg cell population but increased the cytotoxic CD3+CD8+ T cell population. In splenic dendritic cells, CPN/IQ treatment significantly increased the CD11c+CD86+ and CD11c+CD80+ cell populations. In a CT26 distant tumor-rechallenge model, CPN/IQ treatment increased the cytotoxic CD3+CD8+ T cell population and provided 100% survival of mice until 64 days. This study indicates the feasibility of tumor immune microenvironment modulation using LOX-responsive size-transforming nanoparticles. Although we tested the concept in a CT26 cell-derived tumor model, the concept of LOX-responsive collagen matrix- anchoring nanoparticles may be broadly applied to other tumor tissues with LOX-rich tumor microenvironments.

External cold atmospheric plasma-responsive on-site hydrogel for remodeling tumor immune microenvironment.

Although immunotherapy has recently emerged as a promising anti-tumor approach, it remains limited by the immunosuppressive tumor microenvironment. Cold atmospheric plasma irradiation can generate reactive oxygen species and trigger the presentation of tumor-associated antigens. Here, we exploited cold atmospheric plasma for on-site hydrogel application in the tumor environment, aiming to facilitate the sustainable uptake of tumor-associated antigens and nanoadjuvants by dendritic cells. Hyaluronic acid-tyramine conjugate was intratumorally injected as a liquid and formed an on-site hydrogel under irradiation with cold atmospheric plasma. Intratumoral delivery of hyaluronic acid-tyramine conjugate with transforming growth factor ß-blocking nanoadjuvant (TLN) followed by cold atmospheric plasma irradiation yielded a micro-network of TLN-loaded hydrogel (TLN@CHG). In vivo intratumoral injection of TLN@CHG promoted the activation of dendritic cells and more effectively increased the proportion of CD4 T cells and CD8 T cells in the tumor microenvironment, compared to the groups receiving TLN or hydrogel alone. Moreover, in CT26 tumor model mice, cold atmospheric plasma-induced TLN@CHG therapy ablated the primary tumor and provided 100% survival among mice rechallenged with CT26 cells. Taken together, our findings suggest that an on-site hydrogel-based micro-network of TLN has the potential to remodel the tumor immune microenvironment. Although we used TLN in this study, the concept could be extended to support the sustained action of other nanoadjuvants in a hydrogel micro-network.

RNA Nanomedicine: Delivery Strategies and Applications.

Delivery of RNA using nanomaterials has emerged as a new modality to expand therapeutic applications in biomedical research. However, the delivery of RNA presents unique challenges due to its susceptibility to degradation and the requirement for efficient intracellular delivery. The integration of nanotechnologies with RNA delivery has addressed many of these challenges. In this review, we discuss different strategies employed in the design and development of nanomaterials for RNA delivery. We also highlight recent advances in the pharmaceutical applications of RNA delivered via nanomaterials. Various nanomaterials, such as lipids, polymers, peptides, nucleic acids, and inorganic nanomaterials, have been utilized for delivering functional RNAs, including messenger RNA (mRNA), small interfering RNA, single guide RNA, and microRNA. Furthermore, the utilization of nanomaterials has expanded the applications of functional RNA as active pharmaceutical ingredients. For instance, the delivery of antigen-encoding mRNA using nanomaterials enables the transient expression of vaccine antigens, leading to immunogenicity and prevention against infectious diseases. Additionally, nanomaterial-mediated RNA delivery has been investigated for engineering cells to express exogenous functional proteins. Nanomaterials have also been employed for co-delivering single guide RNA and mRNA to facilitate gene editing of genetic diseases. Apart from the progress made in RNA medicine, we discuss the current challenges and future directions in this field.